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1. Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome

Author

Margot A. Cousin, Emma L. Veale, Nikita R. Dsouza, Swarnendu Tripathi, Robyn G. Holden, Maria Arelin, Geoffrey Beek, Mir Reza Bekheirnia, Jasmin Beygo, Vikas Bhambhani, Martin Bialer, Stefania Bigoni, Cyrus Boelman, Jenny Carmichael, Thomas Courtin, Benjamin Cogne, Ivana Dabaj, Diane Doummar, Laura Fazilleau, Alessandra Ferlini, Ralitza H. Gavrilova, John M. Graham, Tobias B. Haack, Jane Juusola, Sarina G. Kant, Saima Kayani, Boris Keren, Petra Ketteler, Chiara Klöckner, Tamara T. Koopmann, Teresa M. Kruisselbrink, Alma Kuechler, Laëtitia Lambert, Xénia Latypova, Robert Roger Lebel, Magalie S. Leduc, Emanuela Leonardi, Andrea M. Lewis, Wendy Liew, Keren Machol, Samir Mardini, Kirsty McWalter, Cyril Mignot, Julie McLaughlin, Alessandra Murgia, Vinodh Narayanan, Caroline Nava, Sonja Neuser, Mathilde Nizon, Davide Ognibene, Joohyun Park, Konrad Platzer, Céline Poirsier, Maximilian Radtke, Keri Ramsey, Cassandra K. Runke, Maria J. Guillen Sacoto, Fernando Scaglia, Marwan Shinawi, Stephanie Spranger, Ee Shien Tan, John Taylor, Anne-Sophie Trentesaux, Filippo Vairo, Rebecca Willaert, Neda Zadeh, Raul Urrutia, Dusica Babovic-Vuksanovic, Michael T. Zimmermann, Alistair Mathie, and Eric W. Klee

Subjects
KCNK9 imprinting syndrome, TASK3 channel, Neurodevelopmental disorder, Electrophysiology, Computational protein modeling, Medicine, Genetics, QH426-470
Abstract

Abstract Background Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood. Methods This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 KIS-affected individuals. We use clinical genetics and computer-assisted facial phenotyping to describe the phenotypic spectrum of KIS. We then interrogate the functional effects of the variants in the encoded TASK3 channel using sequence-based analysis, 3D molecular mechanic and dynamic protein modeling, and in vitro electrophysiological and functional methodologies. Results We describe the broader genetic and phenotypic variability for KIS in a cohort of individuals identifying an additional mutational hotspot at p.Arg131 and demonstrating the common features of this neurodevelopmental disorder to include motor and speech delay, intellectual disability, early feeding difficulties, muscular hypotonia, behavioral abnormalities, and dysmorphic features. The computational protein modeling and in vitro electrophysiological studies discover variability of the impact of KCNK9 variants on TASK3 channel function identifying variants causing gain and others causing loss of conductance. The most consistent functional impact of KCNK9 genetic variants, however, was altered channel regulation. Conclusions This study extends our understanding of KIS mechanisms demonstrating its complex etiology including gain and loss of channel function and consistent loss of channel regulation. These data are rapidly applicable to diagnostic strategies, as KIS is not identifiable from clinical features alone and thus should be molecularly diagnosed. Furthermore, our data suggests unique therapeutic strategies may be needed to address the specific functional consequences of KCNK9 variation on channel function and regulation.

Published
2022
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2. <scp>POU3F3</scp> ‐related disorder: Defining the phenotype and expanding the molecular spectrum

Author

Alessandra Rossi, Lot Snijders Blok, Sonja Neuser, Chiara Klöckner, Konrad Platzer, Laurence Olivier Faivre, Heike Weigand, Maria L. Dentici, Marco Tartaglia, Marcello Niceta, Paolo Alfieri, Siddharth Srivastava, David Coulter, Lacey Smith, Kristin Vinorum, Gerarda Cappuccio, Nicola Brunetti‐Pierri, Deniz Torun, Mutluay Arslan, Mathilde F. Lauridsen, Oliver Murch, Rachel Irving, Sally A. Lynch, Sarju G. Mehta, Jenny Carmichael, Evelien Zonneveld‐Huijssoon, Bert de Vries, Tjitske Kleefstra, Katrine M. Johannesen, Ian T. Westphall, Susan S. Hughes, Sarah Smithson, Julie Evans, Tracy Dudding‐Byth, Marleen Simon, Ellen van Binsbergen, Johanna C. Herkert, Gea Beunders, Henry Oppermann, Mert Bakal, Rikke S. Møller, Guido Rubboli, and Allan Bayat

Subjects
Genetics, Genetics (clinical)
Published
2023
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3. Molecular diagnoses in the congenital malformations caused by ciliopathies cohort of the 100,000 Genomes Project

Author

Jamie M Ellingford, Jenny Carmichael, Carmel Toomes, Christopher M. Watson, Roel P J Bevers, Colin A. Johnson, James A. Poulter, Matthew Roche, Helen K. Brittain, Gabrielle Wheway, Alex Stuckey, Sunayna Best, Chris F. Inglehearn, Jenny Lord, and Katarzyna Szymanska

Subjects
Proband, diagnosis, Genomics, Disease, medical, Ciliopathies, State Medicine, Joubert syndrome, Human Phenotype Ontology, genomics, Genetics, Humans, Medicine, genetics, Abnormalities, Multiple, Eye Abnormalities, Genetics (clinical), business.industry, Cilium, congenital, Kidney Diseases, Cystic, medicine.disease, Ciliopathy, Phenotype, and neonatal diseases and abnormalities, business, hereditary
Abstract

BackgroundPrimary ciliopathies represent a group of inherited disorders due to defects in the primary cilium, the ‘cell’s antenna’. The 100,000 Genomes Project was launched in 2012 by Genomics England (GEL), recruiting National Health Service (NHS) patients with eligible rare diseases and cancer. Sequence data were linked to Human Phenotype Ontology (HPO) terms entered by recruiting clinicians.MethodsEighty-three prescreened probands were recruited to the 100,000 Genomes Project suspected to have congenital malformations caused by ciliopathies in the following disease categories: Bardet-Biedl syndrome (n=45), Joubert syndrome (n=14) and ‘Rare Multisystem Ciliopathy Disorders’ (n=24). We implemented a bespoke variant filtering and analysis strategy to improve molecular diagnostic rates for these participants.ResultsWe determined a research molecular diagnosis for n=43/83 (51.8%) probands. This is 19.3% higher than previously reported by GEL (n=27/83 (32.5%)). A high proportion of diagnoses are due to variants in non-ciliopathy disease genes (n=19/43, 44.2%) which may reflect difficulties in clinical recognition of ciliopathies. n=11/83 probands (13.3%) had at least one causative variant outside the tiers 1 and 2 variant prioritisation categories (GEL’s automated triaging procedure), which would not be reviewed in standard 100,000 Genomes Project diagnostic strategies. These include four structural variants and three predicted to cause non-canonical splicing defects. Two unrelated participants have biallelic likely pathogenic variants in LRRC45, a putative novel ciliopathy disease gene.ConclusionThese data illustrate the power of linking large-scale genome sequence to phenotype information. They demonstrate the value of research collaborations in order to maximise interpretation of genomic data.

Published
2021
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4. Further delineation of the clinical spectrum of White–Sutton syndrome: 12 new individuals and a review of the literature

Author

Siren Berland, Andreas Benneche, Andrew E. Fry, Kate Chandler, Julie Paulsen, Marie Falkenberg Smeland, Nicola Foulds, Neeti Ghali, Katrina Prescott, Jenny Carmichael, Vani Jain, Kay Metcalfe, Oliver Murch, and Emma Hobson

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, Developmental Disabilities, Mutation, Missense, Transposases, Article, Neurodevelopmental disorder, Intellectual Disability, Intellectual disability, Genetics, Humans, Medicine, Missense mutation, Abnormalities, Multiple, Child, Genetics (clinical), business.industry, Infant, Dystrophy, Congenital diaphragmatic hernia, Syndrome, medicine.disease, Phenotype, Pedigree, White (mutation), Child, Preschool, Female, Sensorineural hearing loss, business
Abstract

White–Sutton syndrome (WHSUS) is a neurodevelopmental disorder caused by heterozygous loss-of-function variants in POGZ. Through the Deciphering Developmental Disorders study and clinical testing, we identified 12 individuals from 10 families with pathogenic or likely pathogenic variants in POGZ (eight de novo and two inherited). Most individuals had delayed development and/or intellectual disability. We analyzed the clinical findings in our series and combined it with data from 89 previously reported individuals. The results demonstrate WHSUS is associated with variable developmental delay or intellectual disability, increased risk of obesity, visual defects, craniofacial dysmorphism, sensorineural hearing loss, feeding problems, seizures, and structural brain malformations. Our series includes further individuals with rod-cone dystrophy, cleft lip and palate, congenital diaphragmatic hernia, and duplicated renal drainage system, suggesting these are rare complications of WHSUS. In addition, we describe an individual with a novel, de novo missense variant in POGZ and features of WHSUS. Our work further delineates the phenotypic spectrum of WHSUS highlighting the variable severity of this disorder and the observation of familial pathogenic POGZ variants.

