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5. Monogenic Causes in Familial Stroke Across Intracerebral Hemorrhage and Ischemic Stroke Subtypes Identified by Whole-Exome Sequencing

Author

Chang, Li-Hsin, primary, Chi, Nai-Fang, additional, Chen, Chun-Yu, additional, Lin, Yung-Shuan, additional, Hsu, Shao-Lun, additional, Tsai, Jui-Yao, additional, Huang, Hui-Chi, additional, Lin, Chun-Jen, additional, Chung, Chih-Ping, additional, Tung, Chien-Yi, additional, Jeng, Chung-Jiuan, additional, Lee, Yi-Chung, additional, Liu, Yo-Tsen, additional, and Lee, I-Hui, additional

Published
2022
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6. Clinical characteristics and long‐term outcome of cerebral cavernous malformations‐related epilepsy

Author

Shih, Yen‐Cheng, primary, Chou, Chien‐Chen, additional, Peng, Syu‐Jyun, additional, Yu, Hsiang‐Yu, additional, Hsu, Sanford P. C., additional, Lin, Chun‐Fu, additional, Lee, Cheng‐Chia, additional, Yang, Huai‐Che, additional, Chen, Yi‐Chieh, additional, Kwan, Shang‐Yeong, additional, Chen, Chien, additional, Wang, Shuu‐Jiun, additional, Lin, Chung‐Jung, additional, Lirng, Jiing‐Feng, additional, Shih, Yang‐Hsin, additional, Yen, Der‐Jen, additional, and Liu, Yo‐Tsen, additional

Published
2022
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8. Defects of mutant DNMT1 are linked to a spectrum of neurological disorders

Author

Baets, Jonathan, Duan, Xiaohui, Wu, Yanhong, Smith, Gordon, Seeley, William W., Mademan, Inès, McGrath, Nicole M., Beadell, Noah C., Khoury, Julie, Botuyan, Maria-Victoria, Mer, Georges, Worrell, Gregory A., Hojo, Kaori, DeLeon, Jessica, Laura, Matilde, Liu, Yo-Tsen, Senderek, Jan, Weis, Joachim, Van den Bergh, Peter, Merrill, Shana L., Reilly, Mary M., Houlden, Henry, Grossman, Murray, Scherer, Steven S., De Jonghe, Peter, Dyck, Peter J., and Klein, Christopher J.

Published
2015
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9. Novel HSAN1 Mutation in Serine Palmitoyltransferase Resides at a Putative Phosphorylation Site That Is Involved in Regulating Substrate Specificity

Author

Ernst, Daniela, Murphy, Sinéad, Sathiyanadan, Karthik, Wei, Yu, Othman, Alaa, Laurá, Matilde, Liu, Yo-Tsen, Penno, Anke, Blake, Julian, Donaghy, Michael, Houlden, Henry, Reilly, Mary, Hornemann, Thorsten, Ernst, Daniela, Murphy, Sinéad, Sathiyanadan, Karthik, Wei, Yu, Othman, Alaa, Laurá, Matilde, Liu, Yo-Tsen, Penno, Anke, Blake, Julian, Donaghy, Michael, Houlden, Henry, Reilly, Mary, and Hornemann, Thorsten

Abstract

1-Deoxysphingolipids (1-deoxySL) are atypical sphingolipids that are formed by the enzyme serine palmitoyltransferase (SPT) due to a promiscuous use of l-alanine over its canonical substrate l-serine. Several mutations in SPT are associated with the hereditary sensory and autonomic neuropathy type I (HSAN1). The current hypothesis is that these mutations induce a permanent shift in the affinity from l-serine toward l-alanine which results in a pathologically increased 1-deoxySL formation in HSAN1 patients. Also, wild-type SPT forms 1-deoxySL under certain conditions, and elevated levels were found in individuals with the metabolic syndrome and diabetes. However, the molecular mechanisms which control the substrate shift of the wild-type enzyme are not understood. Here, we report a novel SPTLC2-S384F variant in two unrelated HSAN1 families. Affected patients showed elevated plasma 1-deoxySL levels and expression of the S384F mutant in HEK293 cells increased 1-deoxySL formation. Previously, S384 has been reported as one of the two (S384 and Y387) putative phosphorylation sites in SPTLC2. The phosphorylation of wild-type SPTLC2 was confirmed by isoelectric focusing. The impact of an S384 phosphorylation on SPT activity was tested by creating mutants mimicking either a constitutively phosphorylated (S384D, S384E) or non-phosphorylated (S384A, Y387F, Y387F+S384A) protein. The S384D but not the S384E variant was associated with increased 1-deoxySL formation. The other mutations had no influence on activity and substrate affinity. In summary, our data show that S384F is a novel mutation in HSAN1 and that the substrate specificity of wild-type SPT might by dynamically regulated by a phosphorylation at this position.