Published
2021
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5. Expanding the phenotypic spectrum of Chromosome 16p13.11 microduplication: A multicentric analysis of 206 patients

Author

Asma Hamad, Charlotte A. Sherlaw-Sturrock, Kate Glover, Rachel Salmon, Karen Low, Ramya Nair, Francis H. Sansbury, LettieE. Rawlins, Jenny Carmichael, Rachael Horton, Sarah Wedderburn, Katherine Edgerley, Rachel Irving, Mary Callaghan, Catherine Mercer, Ruth McGowan, Leema Robert, Hannah Titheradge, and Swati Naik

Subjects
Genetics, General Medicine, Genetics (clinical)
Published
2023
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7. BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations

Author

Øyvind L. Busk, Kimberley Bradbury, Arjan Bouman, Philippe M. Campeau, Lynne M. Bird, Cornelia Kraus, Colleen Carlston, Rong Mao, Juliette Piard, Laurence Faivre, Amanda Openshaw, Catherine Ward Melver, Mohnish Suri, Christiane Zweier, François Guillemot, Rolph Pfundt, Janice C. Palumbos, Parthiv Haldipur, Jane A. Hurst, Kimberly McDonald, Margaux Serey-Gaut, Luitgard Graul-Neumann, Karen J. Low, Jenny Carmichael, Patrick Ferrerira, Birgit Elisabeth Kristiansen, Ange-Line Bruel, Constance Motter, Andrea Accogli, Darrah N. Haffner, Suhair Hanna, Ruta Marcinkute, Angela Peron, Marcella Zollino, Sofia Maia, James Lespinasse, Claire E. Turner, Sally Ann Lynch, Richard E. Person, Valeria Capra, Kimberly A. Aldinger, Constance Smith-Hicks, Gyri Aasland Gradek, Ingrid M. Wentzensen, Megha Desai, Manuela Morleo, Aditi Shah Parikh, Marcello Scala, Cristina Dias, Gunnar Houge, Telethon Undiagnosed Disease Program, Anne Slavotinek, Roberta Battini, Mary J. Green, Anna Chassevent, Tara Montgomery, David Viskochil, Tatiana Tvrdik, Dawn L. Earl, Karin Weiss, Felice D'Arco, William B. Dobyns, Ping Yee Billie Au, Daniah Beleford, Erica F. Andersen, Bert B.A. de Vries, Jill Clayton-Smith, Christophe Philippe, and Michael J. Bamshad

Subjects
business.industry, Postnatal microcephaly, Microdeletion syndrome, medicine.disease, Bioinformatics, Hypotonia, Developmental disorder, Autism spectrum disorder, Intellectual disability, Fetal hemoglobin, medicine, Missense mutation, medicine.symptom, business
Abstract

PurposeHeterozygous variants in BCL11A underlie an intellectual developmental disorder with persistence of fetal hemoglobin (BCL11A-IDD, a.k.a. Dias-Logan syndrome). We sought to delineate the genotypic and phenotypic spectrum of BCL11A-IDD.MethodsWe performed an in-depth analysis of 42 patients with BCL11A-IDD ascertained through a collaborative network of clinical and research colleagues. We also reviewed 33 additional affected individuals previously reported in the literature or available through public repositories with clinical information.ResultsMolecular and clinical data analysis of 75 patients with BCL11A-IDD identified 60 unique variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique CNVs (microdeletions involving BCL11A only). We redefined the most frequent manifestations of the condition: intellectual disability, hypotonia, behavioral abnormalities, postnatal microcephaly and autism spectrum disorder. Two thirds of patients have brain MRI abnormalities, and we identified a recurrent posterior fossa phenotype of vermian hypoplasia and/or small brainstem. Truncating BCL11A variants, particularly those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S) isoform, were associated with increased severity.ConclusionsWe expand the clinical delineation of BCL11A-IDD and identify a potential isoform-specific genotype-phenotype correlation. We show that BCL11A-IDD is associated with posterior fossa anomalies and highlight the differences between BCL11A-IDD and 2p16.1p15 microdeletion syndrome.

Published
2021
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8. Genetic and chemotherapeutic causes of germline hypermutation

Author

Christopher A. Odhams, Giuseppe Gallone, Jeremy F. McRae, Angela Barnicoat, Joanna Kaplanis, Petr Danecek, Matthew D. C. Neville, Jenny Carmichael, Tim H. H. Coorens, Patrick J. O’Brien, Matthew E. Hurles, Raheleh Rahbari, Elena Prigmore, Helen V. Firth, Benjamin Ide, Rashesh Sanghvi, Loukas Moutsianas, and Patrick J. Short

Subjects
Genetics, Mutation, Germline mutation, DNA repair, Genetic variation, medicine, Somatic hypermutation, Disease, Biology, medicine.disease_cause, Genome, Germline
Abstract

SummaryMutation in the germline is the source of all evolutionary genetic variation and a cause of genetic disease. Previous studies have shown parental age to be the primary determinant of the number of new germline mutations seen in an individual’s genome. Here we analysed the genome-wide sequences of 21,879 families with rare genetic diseases and identified 12 hypermutated individuals with between two and seven times more de novo single nucleotide variants (dnSNVs) than expected. In most of these families (8/12) the excess mutations could be attributed to the father. We determined that two of these families had genetic drivers of germline hypermutation, with the fathers carrying damaging genetic variation in known DNA repair genes, causing distinctive mutational signatures. For five families, by analysing clinical records and mutational signatures, we determined that paternal exposure to chemotherapeutic agents prior to conception was a key driver of hypermutation. Our results suggest that the germline is well protected from mutagenic effects, hypermutation is rare and relatively modest in degree and that most hypermutated individuals will not have a genetic disease.

Published
2021
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9. Genetic and chemotherapeutic influences on germline hypermutation

Author

Joanna, Kaplanis, Benjamin, Ide, Rashesh, Sanghvi, Matthew, Neville, Petr, Danecek, Tim, Coorens, Elena, Prigmore, Patrick, Short, Giuseppe, Gallone, Jeremy, McRae, Jenny, Carmichael, Angela, Barnicoat, Helen, Firth, Patrick, O'Brien, Raheleh, Rahbari, and Chris, Odhams

Subjects
Male, Parents, Germ Cells, Mutagenesis, Mutation, Age Factors, Genetic Diseases, Inborn, Humans, Polymorphism, Single Nucleotide, Germ-Line Mutation
Abstract

Mutations in the germline generates all evolutionary genetic variation and is a cause of genetic disease. Parental age is the primary determinant of the number of new germline mutations in an individual's genome

Published
2021

10. Erratum to: Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia

Author

Jenny Carmichael, Federico Zara, Konstantinos Ampatzis, Somayeh Bakhtiari, Sherifa A. Hamed, Roman Chrast, Rolf Stucka, Juliane Müller, Gudrun Nürnberg, Nihal Olgaç Dündar, Erik-Jan Kamsteeg, Shoji Tsuji, Maja Di Rocco, Shazia Maqbool, Francisca Millan, Jonathan Baets, Tine Deconinck, Hanan E. Shamseldin, Tim M. Strom, Marcello Scala, Elham Alehabib, Cara M. Skraban, Isabella Ceccherini, Vincenzo Salpietro, Mohammed Anter Abdelhameed, Filippo M. Santorelli, Michele Iacomino, Peter De Jonghe, Yasuhiro Suzuki, Rossella Pasquariello, Anna Uhrova Meszarosova, James T Peterson, Ahmed Alfares, Yoshihisa Takiyama, Rebecca Schüle, Hossein Darvish, Yinghong Wang, Marta Rusmini, Selina Deschner, Adriana P. Rebelo, Fatima Rahman, Tobias B. Haack, Manuela Wiessner, Changlian Zhu, Matthis Synofzik, Filipa Bouçanova, Carsten Bergmann, Wolfgang Hüttel, Frederic Tran Mau-Them, Pavel Seeman, Elodie Lacaze, Andreas R. Janecke, Richard A. Lewis, Jin Yun Helen Chen, Meng-Yuan Ni, Michaela Auer-Grumbach, Andrea Català-Bordes, Ivana Ricca, Sheng Chih Jin, Dieter Gläser, Rita Horvath, Maryam Najafi, Jamileh Rezazadeh Varaghchi, Henry Houlden, Bart P.C. van de Warrenburg, Katheryn Grand, Gökhan Uyanik, Jan Senderek, Jean-Jacques Médard, Özgür Duman, Andrea Pedroni, Willem De Ridder, Reza Maroofian, Saghar Ghasemi Firouzabadi, Michael C. Kruer, H. Küpper, Emmanuelle Schmitt, Alistair T. Pagnamenta, Mary J H Willis, Kaya Bilguvar, Majid Alfadhel, Jonathan De Winter, Stephan Züchner, Saeed Al Tala, Hwei-Jen Lee, John M. Graham, Amy Goldstein, Ruben Portier, Stephanie Efthymiou, Yiran Xu, Ludger Schöls, Christian Beetz, Maria Gabriela Otero, Nicholas W. Wood, Najwa Anwar, Martin Kuchar, Fowzan S. Alkuraya, Tyler Mark Pierson, David Dredge, Nourelhoda A Haridy, Laetitia Lambert, Hiroyuki Ishiura, Peter Nürnberg, Luca Bartesaghi, Kishin Koh, and Haitian Nan

Subjects
medicine.medical_specialty, business.industry, medicine, Neurology (clinical), Complicated hereditary spastic paraplegia, Original Articles, business, Dermatology
Abstract

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

Published
2021

11. RERE deficiency contributes to the development of orofacial clefts in humans and mice

Author

Valerie K. Jordan, Tiana M. Scott, Daryl A. Scott, Bum Jun Kim, Peter Kundert, Jenny Carmichael, and Hitisha P. Zaveri

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Cleft Lip, Embryonic Development, Chromosome Disorders, Mice, Transgenic, Nerve Tissue Proteins, Wnt1 Protein, Biology, Mesoderm, 03 medical and health sciences, 0302 clinical medicine, Cranial neural crest, Neurodevelopmental disorder, Genetics, medicine, Animals, Humans, Molecular Biology, Genetics (clinical), Cell Proliferation, Mice, Knockout, 1p36 deletion syndrome, Embryogenesis, Chromosome, Gene Expression Regulation, Developmental, Embryo, General Medicine, medicine.disease, Phenotype, Cleft Palate, Mice, Inbred C57BL, Repressor Proteins, Disease Models, Animal, 030104 developmental biology, Chromosomes, Human, Pair 1, Neural Crest, PAX7, Chromosome Deletion, 030217 neurology & neurosurgery
Abstract

Deletions of chromosome 1p36 are the most common telomeric deletions in humans and are associated with an increased risk of orofacial clefting. Deletion/phenotype mapping, combined with data from human and mouse studies, suggests the existence of multiple 1p36 genes associated with orofacial clefting including SKI, PRDM16, PAX7 and GRHL3. The arginine–glutamic acid dipeptide (RE) repeats gene (RERE) is located in the proximal critical region for 1p36 deletion syndrome and encodes a nuclear receptor co-regulator. Pathogenic RERE variants have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye or heart (NEDBEH). Cleft lip has previously been described in one individual with NEDBEH. Here we report the first individual with NEDBEH to have a cleft palate. We confirm that RERE is broadly expressed in the palate during mouse embryonic development, and we demonstrate that the majority of RERE-deficient mouse embryos on C57BL/6 background have cleft palate. We go on to show that ablation of Rere in cranial neural crest (CNC) cells, mediated by a Wnt1-Cre, leads to delayed elevation of the palatal shelves and cleft palate and that proliferation of mesenchymal cells in the palatal shelves is significantly reduced in Rereflox/flox; Wnt1-Cre embryos. We conclude that loss of RERE function contributes to the development of orofacial clefts in individuals with proximal 1p36 deletions and NEDBEH and that RERE expression in CNC cells and their derivatives is required for normal palatal development.

Published
2021

12. Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia

Author

Juliane S Müller, Adriana P. Rebelo, Fatima Rahman, Isabella Ceccherini, Shoji Tsuji, Pavel Seeman, Elodie Lacaze, Andreas R. Janecke, Sherifa A. Hamed, Elham Alehabib, Vincenzo Salpietro, Hossein Darvish, Sheng Chih Jin, Katheryn Grand, Gökhan Uyanik, Henry Houlden, Rolf Stucka, Ahmed Alfares, Francisca Millan, Andrea Pedroni, Hanna Küpper, Najwa Anwar, Andrea Catala Bordes, Michele Iacomino, Dieter Gläser, Tine Deconinck, Maja Di Rocco, Federico Zara, Jin Yun Helen Chen, Shazia Maqbool, Martin Kuchar, Kishin Koh, Tim M. Strom, Filippo M. Santorelli, Nicholas W. Wood, Stephanie Efthymiou, Marcello Scala, Selina Deschner, Jenny Carmichael, Cara M. Skraban, Gudrun Nürnberg, Maria Gabriela Otero, Michael C. Kruer, Hanan E. Shamseldin, Bart P.C. van de Warrenburg, Yasuhiro Suzuki, Haitian Nan, Somayeh Bakhtiari, Willem De Ridder, Roman Chrast, Ivana Ricca, Changlian Zhu, Rebecca Schüle, Jonathan Baets, Rossella Pasquariello, Peter De Jonghe, Fowzan S. Alkuraya, Nihal Olgaç Dündar, Majid Alfadhel, Yinghong Wang, Jamileh Rezazadeh Varaghchi, Tyler Mark Pierson, David Dredge, Peter Nürnberg, Marta Rusmini, Nourelhoda A Haridy, Yoshihisa Takiyama, Manuela Wiessner, Maryam Najafi, Saghar Ghasemi Firouzabadi, Matthis Synofzik, Frederic Tran Mau-Them, Christian Beetz, Konstantinos Ampatzis, James T Peterson, Emmanuelle Schmitt, Laetitia Lambert, Erik-Jan Kamsteeg, Kaya Bilguvar, Richard A. Lewis, Jonathan De Winter, Hwei-Jen Lee, Hiroyuki Ishiura, Jean-Jacques Médard, Luca Bartesaghi, Mary J H Willis, Anna Uhrova Meszarosova, Rita Horvath, Filipa Bouçanova, Carsten Bergmann, Wolfgang Hüttel, Meng-Yuan Ni, Mohammed Anter Abdelhameed, Tobias B. Haack, Jan Senderek, Özgür Duman, Alistair T. Pagnamenta, John M. Graham, Yiran Xu, Amy Goldstein, Ruben Portier, Michaela Auer-Grumbach, Ludger Schöls, Reza Maroofian, Stephan Züchner, Saeed Al Tala, Genomics England Research Consortium, and PREPARE Network

Subjects
0301 basic medicine, Male, Hereditary spastic paraplegia, Mitochondrial disease, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 03 medical and health sciences, Mice, 0302 clinical medicine, genetics [Spastic Paraplegia, Hereditary], mitochondrial disorder, medicine, Missense mutation, Animals, Humans, HSP, autosomal recessive, hereditary spastic paraplegia, HPDL, genetics [Oxygenases], Spasticity, ddc:610, Spastic tetraplegia, Zebrafish, Homogentisate 1,2-dioxygenase, Genetics, Errata, business.industry, Spastic Paraplegia, Hereditary, medicine.disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Hallucinogen persisting perception disorder, Pedigree, Rats, 030104 developmental biology, Mutation, Oxygenases, Female, Neurology (clinical), Human medicine, medicine.symptom, business, Spastic quadriplegia, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 237881.pdf (Publisher’s version ) (Open Access) Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

Published
2021
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13. Diagnosis of lethal or prenatal-onset autosomal recessive disorders by parental exome sequencing

Author

Jenny Carmichael, Emma Kivuva, Andrew E. Fry, Ravi Savarirayan, Charu Deshpande, Deirdre Cilliers, Angela F. Brady, Jacqueline Eason, Andrew Parrish, Emma L. Baple, Karen Stals, Emma Wakeling, Richard Caswell, Ruth Newbury-Ecob, Lisa Bradley, Victoria McKay, Garan Jones, Hana Lango Allen, Abhijit Dixit, Ellen Thomas, Peter D. Turnpenny, Carolyn Tysoe, Bruce Castle, Vinod Varghese, Matthew Wakeling, Adam C. Gunning, Helen Cox, Michael W. Parker, Muriel Holder, Alan Fryer, Helena Carley, Nora Shannon, Frances Elmslie, Deborah J. Shears, Sarah F. Smithson, Sian Ellard, Julia Rankin, Claire Searle, Julia Baptista, Tessa Homfray, and Pradeep Vasudevan

Subjects
0301 basic medicine, Genetics, Pregnancy, Fetus, Genetic heterogeneity, Obstetrics and Gynecology, Prenatal diagnosis, 030105 genetics & heredity, Biology, medicine.disease, Bioinformatics, Phenotype, 3. Good health, 03 medical and health sciences, 030104 developmental biology, medicine, Gene, Exome, Genetics (clinical), Exome sequencing
Abstract

Objective Rare genetic disorders resulting in prenatal or neonatal death are genetically heterogeneous, but testing is often limited by the availability of fetal DNA, leaving couples without a potential prenatal test for future pregnancies. We describe our novel strategy of exome sequencing parental DNA samples to diagnose recessive monogenic disorders in an audit of the first 50 couples referred. Method Exome sequencing was carried out in a consecutive series of 50 couples who had 1 or more pregnancies affected with a lethal or prenatal-onset disorder. In all cases, there was insufficient DNA for exome sequencing of the affected fetus. Heterozygous rare variants (MAF < 0.001) in the same gene in both parents were selected for analysis. Likely, disease-causing variants were tested in fetal DNA to confirm co-segregation. Results Parental exome analysis identified heterozygous pathogenic (or likely pathogenic) variants in 24 different genes in 26/50 couples (52%). Where 2 or more fetuses were affected, a genetic diagnosis was obtained in 18/29 cases (62%). In most cases, the clinical features were typical of the disorder, but in others, they result from a hypomorphic variant or represent the most severe form of a variable phenotypic spectrum. Conclusion We conclude that exome sequencing of parental samples is a powerful strategy with high clinical utility for the genetic diagnosis of lethal or prenatal-onset recessive disorders. © 2017 The Authors Prenatal Diagnosis published by John Wiley & Sons Ltd.

Published
2017
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14. Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration

Author

Gavin Arno, Keren J. Carss, Sarah Hull, Ceniz Zihni, Anthony G. Robson, Alessia Fiorentino, Alison J. Hardcastle, Graham E. Holder, Michael E. Cheetham, Vincent Plagnol, Anthony T. Moore, F. Lucy Raymond, Karl Matter, Maria S. Balda, Andrew R. Webster, Graeme Black, Georgina Hall, Stuart Ingram, Rachel Gillespie, Forbes Manson, Panagiotis Sergouniotis, Chris Inglehearn, Carmel Toomes, Manir Ali, Martin McKibbin, James Poulter, Kamron Khan, Emma Lord, Andrea Nemeth, Susan Downes, Stephanie Halford, Jing Yu, Stefano Lise, Nikos Ponitkos, Michel Michaelides, Veronica van Heyningen, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Ruth Armstrong, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Maria Bitner-Glindzicz, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Natalie Canham, Jenny Carmichael, Keren Carss, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Virginia Clowes, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Charu Deshpande, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, Frances Flinter, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Neeti Ghali, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Detelina Grozeva, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Simon Holden, Muriel Holder, Susan Holder, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Jane Hurst, Roger James, Stephen Jolles, Dragana Josifova, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Melissa Lees, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Sarju Mehta, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Soo-Mi Park, Alasdair Parker, John Pasi, Chris Patch, Joan Paterson, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Julia Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Elisabeth Rosser, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Alba Sanchis-Juan, Richard Sandford, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Richard Scott, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie Vogt, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Emma Wakeling, Ivy Wanjiku, Timothy Q. Warner, Evangeline Wassmer, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Pediatric surgery, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), and Med Microbiol, Infect Dis & Infect Prev

Subjects
Male, 0301 basic medicine, Retinal degeneration, Biallelic Mutation, RHOA, PROTEIN, Eye, Medical and Health Sciences, ACTIVATION, chemistry.chemical_compound, 0302 clinical medicine, 2.1 Biological and endogenous factors, Missense mutation, Exome, Aetiology, Genetics (clinical), Genetics & Heredity, Genetics, biology, Retinal Degeneration, Cell Polarity, MOSAIC EYES, Biological Sciences, Middle Aged, Phenotype, inherited retinal dystrophy, Pedigree, UK Inherited Retinal Disease Consortium, Female, apicobasal polarity, Retinal Dystrophies, Adult, NIHR Bioresource - Rare Diseases Consortium, ARHGEF18, Genotype, Mutation, Missense, Nerve Tissue Proteins, Retina, 03 medical and health sciences, Rare Diseases, retinitis pigmentosa, Report, CRB1, Retinitis pigmentosa, medicine, Humans, Amino Acid Sequence, Eye Proteins, Eye Disease and Disorders of Vision, Alleles, Human Genome, Neurosciences, Genetic Variation, Membrane Proteins, Epithelial Cells, Retinal, CELL FEATURES, medicine.disease, NUCLEOTIDE EXCHANGE FACTOR, p114RhoGEF, 030104 developmental biology, INTEGRATIVE GENOMICS VIEWER, OKO-MEDUZY, chemistry, Mutation, MORPHOGENESIS, 030221 ophthalmology & optometry, biology.protein, Missense, rhoA GTP-Binding Protein, Rho Guanine Nucleotide Exchange Factors, Genome-Wide Association Study
Abstract