Published
2021

10. The clinical and imaging features of FLNApositive and negative periventricular nodular heterotopia

Author

Lu, Yan-Ting, Hsu, Chung-Yao, Liu, Yo-Tsen, Chan, Chung-Kin, Chuang, Yao-Chung, Lin, Chih-Hsiang, Chang, Kai-Ping, Ho, Chen-Jui, Ng, Ching-Ching, Lim, Kheng-Seang, and Tsai, Meng-Han

Abstract

Periventricular nodular heterotopia (PVNH) is caused by abnormal neuronal migration, resulting in the neurons accumulate as nodules along the surface of the lateral ventricles. PVNH often cause epilepsy, psychomotor development or cognition problem. Mutations in FLNA(Filamin A) is the most common underlying genetic etiology. Our purpose is to delineate the clinical and imaging spectrum that differentiates FLNA-positive and FLNA-negative PVNH patients.

Published
2022
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16. Genetic and clinical characteristics of NEFL-related Charcot-Marie-Tooth disease

Author

Horga, Alejandro, Laurà, Matilde, Jaunmuktane, Zane, Jerath, Nivedita U, Gonzalez, Michael A, Polke, James M, Poh, Roy, Blake, Julian C, Liu, Yo-Tsen, Wiethoff, Sarah, Bettencourt, Conceição, Lunn, Michael Pt, Manji, Hadi, Hanna, Michael G, Houlden, Henry, Brandner, Sebastian, Züchner, Stephan, Shy, Michael, and Reilly, Mary M

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Cerebellar Ataxia, Genotype, neurofilament light polypeptide, charcot-Marie-Tooth disease, Axons, nervous system diseases, Pedigree, NEFL, Phenotype, stomatognathic system, Sural Nerve, Neurofilament Proteins, Mutation, whole-exome sequencing, Humans
Abstract

To analyse and describe the clinical and genetic spectrum of Charcot-Marie-Tooth disease (CMT) caused by mutations in the neurofilament light polypeptide gene (NEFL).

Published
2017

17. Aberrant Sensory Gating of the Primary Somatosensory Cortex Contributes to the Motor Circuit Dysfunction in Paroxysmal Kinesigenic Dyskinesia

Author

Liu, Yo-Tsen, primary, Chen, Yi-Chieh, additional, Kwan, Shang-Yeong, additional, Chou, Chien-Chen, additional, Yu, Hsiang-Yu, additional, Yen, Der-Jen, additional, Liao, Kwong-Kum, additional, Chen, Wei-Ta, additional, Lin, Yung-Yang, additional, Chen, Rou-Shayn, additional, Jih, Kang-Yang, additional, Lu, Shu-Fen, additional, Wu, Yu-Te, additional, Wang, Po-Shan, additional, and Hsiao, Fu-Jung, additional

Published
2018
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21. A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy

Author

Tsai, Pei-Chien, primary, Soong, Bing-Wen, additional, Mademan, Inès, additional, Huang, Yen-Hua, additional, Liu, Chia-Rung, additional, Hsiao, Cheng-Tsung, additional, Wu, Hung-Ta, additional, Liu, Tze-Tze, additional, Liu, Yo-Tsen, additional, Tseng, Yen-Ting, additional, Lin, Kon-Ping, additional, Yang, Ueng-Cheng, additional, Chung, Ki Wha, additional, Choi, Byung-Ok, additional, Nicholson, Garth A., additional, Kennerson, Marina L., additional, Chan, Chih-Chiang, additional, De Jonghe, Peter, additional, Cheng, Tzu-Hao, additional, Liao, Yi-Chu, additional, Züchner, Stephan, additional, Baets, Jonathan, additional, and Lee, Yi-Chung, additional

Published
2017
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22. PRRT2 missense mutations cluster near C‐terminus and frequently lead to protein mislocalization.

Author

Tsai, Meng‐Han, Nian, Fang‐Shin, Hsu, Mei‐Hsin, Liu, Wei‐Szu, Liu, Yo‐Tsen, Liu, Chen, Lin, Po‐Hsi, Hwang, Daw‐Yang, Chuang, Yao‐Chung, and Tsai, Jin‐Wu

Subjects
MISSENSE mutation, MUTANT proteins, IMMOBILIZED proteins, BLOOD proteins, AMINO acid residues
Abstract