Mutations in more than 250 genes are implicated in inherited retinal dystrophy; the encoded proteins are involved in a broad spectrum of pathways. The presence of unsolved families after highly parallel sequencing strategies suggests that further genes remain to be identified. Whole-exome and -genome sequencing studies employed here in large cohorts of affected individuals revealed biallelic mutations in ARHGEF18 in three such individuals. ARHGEF18 encodes ARHGEF18, a guanine nucleotide exchange factor that activates RHOA, a small GTPase protein that is a key component of tight junctions and adherens junctions. This biological pathway is known to be important for retinal development and function, as mutation of CRB1, encoding another component, causes retinal dystrophy. The retinal structure in individuals with ARHGEF18 mutations resembled that seen in subjects with CRB1 mutations. Five mutations were found on six alleles in the three individuals: c.808A>G (p.Thr270Ala), c.1617+5G>A (p.Asp540Glyfs ∗ 63), c.1996C>T (p.Arg666 ∗ ), c.2632G>T (p.Glu878 ∗ ), and c.2738_2761del (p.Arg913_Glu920del). Functional tests suggest that each disease genotype might retain some ARHGEF18 activity, such that the phenotype described here is not the consequence of nullizygosity. In particular, the p.Thr270Ala missense variant affects a highly conserved residue in the DBL homology domain, which is required for the interaction and activation of RHOA. Previously, knock-out of Arhgef18 in the medaka fish has been shown to cause larval lethality which is preceded by retinal defects that resemble those seen in zebrafish Crumbs complex knock-outs. The findings described here emphasize the peculiar sensitivity of the retina to perturbations of this pathway, which is highlighted as a target for potential therapeutic strategies.

Published
2017
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15. Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Author

Keren J. Carss, Gavin Arno, Marie Erwood, Jonathan Stephens, Alba Sanchis-Juan, Sarah Hull, Karyn Megy, Detelina Grozeva, Eleanor Dewhurst, Samantha Malka, Vincent Plagnol, Christopher Penkett, Kathleen Stirrups, Roberta Rizzo, Genevieve Wright, Dragana Josifova, Maria Bitner-Glindzicz, Richard H. Scott, Emma Clement, Louise Allen, Ruth Armstrong, Angela F. Brady, Jenny Carmichael, Manali Chitre, Robert H.H. Henderson, Jane Hurst, Robert E. MacLaren, Elaine Murphy, Joan Paterson, Elisabeth Rosser, Dorothy A. Thompson, Emma Wakeling, Willem H. Ouwehand, Michel Michaelides, Anthony T. Moore, Andrew R. Webster, F. Lucy Raymond, Timothy Aitman, Hana Alachkar, Sonia Ali, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Natalie Canham, Keren Carss, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Colin Church, Naomi Clements-Brod, Virginia Clowes, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Charu Deshpande, Lisa Devlin, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, Frances Flinter, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Neeti Ghali, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Simon Holden, Muriel Holder, Susan Holder, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Melissa Lees, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Sarju Mehta, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Sofia Papadia, Soo-Mi Park, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Julia Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Richard Sandford, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Richard Scott, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie Vogt, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Evangeline Wassmer, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Pediatric surgery, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), Rue-Albrecht, K, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Med Microbiol, Infect Dis & Infect Prev, RS: CARIM - R1.03 - Cell biochemistry of thrombosis and haemostasis, Biochemie, Raymond, Lucy [0000-0003-2652-3355], Apollo - University of Cambridge Repository, Vascular Medicine, and Paediatric Infectious Diseases / Rheumatology / Immunology

Subjects
0301 basic medicine, Male, DNA Mutational Analysis, EXOME, PROTEIN, Eye, whole-genome sequence, NIHR-BioResource Rare Diseases Consortium, Medical and Health Sciences, Choroideremia, ACTIVATION, 0302 clinical medicine, Ethnicity, 2.1 Biological and endogenous factors, Exome, rare sequence variant, Copy-number variation, Aetiology, MUTATION, Genetics (clinical), Exome sequencing, Genetics & Heredity, Genetics, Genome, Adaptor Proteins, Biological Sciences, DYSTROPHY, copy-number variants, Female, Human, Common disease-common variant, LEBER CONGENITAL AMAUROSIS, Ethnic Groups, Genes, Recessive, Biology, DIAGNOSIS, Article, 03 medical and health sciences, Rare Diseases, Retinal Diseases, STARGARDT DISEASE, Clinical Research, REVEALS, Journal Article, medicine, Recessive, Humans, retinal dystrophy, Eye Disease and Disorders of Vision, Alleles, Adaptor Proteins, Signal Transducing, Whole genome sequencing, Base Sequence, Genome, Human, Human Genome, Signal Transducing, Neurosciences, Genetic Variation, medicine.disease, GENE, Introns, Stargardt disease, Good Health and Well Being, 030104 developmental biology, Genes, Mutation, 030221 ophthalmology & optometry, Human genome
Abstract

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.

Published
2017
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16. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Author

Kathleen M. Gorman, Esther Meyer, Detelina Grozeva, Egidio Spinelli, Amy McTague, Alba Sanchis-Juan, Keren J. Carss, Emily Bryant, Adi Reich, Amy L. Schneider, Ronit M. Pressler, Michael A. Simpson, Geoff D. Debelle, Evangeline Wassmer, Jenny Morton, Diana Sieciechowicz, Eric Jan-Kamsteeg, Alex R. Paciorkowski, Mary D. King, J. Helen Cross, Annapurna Poduri, Heather C. Mefford, Ingrid E. Scheffer, Tobias B. Haack, Gary McCullagh, John J. Millichap, Gemma L. Carvill, Jill Clayton-Smith, Eamonn R. Maher, F. Lucy Raymond, Manju A. Kurian, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Siddharth Banka, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Saeed Al Turki, Carl Anderson, Richard Anney, Dinu Antony, Maria Soler Artigas, Muhammad Ayub, Senduran Balasubramaniam, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Ewan Birney, Douglas Blackwood, Martin Bobrow, Elena Bochukova, Patrick Bolton, Rebecca Bounds, Chris Boustred, Gerome Breen, Mattia Calissano, Keren Carss, Krishna Chatterjee, Lu Chen, Antonio Ciampi, Sebhattin Cirak, Peter Clapham, Gail Clement, Guy Coates, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Aaron Day-Williams, Ian N.M. Day, Thomas Down, Yuanping Du, Ian Dunham, Sarah Edkins, Peter Ellis, David Evans, Sadaf Faroogi, Ghazaleh Fatemifar, David R. Fitzpatrick, Paul Flicek, James Flyod, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Louise Gallagher, Matthias Geihs, Daniel Geschwind, Heather Griffin, Xueqin Guo, Xiaosen Guo, Hugh Gurling, Deborah Hart, Audrey Hendricks, Peter Holmans, Bryan Howie, Liren Huang, Tim Hubbard, Steve E. Humphries, Pirro Hysi, David K. Jackson, Yalda Jamshidi, Tian Jing, Chris Joyce, Jane Kaye, Thomas Keane, Julia Keogh, John Kemp, Karen Kennedy, Anja Kolb-Kokocinski, Genevieve Lachance, Cordelia Langford, Daniel Lawson, Irene Lee, Monkol Lek, Jieqin Liang, Hong Lin, Rui Li, Yingrui Li, Ryan Liu, Jouko Lönnqvist, Margarida Lopes, Valentina Iotchkova, Daniel MacArthur, Jonathan Marchini, John Maslen, Mangino Massimo, Iain Mathieson, Gaëlle Marenne, Peter McGuffin, Andrew McIntosh, Andrew G. McKechanie, Andrew McQuillin, Sarah Metrustry, Hannah Mitchison, Alireza Moayyeri, James Morris, Francesco Muntoni, Kate Northstone, Michael O'Donnovan, Alexandros Onoufriadis, Stephen O'Rahilly, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy R. Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, Olli Pietilainen, Vincent Plagnol, Lydia Quaye, Michael A. Quail, Karola Rehnström, Susan Ring, Graham R.S. Ritchie, Nicola Roberts, David B. Savage, Peter Scambler, Stephen Schiffels, Miriam Schmidts, Nadia Schoenmakers, Robert K. Semple, Eva Serra, Sally I. Sharp, So-Youn Shin, David Skuse, Kerrin Small, Lorraine Southam, Olivera Spasic-Boskovic, David St Clair, Jim Stalker, Elizabeth Stevens, Beate St Pourcian, Jianping Sun, Jaana Suvisaari, Ionna Tachmazidou, Martin D. Tobin, Ana Valdes, Margriet Van Kogelenberg, Peter M. Visscher, Louise V. Wain, James T.R. Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Elanor Wheeler, Tamieka Whyte, Hywel Williams, Kathleen A. Williamson, Crispian Wilson, Kim Wong, ChangJiang Xu, Jian Yang, Fend Zhang, Pingbo Zhang, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gavin Arno, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Jenny Carmichael, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Michel Michaelides, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Pediatric surgery, APH - Aging & Later Life, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and APH - Quality of Care

Subjects
0301 basic medicine, Male, Adolescent, Loss of Heterozygosity, Context (language use), Postnatal microcephaly, Neurotransmission, medicine.disease_cause, Bioinformatics, Synaptic Transmission, Loss of heterozygosity, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Calcium Channels, N-Type, Report, Genetics, medicine, Humans, Child, Genetics (clinical), Mutation, Dyskinesias, business.industry, Infant, medicine.disease, Hypotonia, Pedigree, 030104 developmental biology, Dyskinesia, Child, Preschool, Calcium, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

© 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.

Published
2018
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17. De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures

Author

Yoko Ito, Keren J. Carss, Sofia T. Duarte, Taila Hartley, Boris Keren, Manju A. Kurian, Isabelle Marey, Perinne Charles, Carla Mendonça, Caroline Nava, Rolph Pfundt, Alba Sanchis-Juan, Hans van Bokhoven, Anthony van Essen, Conny van Ravenswaaij-Arts, Kym M. Boycott, Kristin D. Kernohan, Sarah Dyack, F. Lucy Raymond, Timothy Aitman, David Bennett, Mark Caulfield, Patrick Chinnery, Daniel Gale, Ania Koziell, Taco W. Kuijpers, Michael A. Laffan, Eamonn Maher, Hugh S. Markus, Nicholas W. Morrell, Willem H. Ouwehand, David J. Perry, Irene Roberts, Kenneth G.C. Smith, Adrian Thrasher, Hugh Watkins, Catherine Williamson, Geoffrey Woods, Sofie Ashford, John R. Bradley, Debra Fletcher, Tracey Hammerton, Roger James, Nathalie Kingston, Christopher J. Penkett, Kathleen Stirrups, Marijke Veltman, Tim Young, Matthew Brown, Naomi Clements-Brod, John Davis, Eleanor Dewhurst, Helen Dolling, Marie Erwood, Amy Frary, Rachel Linger, Jennifer M. Martin, Sofia Papadia, Karola Rehnstrom, Hannah Stark, David Allsup, Steve Austin, Tamam Bakchoul, Tadbir K. Bariana, Paula Bolton-Maggs, Elizabeth Chalmers, Janine Collins, Peter Collins, Wendy N. Erber, Tamara Everington, Remi Favier, Kathleen Freson, Bruce Furie, Michael Gattens, Johanna Gebhart, Keith Gomez, Daniel Greene, Andreas Greinacher, Paolo Gresele, Daniel Hart, Johan W.M. Heemskerk, Yvonne Henskens, Rashid Kazmi, David Keeling, Anne M. Kelly, Michele P. Lambert, Claire Lentaigne, Ri Liesner, Mike Makris, Sarah Mangles, Mary Mathias, Carolyn M. Millar, Andrew Mumford, Paquita Nurden, Jeanette Payne, John Pasi, Kathelijne Peerlinck, Shoshana Revel-Vilk, Michael Richards, Matthew Rondina, Catherine Roughley, Sol Schulman, Harald Schulze, Marie Scully, Suthesh Sivapalaratnam, Matthew Stubbs, R. Campbell Tait, Kate Talks, Jecko Thachil, Cheng-Hock Toh, Ernest Turro, Chris Van Geet, Minka De Vries, Timothy Q. Warner, Henry Watson, Sarah Westbury, Abigail Furnell, Rutendo Mapeta, Paula Rayner-Matthews, Ilenia Simeoni, Simon Staines, Jonathan Stephens, Christopher Watt, Deborah Whitehorn, Antony Attwood, Louise Daugherty, Sri V.V. Deevi, Csaba Halmagyi, Fengyuan Hu, Vera Matser, Stuart Meacham, Karyn Megy, Olga Shamardina, Catherine Titterton, Salih Tuna, Ping Yu, Julie von Ziegenweldt, William Astle, Marta Bleda, Stefan Gräf, Matthias Haimel, Hana Lango-Allen, Sylvia Richardson, Paul Calleja, Stuart Rankin, Wojciech Turek, Julie Anderson, Christine Bryson, Jenny Carmichael, Coleen McJannet, Sophie Stock, Louise Allen, Gautum Ambegaonkar, Ruth Armstrong, Gavin Arno, Maria Bitner-Glindzicz, Angie Brady, Natalie Canham, Manali Chitre, Emma Clement, Virginia Clowes, Patrick Deegan, Charu Deshpande, Rainer Doffinger, Helen Firth, Frances Flinter, Courtney French, Alice Gardham, Neeti Ghali, Paul Gissen, Detelina Grozeva, Robert Henderson, Anke Hensiek, Simon Holden, Muriel Holder, Susan Holder, Jane Hurst, Dragana Josifova, Deepa Krishnakumar, Melissa Lees, Robert MacLaren, Anna Maw, Sarju Mehta, Michel Michaelides, Anthony Moore, Elaine Murphy, Soo-Mi Park, Alasdair Parker, Chris Patch, Joan Paterson, Julia Rankin, Evan Reid, Elisabeth Rosser, Richard Sandford, Saikat Santra, Richard Scott, Aman Sohal, Penelope Stein, Ellen Thomas, Dorothy Thompson, Marc Tischkowitz, Julie Vogt, Emma Wakeling, Evangeline Wassmer, Andrew Webster, Sonia Ali, Souad Ali, Harm J. Boggard, Colin Church, Gerry Coghlan, Victoria Cookson, Paul A. Corris, Amanda Creaser-Myers, Rosa DaCosta, Natalie Dormand, Mélanie Eyries, Henning Gall, Pavandeep K. Ghataorhe, Stefano Ghio, Ardi Ghofrani, J. Simon R. Gibbs, Barbara Girerd, Alan Greenhalgh, Charaka Hadinnapola, Arjan C. Houweling, Marc Humbert, Anna Huis in’t Veld, Fiona Kennedy, David G. Kiely, Gabor Kovacs, Allan Lawrie, Rob V. Mackenzie Ross, Rajiv Machado, Larahmie Masati, Sharon Meehan, Shahin Moledina, David Montani, Shokri Othman, Andrew J. Peacock, Joanna Pepke-Zaba, Val Pollock, Gary Polwarth, Lavanya Ranganathan, Christopher J. Rhodes, Kevin Rue-Albrecht, Gwen Schotte, Debbie Shipley, Florent Soubrier, Laura Southgate, Laura Scelsi, Jay Suntharalingam, Yvonne Tan, Mark Toshner, Carmen M. Treacy, Richard Trembath, Anton Vonk Noordegraaf, Sara Walker, Ivy Wanjiku, John Wharton, Martin Wilkins, Stephen J. Wort, Katherine Yates, Hana Alachkar, Richard Antrobus, Gururaj Arumugakani, Chiara Bacchelli, Helen Baxendale, Claire Bethune, Shahnaz Bibi, Claire Booth, Michael Browning, Siobhan Burns, Anita Chandra, Nichola Cooper, Sophie Davies, Lisa Devlin, Elizabeth Drewe, David Edgar, William Egner, Rohit Ghurye, Kimberley Gilmour, Sarah Goddard, Pavel Gordins, Sofia Grigoriadou, Scott Hackett, Rosie Hague, Lorraine Harper, Grant Hayman, Archana Herwadkar, Aarnoud Huissoon, Stephen Jolles, Peter Kelleher, Dinakantha Kumararatne, Sara Lear, Hilary Longhurst, Lorena Lorenzo, Jesmeen Maimaris, Ania Manson, Elizabeth McDermott, Sai Murng, Sergey Nejentsev, Sadia Noorani, Eric Oksenhendler, Mark Ponsford, Waseem Qasim, Isabella Quinti, Alex Richter, Crina Samarghitean, Ravishankar Sargur, Sinisa Savic, Suranjith Seneviratne, Carrock Sewell, Emily Staples, Hans Stauss, James Thaventhiran, Moira Thomas, Steve Welch, Lisa Willcocks, Nigel Yeatman, Patrick Yong, Phil Ancliff, Christian Babbs, Mark Layton, Eleni Louka, Simon McGowan, Adam Mead, Noémi Roy, Jenny Chambers, Peter Dixon, Cecelia Estiu, Bill Hague, Hanns-Ulrich Marschall, Michael Simpson, Sam Chong, Ingrid Emmerson, Lionel Ginsberg, David Gosal, Rob Hadden, Rita Horvath, Mohamed Mahdi-Rogers, Adnan Manzur, Andrew Marshall, Emma Matthews, Mark McCarthy, Mary Reilly, Tara Renton, Andrew Rice, Andreas Themistocleous, Tom Vale, Natalie Van Zuydam, Suellen Walker, Liz Ormondroyd, Gavin Hudson, Wei Wei, Patrick Yu Wai Man, James Whitworth, Maryam Afzal, Elizabeth Colby, Moin Saleem, Omid S. Alavijeh, H. Terry Cook, Sally Johnson, Adam P. Levine, Edwin K.S. Wong, Rhea Tan, Alex MacKenzie, Jacek Majewski, Michael Brudno, Dennis Bulman, David Dyment, Freson, Kathleen, Peerlinck, Kathelijne, Van Geet, Christel, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Med Microbiol, Infect Dis & Infect Prev, Medical Research Council (MRC), Clinical Cognitive Neuropsychiatry Research Program (CCNP), APH - Aging & Later Life, Pediatric surgery, Human genetics, ACS - Atherosclerosis & ischemic syndromes, CCA - Cancer biology and immunology, CCA - Cancer Treatment and quality of life, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, and Molecular cell biology and Immunology

Subjects
0301 basic medicine, Male, Care4Rare Canada Consortium, WAVE FAMILY PROTEINS, actin cytoskeleton, PROTEIN, HDE NEU PED, medicine.disease_cause, Whole Exome Sequencing, 0302 clinical medicine, Neurodevelopmental disorder, SYNAPTIC PLASTICITY, Intellectual disability, WAVE1 complex, PLASTICITY, EXCHANGE, 11 Medical and Health Sciences, Exome sequencing, Genetics (clinical), seizures, Genetics & Heredity, Genetics, Mutation, WASF1, DENDRITIC SPINES, developmental delay, Female, DISEASE GENE-DISCOVERY, Adult, Heterozygote, GENES, DISORDERS, autism, Biology, ACTIN, 03 medical and health sciences, Young Adult, Seizures, Report, Intellectual Disability, Exome Sequencing, medicine, Humans, PROTRUSIONS, recurrent de novo truncating mutations, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], COMPLEX, lamellipodia, neurodevelopmental disorder, Actin remodeling, Heterozygote advantage, NIHR BioResource, 06 Biological Sciences, medicine.disease, Actin cytoskeleton, Wiskott-Aldrich Syndrome Protein Family, 030104 developmental biology, WAVE, RETARDATION, 030217 neurology & neurosurgery
Abstract

Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:103 issue:1 pages:144-153 ispartof: location:United States status: published

Published
2018
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18. Indiscernibles and Plato’s Forms vs. Parmenides

Author

Jenny Carmichael

Subjects
Contemporary philosophy, Philosophy, Indiscernibles, Zeno's paradoxes, Epistemology
Abstract

In Parmenides, the young Socrates defends several candidate forms against Parmenides, who makes five objections: the objection of forms of common things, the question of the part vs. the whole, the third man argument, infinite regress, and the greatest difficulty problem. I define forms in terms of Leibniz’s Principle of the Identity of Indiscernibles (PII) in an attempt to overcome Parmenides’ opposition. I show that the main force in Parmenides’ objections consists of absurdities that emerge in relations between forms and particulars: absurdities that are avoided if the form and its instantiation in the particular are identical.