Summary: Objective: Variants in human PRRT2 cause paroxysmal kinesigenic dyskinesia (PKD) and other neurological disorders. Most reported variants resulting in truncating proteins failed to localize to cytoplasmic membrane. The present study identifies novel PRRT2 variants in PKD and epilepsy patients and evaluates the functional consequences of PRRT2 missense variations. Methods: We investigated two families with PKD and epilepsies using Sanger sequencing and a multiple gene panel. Subcellular localization of mutant proteins was investigated using confocal microscopy and cell surface biotinylation assay in Prrt2‐transfected cells. Results: Two novel PRRT2 variants, p.His232Glnfs*10 and p.Leu298Pro, were identified, and functional study revealed impaired localization of both mutant proteins to the plasma membrane. Further investigation of other reported missense variants revealed decreased protein targeting to the plasma membrane in eight of the 13 missense variants examined (p.Trp281Arg, p.Ala287Thr, p.Ala291Val, p.Arg295Gln, p.Leu298Pro, p.Ala306Asp, p.Gly324Glu, and p.Gly324Arg). In contrast, all benign variants we tested exhibited predominant localization to the plasma membrane similar to wild‐type Prrt2. Most likely pathogenic variants were located at conserved amino acid residues near the C‐terminus, whereas truncating variants spread throughout the gene. Significance: PRRT2 missense variants clustering at the C‐terminus often lead to protein mislocalization. Failure in protein targeting to the plasma membrane by PRRT2 variants may be a key mechanism in causing PKD and related neurological disorders. [ABSTRACT FROM AUTHOR]

Published
2019
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23. Exome sequencing identifies a significant variant in methionyl-tRNA synthetase (MARS) in a family with late-onset CMT2

Author

Mary M. Reilly, Stephan Züchner, Fiorella Speziani, Heather M. McLaughlin, Henry Houlden, Liu Yo-Tsen, Min Guo, Michael A. Gonzalez, Anthony Antonellis, Xiang-Lei Yang, and Marios Hadjivassilious

Subjects
Male, congenital, hereditary, and neonatal diseases and abnormalities, DNA Mutational Analysis, Penetrance, Methionine-tRNA Ligase, Disease, Biology, Article, Charcot-Marie-Tooth Disease, Genetic variation, Humans, Exome, Gene, Sex Chromosome Aberrations, Exome sequencing, Aged, 80 and over, Chromosome Aberrations, Genetics, Chromosomes, Human, X, Genetic heterogeneity, Genetic Variation, Sequence Analysis, DNA, Phenotype, Pedigree, nervous system diseases, Psychiatry and Mental health, Surgery, Neurology (clinical)
Abstract

Charcot–Marie–Tooth (CMT) disease is a genetically heterogeneous condition with >50 genes now being identified. Thanks to new technological developments, namely, exome sequencing, the ability to identify additional rare genes in CMT has been drastically improved. Here we present data suggesting that MARS is a very rare novel cause of late-onset CMT2. This is supported by strong functional and evolutionary evidence, yet the absence of additional unrelated cases warrant future studies to substantiate this conclusion.

Published
2013
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24. Clinical and biophysical characterization of 19 GJB1 mutations

Author

Tsai, Pei‐Chien, primary, Yang, De‐Ming, additional, Liao, Yi‐Chu, additional, Chiu, Tai‐Yu, additional, Kuo, Hung‐Chou, additional, Su, Yu‐Ping, additional, Guo, Yuh‐Cherng, additional, Soong, Bing‐Wen, additional, Lin, Kon‐Ping, additional, Liu, Yo‐Tsen, additional, and Lee, Yi‐Chung, additional

Published
2016
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25. PRRT2 mutations lead to neuronal dysfunction and neurodevelopmental defects

Author

Liu, Yo-Tsen, primary, Nian, Fang-Shin, additional, Chou, Wan-Ju, additional, Tai, Chin-Yin, additional, Kwan, Shang-Yeong, additional, Chen, Chien, additional, Kuo, Pei-Wen, additional, Lin, Po-Hsi, additional, Chen, Chin-Yi, additional, Huang, Chia-Wei, additional, Lee, Yi-Chung, additional, Soong, Bing-Wen, additional, and Tsai, Jin-Wu, additional

Published
2016
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27. Defects of mutant DNMT1 are linked to a spectrum of neurological disorders