Published
2013
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19. Site-Specific Conjugation of Monodispersed DOTA-PEGn to a Thiolated Diabody Reveals the Effect of Increasing PEG Size on Kidney Clearance and Tumor Uptake with Improved 64-Copper PET Imaging

Author

Peter J. Hudson, Fabio Turatti, John E. Shively, Erasmus Poku, Lin Li, Anne-Line Anderson, David Tai Leong, Michael Paul Wheatcroft, Desiree Crow, David Colcher, James R. Bading, Jenny Carmichael, Andrew Raubitschek, and Paul J. Yazaki

Subjects
Biomedical Engineering, Mice, Nude, Pharmaceutical Science, chemistry.chemical_element, Bioengineering, Conjugated system, Kidney, Article, Polyethylene Glycols, Heterocyclic Compounds, 1-Ring, Mice, chemistry.chemical_compound, Neoplasms, PEG ratio, medicine, Animals, DOTA, Tissue Distribution, Sulfhydryl Compounds, Binding site, Pharmacology, Binding Sites, Molecular Structure, biology, Chemistry, Organic Chemistry, Copper, medicine.anatomical_structure, Copper Radioisotopes, Biochemistry, Positron-Emission Tomography, biology.protein, Biophysics, Female, Radiopharmaceuticals, Antibody, Neoplasm Transplantation, Biotechnology, Conjugate
Abstract

Optimal PET imaging of tumors with radiolabeled engineered antibodies requires, among other parameters, matching blood clearance and tumor uptake with the half-life of the engineered antibody. Although diabodies have favorable molecular sizes (50 kDa) for rapid blood clearance (t(1/2) = 30-60 min) and are bivalent, thereby increasing tumor uptake, they exhibit substantial kidney uptake as their major route of clearance, which is especially evident when they are labeled with the PET isotope (64)Cu (t(1/2) = 12 h). To overcome this drawback, diabodies may be conjugated to PEG, a modification that increases the apparent molecular size of the diabody and reduces kidney uptake without adversely affecting tumor uptake or the tumor to blood ratio. We show here that site-specific attachment of monodispersed PEGn of increasing molecular size (n = 12, 24, and 48) can uniformly increase the apparent molecular size of the PEG-diabody conjugate, decrease kidney uptake, and increase tumor uptake, the latter due to the increased residence time of the conjugate in the blood. Since the monodispersed PEGs were preconjugated to the chelator DOTA, the conjugates were able to bind radiometals such as (111)In and (64)Cu that can be used for SPECT and PET imaging, respectively. To allow conjugation of the DOTA-PEG to the diabody, the DOTA-PEG incorporated a terminal cysteine conjugated to a vinyl sulfone moiety. In order to control the conjugation chemistry, we have engineered a surface thiolated diabody that incorporates two cysteines per monomer (four per diabody). The thiolated diabody was expressed and purified from bacterial fermentation and only needs to be reduced prior to conjugation to the DOTA-PEGn-Cys-VS. This novel imaging agent (a diabody with DOTA-PEG48-Cys-VS attached to introduced thiols) gave up to 80%ID/g of tumor uptake with a tumor to blood ratio (T/B) of 8 at 24 h when radiolabeled with (111)In and 37.9% ID/g of tumor uptake (T/B = 8) at 44 h when radiolabeled with (64)Cu in PET imaging in an animal model. Tumor uptake was significantly improved from the 50% ID/g at 24 h observed with diabodies that were pegylated on surface lysine residues. Importantly, there was no loss of immunoreactivity of the site-specific Cys-conjugated diabody to its antigen (TAG-72) compared to the parent, unconjugated diabody. We propose that thiolated diabodies conjugated to DOTAylated monodisperse PEGs have the potential for superior SPECT and PET imaging in a clinical setting.

Published
2011
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20. Genetic defects of human brain development

Author

Christopher Geoffrey Woods and Jenny Carmichael

Subjects
Human Development, General Neuroscience, Neuronal migration, Brain, Lissencephaly, Human brain, Biology, Nervous System Malformations, medicine.disease, medicine.anatomical_structure, Genetic etiology, medicine, Humans, Neurology (clinical), Neuroscience
Abstract

This review focuses on malformations of the central nervous system that have a genetic etiology. One can view each malformation as giving us unique details on a map entitled "how to make a human brain." The gene(s) that cause each malformation are being identified, allowing discovery of their specific role in neurodevelopment, and defining a "road" on the map. The malformation is then the developmental consequence of "taking a wrong turn." Assimilation of complementary data from other species with human malformation phenotype and genotype is revealing just how wonderful and complex the neurodevelopment map is. Here we highlight recent research on brain malformations and how this is illuminating the map of normal human brain formation.

Published
2006
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21. Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin

Author

Jenny Carmichael, Chantal Diaz-Latoud, Olivier Sauvageot, Andreas Wyttenbach, David C. Rubinsztein, and Andre-Patrik Arrigo

Subjects
Programmed cell death, Huntingtin, Cell Survival, Blotting, Western, Green Fluorescent Proteins, Cytochrome c Group, Nerve Tissue Proteins, Biology, Mitochondrion, Protein aggregation, Transfection, Immunoenzyme Techniques, Hsp27, Cricetinae, Heat shock protein, Genetics, Huntingtin Protein, Animals, Humans, Enzyme Inhibitors, Phosphorylation, Molecular Biology, Heat-Shock Proteins, Genetics (clinical), Nuclear Proteins, Haplorhini, General Medicine, Caspase Inhibitors, Glutathione, Up-Regulation, Cell biology, Luminescent Proteins, Biochemistry, COS Cells, Mutation, biology.protein, Peptides, Reactive Oxygen Species, Intracellular, Protein Binding
Abstract

Neuronal loss and intraneuronal protein aggregates are characteristics of Huntington's disease (HD), which is one of 10 known neurodegenerative disorders caused by an expanded polyglutamine [poly(Q)] tract in the disease protein. N-terminal fragments of mutant huntingtin produce intracellular aggregates and cause toxicity. Several studies have shown that chaperones suppress poly(Q) aggregation and toxicity/cell death, but the mechanisms by which they prevent poly(Q)-mediated cell death remain unclear. In the present study, we identified heat shock protein 27 (HSP27) as a suppressor of poly(Q) mediated cell death, using a cellular model of HD. In contrast to HSP40/70 chaperones, we showed that HSP27 suppressed poly(Q) death without suppressing poly(Q) aggregation. We tested the hypotheses that HSP27 may reduce poly(Q)-mediated cell death either by binding cytochrome c and inhibiting the mitochondrial death pathway or by protecting against reactive oxygen species (ROS). While poly(Q)-induced cell death was reduced by inhibiting cytochrome c (cyt c) release from mitochondria, protection by HSP27 was regulated by its phosphorylation status and was independent of its ability to bind to cyt c. However, we observed that mutant huntingtin caused increased levels of ROS in neuronal and non-neuronal cells. ROS contributed to cell death because both N-acetyl-L-cysteine and glutathione in its reduced form suppressed poly(Q)-mediated cell death. HSP27 decreased ROS in cells expressing mutant huntingtin, suggesting that this chaperone protects cells against oxidative stress. We propose that a poly(Q) mutation can induce ROS that directly contribute to cell death and that HSP27 is an antagonist of this process.

Published
2002
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22. Bacterial and yeast chaperones reduce both aggregate formation and cell death in mammalian cell models of Huntington's disease

Author

Alan R. Fersht, Jenny Carmichael, David C. Rubinsztein, Adrian Woolfson, Jean Chatellier, and Cesar Milstein

Subjects
Saccharomyces cerevisiae Proteins, Mutant, Transfection, Models, Biological, PC12 Cells, Inclusion bodies, Fungal Proteins, Exon, Huntington's disease, Heat shock protein, medicine, Animals, Heat-Shock Proteins, Cell Nucleus, Inclusion Bodies, Genetics, Fungal protein, Multidisciplinary, Cell Death, biology, Chaperonin 60, Biological Sciences, medicine.disease, Rats, Cell nucleus, Huntington Disease, medicine.anatomical_structure, Amino Acid Substitution, Chaperone (protein), COS Cells, Mutation, biology.protein, Peptides, Protein Binding
Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative condition caused by expansions of more than 35 uninterrupted CAG repeats in exon 1 of the huntingtin gene. The CAG repeats in HD and the other seven known diseases caused by CAG codon expansions are translated into long polyglutamine tracts that confer a deleterious gain of function on the mutant proteins. Intraneuronal inclusions comprising aggregates of the relevant mutant proteins are found in the brains of patients with HD and related diseases. It is crucial to determine whether the formation of inclusions is directly pathogenic, because a number of studies have suggested that aggregates may be epiphenomena or even protective. Here, we show that fragments of the bacterial chaperone GroEL and the full-length yeast heat shock protein Hsp104 reduce both aggregate formation and cell death in mammalian cell models of HD, consistent with a causal link between aggregation and pathology.

Published
2000
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23. Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease

Author

Julia Rankin, Yolanda Narain, Robert A. Furlong, Andreas Wyttenbach, Jina Swartz, David C. Rubinsztein, and Jenny Carmichael

Subjects
Proteasome Endopeptidase Complex, Time Factors, Huntingtin, Blotting, Western, Lactacystin, Cysteine Proteinase Inhibitors, Protein aggregation, Biology, Transfection, chemistry.chemical_compound, Ubiquitin, Multienzyme Complexes, Heat shock protein, Tumor Cells, Cultured, medicine, Animals, Humans, HSP70 Heat-Shock Proteins, Heat-Shock Proteins, Multidisciplinary, Cell Death, Temperature, Exons, Biological Sciences, HSP40 Heat-Shock Proteins, Immunohistochemistry, Molecular biology, Acetylcysteine, Rats, Hsp70, Cysteine Endopeptidases, Huntington Disease, chemistry, COS Cells, Proteasome inhibitor, biology.protein, Carrier Proteins, Peptides, Plasmids, medicine.drug
Abstract

Huntington's disease (HD), spinocerebellar ataxias types 1 and 3 (SCA1, SCA3), and spinobulbar muscular atrophy (SBMA) are caused by CAG/polyglutamine expansion mutations. A feature of these diseases is ubiquitinated intraneuronal inclusions derived from the mutant proteins, which colocalize with heat shock proteins (HSPs) in SCA1 and SBMA and proteasomal components in SCA1, SCA3, and SBMA. Previous studies suggested that HSPs might protect against inclusion formation, because overexpression of HDJ-2/HSDJ (a human HSP40 homologue) reduced ataxin-1 (SCA1) and androgen receptor (SBMA) aggregate formation in HeLa cells. We investigated these phenomena by transiently transfecting part of huntingtin exon 1 in COS-7, PC12, and SH-SY5Y cells. Inclusion formation was not seen with constructs expressing 23 glutamines but was repeat length and time dependent for mutant constructs with 43–74 repeats. HSP70, HSP40, the 20S proteasome and ubiquitin colocalized with inclusions. Treatment with heat shock and lactacystin, a proteasome inhibitor, increased the proportion of mutant huntingtin exon 1-expressing cells with inclusions. Thus, inclusion formation may be enhanced in polyglutamine diseases, if the pathological process results in proteasome inhibition or a heat-shock response. Overexpression of HDJ-2/HSDJ did not modify inclusion formation in PC12 and SH-SY5Y cells but increased inclusion formation in COS-7 cells. To our knowledge, this is the first report of an HSP increasing aggregation of an abnormally folded protein in mammalian cells and expands the current understanding of the roles of HDJ-2/HSDJ in protein folding.

Published
2000
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24. A potential role for the clathrin adaptor GGA in Drosophila spermatogenesis

Author

Jenny Carmichael, Jennifer Hirst, Hirst, Jennifer [0000-0001-9063-8494], and Apollo - University of Cambridge Repository

Subjects
Male, Transgene, Clathrin, 03 medical and health sciences, 0302 clinical medicine, RNA interference, clathrin, spermatocytes, Testis, Animals, Drosophila Proteins, lcsh:QH573-671, GGA, Gene, 030304 developmental biology, 0303 health sciences, Gene knockdown, adaptor, biology, lcsh:Cytology, fungi, Cell Biology, biology.organism_classification, AP-1, Phenotype, Molecular biology, acroblast, spermatogenesis, Cell biology, Transcription Factor AP-1, Adaptor Proteins, Vesicular Transport, Fertility, biology.protein, Female, RNA Interference, Drosophila, Drosophila melanogaster, Spermatogenesis, 030217 neurology & neurosurgery, Research Article, spermatids
Abstract

Background GGAs (Golgi-localised, γ-ear containing, ADP ribosylation factor-binding) are a family of clathrin adaptors that sort a number of biologically important transmembrane proteins into clathrin-coated vesicles. Knockout and knockdown studies to determine GGA function are confounded by the fact that there are 3 GGA genes in mammalian cells. Thus Drosophila melanogaster is a useful model system to study tissue expression profiles and knockdown phenotypes as there is a single GGA ortholog. Results Here we have quantified protein expression in Drosophila and show that there is >3-fold higher expression of GGA in male flies relative to female flies. In female flies the majority of GGA expression is in the head. In male flies GGA is not only expressed at high levels in the head but there is a gender specific increased expression which is due to the abundant expression of GGA in the testes. Using a highly specific antibody we have localised endogenous GGA protein in testes squashes, and visualised it in somatic and germ line cells. We show that GGA is expressed during multiple stages of sperm development, and co-stains with a marker of the trans-Golgi Network. This is most striking at the acroblast of early spermatids. In spite of the high expression of GGA in testes, knocking down its expression by >95% using transgenic RNAi fly lines did not affect male fertility. Therefore spermatogenesis in the male flies appears to progress normally with Conclusion In Drosophila we have uncovered a potential role for GGA in the testes of male flies. The gender specific higher expression of GGA, its specific enrichment in testes and its localisation to developing spermatocytes and at the acroblast of spermatids supports a role for GGA function in Drosophila spermatogenesis, even though spermatogenesis still occurs when GGA expression is depleted to

Published
2011

25. Huntington's disease: from pathology and genetics to potential therapies

Author

Chien-Wen Chen, Sara Imarisio, Janet E. Davies, Benjamin R. Underwood, Shinji Saiki, Evangelia K. Ttofi, Jenny Carmichael, David C. Rubinsztein, Gauri Krishna, Viktor I. Korolchuk, and Claudia Rose

Subjects
Models, Molecular, congenital, hereditary, and neonatal diseases and abnormalities, Proteasome Endopeptidase Complex, Huntingtin, Transcription, Genetic, Mutant, Nerve Tissue Proteins, Biology, Biochemistry, Huntington's disease, Mutant protein, mental disorders, Huntingtin Protein, medicine, Animals, Humans, Molecular Biology, Genetics, Ubiquitin, Nuclear Proteins, Cell Biology, Polyglutamine tract, medicine.disease, Mitochondria, Protein Structure, Tertiary, Huntington Disease, Mutation, Trinucleotide repeat expansion, Reactive Oxygen Species, Trinucleotide Repeat Expansion, Genetic screen
Abstract

Huntington's disease (HD) is a devastating autosomal dominant neurodegenerative disease caused by a CAG trinucleotide repeat expansion encoding an abnormally long polyglutamine tract in the huntingtin protein. Much has been learnt since the mutation was identified in 1993. We review the functions of wild-type huntingtin. Mutant huntingtin may cause toxicity via a range of different mechanisms. The primary consequence of the mutation is to confer a toxic gain of function on the mutant protein and this may be modified by certain normal activities that are impaired by the mutation. It is likely that the toxicity of mutant huntingtin is revealed after a series of cleavage events leading to the production of N-terminal huntingtin fragment(s) containing the expanded polyglutamine tract. Although aggregation of the mutant protein is a hallmark of the disease, the role of aggregation is complex and the arguments for protective roles of inclusions are discussed. Mutant huntingtin may mediate some of its toxicity in the nucleus by perturbing specific transcriptional pathways. HD may also inhibit mitochondrial function and proteasome activity. Importantly, not all of the effects of mutant huntingtin may be cell-autonomous, and it is possible that abnormalities in neighbouring neurons and glia may also have an impact on connected cells. It is likely that there is still much to learn about mutant huntingtin toxicity, and important insights have already come and may still come from chemical and genetic screens. Importantly, basic biological studies in HD have led to numerous potential therapeutic strategies.

Published
2008

26. Huntington's disease: molecular basis of neurodegeneration

Author

David C. Rubinsztein and Jenny Carmichael

Subjects
Huntingtin, Biology, Huntington's disease, Trinucleotide Repeats, medicine, Huntingtin Protein, Humans, Molecular Biology, Cell Aggregation, Neurons, Cell Death, Neurodegeneration, Neurotoxicity, Brain, Polyglutamine tract, medicine.disease, Cell aggregation, Corpus Striatum, Cell biology, Huntington Disease, Mutation, Nerve Degeneration, Molecular Medicine, Chromosomes, Human, Pair 4, Trinucleotide repeat expansion, Peptides
Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HD gene. The expanded repeats are translated into an abnormally long polyglutamine tract close to the N-terminus of the HD gene product (‘huntingtin’). Studies in humans and mouse models suggest that the mutation is associated with a deleterious gain-of-function. Several studies have suggested that the large huntingtin protein is cleaved to produce a shorter N-terminal fragment containing the polyglutamine expansion, and that the polyglutamine expansion causes the protein fragment to misfold and form aggregates (inclusions) in the nuclei and processes of neurons. It is likely that neurotoxicity is caused by the misfolded protein in its soluble form, and/or in aggregates, and/or in the process of aggregation. A wide range of potential mechanisms for neurotoxicity have been proposed, including caspase activation, dysregulation of transcriptional pathways, increased production of reactive oxygen species, and inhibition of proteasome activity. In this review we consider the current status of research in the field and possible mechanisms whereby the HD mutation might result in neurodegeneration.

Published
2003

27. The bacterial chaperonin GroEL requires GroES to reduce aggregation and cell death in a COS-7 cell model of Huntington's disease

Author

Jenny Carmichael, Coralie Vacher, and David C. Rubinsztein

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Huntingtin, Mutant, Blotting, Western, Nerve Tissue Proteins, Transfection, Models, Biological, Chaperonin, Mutant protein, mental disorders, Chaperonin 10, Animals, Genetics, Inclusion Bodies, biology, Cell Death, General Neuroscience, Nuclear Proteins, GroES, Chaperonin 60, Polyglutamine tract, GroEL, Immunohistochemistry, nervous system diseases, Cell biology, Huntington Disease, Chaperone (protein), COS Cells, Mutation, biology.protein, Peptides
Abstract

Huntington's disease (HD) is caused by expansions of more than 35 CAG repeats in the HD gene. These repeats are translated into a long polyglutamine tract that confers a deleterious gain-of-function on the mutant protein. Intraneuronal inclusions comprising mutant huntingtin are found in HD patient brains. Here we show that the bacterial chaperonin GroEL can reduce aggregation of mutant huntingtin in COS-7 cells and requires GroES for efficient activity, analogous to what has been described in bacteria. The reduction in aggregation of mutant huntingtin by GroEL/GroES was associated with protection against polyglutamine-induced cell death.

Published
2002

28. Modulation of polyglutamine-induced cell death by genes identified by expression profiling

Author

Jenny Carmichael, Jina Swartz, Andreas Wyttenbach, Hiroko Kita, Kikuya Kato, Shizuko Muro, David C. Rubinsztein, and Kenichi Matsubara

Subjects
Cell, Nerve Tissue Proteins, Biology, Gene expression, Genetics, medicine, Huntingtin Protein, Animals, Humans, Molecular Biology, Gene, Genetics (clinical), Regulation of gene expression, Cell Death, Gene Expression Profiling, Nuclear Proteins, General Medicine, Polyglutamine tract, Cell biology, Gene expression profiling, medicine.anatomical_structure, PFKM, Gene Expression Regulation, COS Cells, Peptides
Abstract

The majority of triplet-repeat diseases are caused by mutated genes with an extended polyglutamine tract, exemplified by Huntington's disease (HD). In order to model HD pathogenesis in a controlled system, we developed stable PC12 cell lines that express exon 1 fragments of the huntingtin gene with 23 or 74 polyglutamines driven by an inducible doxycycline (dox)-sensitive promoter (HD-23Q or HD-74Q). We aimed to identify early perturbations induced by the mutation by studying expression levels of 1824 genes at 0, 5, 10 and 18 hours after induction, using adaptor-tagged competitive PCR (ATAC-PCR). At these time points, the cells show no appreciable death or mitochondrial impairment and very low inclusion levels. A total of 126 genes, including 69 known genes, exhibited statistically significant alterations in the HD-74Q cell lines but no changes in the HD-23Q lines. We tested 11 of these genes for their abilities to modulate polyglutamine-induced cell death in transiently transfected cell models. Five genes [glucose transporter 1 (Glut1), phosphofructokinase muscle isozyme (Pfkm), prostate glutathione-S -transferase 2 (Gstm2), RNA-binding motif protein 3 (Rbm3) and KRAB-A interacting protein 1 (Krip-1)] significantly suppressed cell death in both neuronal precursor and non-neuronal cell lines, suggesting that these transcriptional changes were relevant to polyglutamine pathology. The efficient recovery of functionally relevant genes supports the utility of gene expression profiling for discovering pathways related to pathogenesis, and the importance of analyzing molecular events in the early stages of disease.

Published
2002

29. Glycogen synthase kinase-3beta inhibitors prevent cellular polyglutamine toxicity caused by the Huntington's disease mutation

Author

David C. Rubinsztein, Yi Ping Bao, Katherine L. Sugars, and Jenny Carmichael

Subjects
Programmed cell death, Indoles, Transcription, Genetic, HSP27 Heat-Shock Proteins, Biochemistry, Maleimides, Glycogen Synthase Kinase 3, Huntington's disease, Hsp27, GSK-3, medicine, Tumor Cells, Cultured, Animals, Humans, HSP70 Heat-Shock Proteins, Enzyme Inhibitors, Glycogen synthase, Molecular Biology, Heat-Shock Proteins, beta Catenin, Cell Aggregation, Glycogen Synthase Kinase 3 beta, biology, Cell Death, Wild type, Cell Biology, medicine.disease, Molecular biology, Neoplasm Proteins, Heat shock factor, Cytoskeletal Proteins, Huntington Disease, Proto-Oncogene Proteins c-bcl-2, Toxicity, COS Cells, Mutation, biology.protein, Trans-Activators, Lithium Chloride, Peptides, Molecular Chaperones
Abstract

Huntington's disease is one of nine known neurodegenerative disorders caused by an expanded polyglutamine (poly(Q)) tract in the disease protein. These diseases are associated with intraneuronal protein aggregates. Heat-inducible chaperones like HSP70 and HSP27 suppress poly(Q) aggregation and/or toxicity/cell death. Heat shock transcription factors, including HSF-1, regulate HSP70 and HSP27 expression. HSF-1 activity is reduced by glycogen synthase kinase-3 (GSK-3) and enhanced by GSK-3 inhibitors, like lithium. Thus, we hypothesized that lithium treatment may partially rescue death in Huntington's disease cell models. LiCl reduced poly(Q) toxicity in neuronal and nonneuronal cell lines, but this was not associated with elevation of HSP70 or HSP27. The protective effect of lithium involved GSK-3beta inhibition, since poly(Q) toxicity was also reduced by SB216763, a GSK-3beta inhibitor, and by overexpression of a dominant-negative GSK-3beta mutant. LiCl and SB216763 increased beta-catenin-dependent T-cell factor-mediated transcription. Since beta-catenin overexpression protected cells from poly(Q) toxicity, we tested whether this pathway was impaired by a poly(Q) expansion mutation. Cells expressing expanded repeats had reduced beta-catenin levels associated with a parallel decrease in T-cell factor-mediated transcription, compared with cells expressing wild type constructs. Since LiCl can protect against polyglutamine toxicity in cell lines, it is an excellent candidate for further in vivo therapeutic trials.

Published
2002

30. Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntingtons disease

Author

Hiroko Kita, Michelle Maxwell, Andreas Wyttenbach, J.L. Bradley, Kikuya Kato, David C. Rubinsztein, Thomas Thykjaer, Anthony H.V. Schapira, Rosemary L. Brown, Torben F. Ørntoft, Jenny Carmichael, and Jina Swartz

Subjects
Proteasome Endopeptidase Complex, Huntingtin, Transcription, Genetic, Response element, Mitosis, Nerve Tissue Proteins, Biology, PC12 Cells, Cell Line, Huntington's disease, Multienzyme Complexes, Cyclic AMP, Neurites, Genetics, medicine, Huntingtin Protein, Animals, Humans, HSP70 Heat-Shock Proteins, Cloning, Molecular, Molecular Biology, Heat-Shock Proteins, Genetics (clinical), Inclusion Bodies, Neurons, Regulation of gene expression, Cell Death, Ubiquitin, Nuclear Proteins, Exons, General Medicine, HSP40 Heat-Shock Proteins, Polyglutamine tract, medicine.disease, Molecular biology, Rats, Cell biology, Cysteine Endopeptidases, Huntington Disease, Gene Expression Regulation, Solubility, Mutation, Peptides, Trinucleotide Repeat Expansion, Trinucleotide repeat expansion
Abstract

Huntington's disease (HD) is one of 10 known diseases caused by a (CAG)(n) trinucleotide repeat expansion that is translated into an abnormally long polyglutamine tract. We have developed stable inducible neuronal (PC12) cell lines that express huntingtin exon 1 with varying CAG repeat lengths under doxycycline (dox) control. The expression of expanded repeats is associated with aggregate formation, caspase-dependent cell death and decreased neurite outgrowth. Post-mitotic cells expressing mutant alleles were more prone to cell death compared with identical cycling cells. To determine early metabolic changes induced by this mutation in cell models, we studied changes in gene expression after 18 h dox induction, using Affymetrix arrays, cDNA filters and adapter-tagged competitive PCR (ATAC-PCR). At this time point there were low rates of inclusion formation, no evidence of mitochondrial compromise and no excess cell death in the lines expressing expanded compared with wild-type repeats. The expression profiles suggest novel targets for the HD mutation and were compatible with impaired cAMP response element (CRE)-mediated transcription, which we confirmed using CRE-luciferase reporter assays. Reduced CRE-mediated transcription may contribute to the loss of neurite outgrowth and cell death in polyglutamine diseases, as these phenotypes were partially rescued by treating cells with cAMP or forskolin.

Published
2001

31. Correction to 'Site-Specific Conjugation of Monodispersed DOTA-PEGn to Thiolated Diabody Reveals Effect of Increasing Peg Size on Kidney Clearance and Tumor Uptake with Improved 64-Copper PET Imaging'

Author

Lin Li, Desiree Crow, Fabio Turatti, James R. Bading, Anne-Line Anderson, Erasmus Poku, Paul J. Yazaki, Jenny Carmichael, David Leong, David Wheatcroft, Andrew A. Raubitschek, Peter J. Hudson, David Colcher, and John E. Shively

Subjects
Pharmacology, Organic Chemistry, Biomedical Engineering, Pharmaceutical Science, Bioengineering, Biotechnology
Published
2011
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33. Huntington's disease: from pathology and genetics to potential therapies.

Author

Sara Imarisio, Jenny Carmichael, Viktor Korolchuk, Chien-Wen Chen, Shinji Saiki, Claudia Rose, Gauri Krishna, Janet E. Davies, Evangelia Ttofi, Benjamin R. Underwood, and David C. Rubinsztein

Subjects
*HUNTINGTON disease, *POLYCYSTIC kidney disease, *PREVENTIVE medicine, *TOXICITY testing
Abstract

Huntington's disease (HD) is a devastating autosomal dominant neurodegenerative disease caused by a CAG trinucleotide repeat expansion encoding an abnormally long polyglutamine tract in the huntingtin protein. Much has been learnt since the mutation was identified in 1993. We review the functions of wild-type huntingtin. Mutant huntingtin may cause toxicity via a range of different mechanisms. The primary consequence of the mutation is to confer a toxic gain of function on the mutant protein and this may be modified by certain normal activities that are impaired by the mutation. It is likely that the toxicity of mutant huntingtin is revealed after a series of cleavage events leading to the production of N-terminal huntingtin fragment(s) containing the expanded polyglutamine tract. Although aggregation of the mutant protein is a hallmark of the disease, the role of aggregation is complex and the arguments for protective roles of inclusions are discussed. Mutant huntingtin may mediate some of its toxicity in the nucleus by perturbing specific transcriptional pathways. HD may also inhibit mitochondrial function and proteasome activity. Importantly, not all of the effects of mutant huntingtin may be cell-autonomous, and it is possible that abnormalities in neighbouring neurons and glia may also have an impact on connected cells. It is likely that there is still much to learn about mutant huntingtin toxicity, and important insights have already come and may still come from chemical and genetic screens. Importantly, basic biological studies in HD have led to numerous potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

Published
2008
Full Text
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