Author

UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, Baets, Jonathan, Duan, Xiaohui, Wu, Yanhong, Smith, Gordon, Seeley, William W., Mademan, Inès, McGrath, Nicole M., Beadell, Noah C., Khoury, Julie, Botuyan, Maria-Victoria, Mer, Georges, Worrell, Gregory A., Hojo, Kaori, DeLeon, Jessica, Laura, Matilde, Liu, Yo-Tsen, Senderek, Jan, Weis, Joachim, Van den Bergh, Peter, Merrill, Shana L., Reilly, Mary M., Houlden, Henry, Grossman, Murray, Scherer, Steven S., De Jonghe, Peter, Dyck, Peter J., Klein, Christopher J., UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, Baets, Jonathan, Duan, Xiaohui, Wu, Yanhong, Smith, Gordon, Seeley, William W., Mademan, Inès, McGrath, Nicole M., Beadell, Noah C., Khoury, Julie, Botuyan, Maria-Victoria, Mer, Georges, Worrell, Gregory A., Hojo, Kaori, DeLeon, Jessica, Laura, Matilde, Liu, Yo-Tsen, Senderek, Jan, Weis, Joachim, Van den Bergh, Peter, Merrill, Shana L., Reilly, Mary M., Houlden, Henry, Grossman, Murray, Scherer, Steven S., De Jonghe, Peter, Dyck, Peter J., and Klein, Christopher J.

Abstract

We report a broader than previously appreciated clinical spectrum for hereditary sensory and autonomic neuropathy type 1E (HSAN1E) and a potential pathogenic mechanism for DNA methyltransferase (DNMT1) mutations. The clinical presentations and genetic characteristics of nine newly identified HSAN1E kinships (45 affected subjects) were investigated. Five novel mutations of DNMT1 were discovered; p.C353F, p.T481P, p.P491L, p.Y524D and p.I531N, all within the target-sequence domain, and two mutations (p.T481P, p.P491L) arising de novo. Recently, HSAN1E has been suggested as an allelic disorder of autosomal dominant cerebellar ataxia, deafness and narcolepsy. Our results indicate that all the mutations causal for HSAN1E are located in the middle part or N-terminus end of the TS domain, whereas all the mutations causal for autosomal dominant cerebellar ataxia, deafness and narcolepsy are located in the C-terminus end of the TS domain. The impact of the seven causal mutations in this cohort was studied by cellular localization experiments. The binding efficiency of the mutant DNMT proteins at the replication foci and heterochromatin were evaluated. Phenotypic characterizations included electromyography, brain magnetic resonance and nuclear imaging, electroencephalography, sural nerve biopsies, sleep evaluation and neuropsychometric testing. The average survival of HSAN1E was 53.6 years. [standard deviation = 7.7, range 43-75 years], and mean onset age was 37.7 years. (standard deviation = 8.6, range 18-51 years). Expanded phenotypes include myoclonic seizures, auditory or visual hallucinations, and renal failure. Hypersomnia, rapid eye movement sleep disorder and/or narcolepsy were identified in 11 subjects. Global brain atrophy was found in 12 of 14 who had brain MRI. EEGs showed low frequency (delta waves) frontal-predominant abnormality in five of six patients. Marked variability in cognitive deficits was observed, but the majority of patients (89%) developed significa

Published
2015

28. Novel HSAN1 mutation in serine palmitoyltransferase resides at a putative phosphorylation site that is involved in regulating substrate specificity

Author

Ernst, Daniela, Murphy, Sinéad M, Sathiyanadan, Karthik, Wei, Yu, Othman, Alaa, Laurá, Matilde, Liu, Yo-Tsen, Penno, Anke, Blake, Julian, Donaghy, Michael, Houlden, Henry, Reilly, Mary M, Hornemann, Thorsten, Ernst, Daniela, Murphy, Sinéad M, Sathiyanadan, Karthik, Wei, Yu, Othman, Alaa, Laurá, Matilde, Liu, Yo-Tsen, Penno, Anke, Blake, Julian, Donaghy, Michael, Houlden, Henry, Reilly, Mary M, and Hornemann, Thorsten

Abstract

1-Deoxysphingolipids (1-deoxySL) are atypical sphingolipids that are formed by the enzyme serine palmitoyltransferase (SPT) due to a promiscuous use of L-alanine over its canonical substrate L-serine. Several mutations in SPT are associated with the hereditary sensory and autonomic neuropathy type I (HSAN1). The current hypothesis is that these mutations induce a permanent shift in the affinity from L-serine toward L-alanine which results in a pathologically increased 1-deoxySL formation in HSAN1 patients. Also, wild-type SPT forms 1-deoxySL under certain conditions, and elevated levels were found in individuals with the metabolic syndrome and diabetes. However, the molecular mechanisms which control the substrate shift of the wild-type enzyme are not understood. Here, we report a novel SPTLC2-S384F variant in two unrelated HSAN1 families. Affected patients showed elevated plasma 1-deoxySL levels and expression of the S384F mutant in HEK293 cells increased 1-deoxySL formation. Previously, S384 has been reported as one of the two (S384 and Y387) putative phosphorylation sites in SPTLC2. The phosphorylation of wild-type SPTLC2 was confirmed by isoelectric focusing. The impact of an S384 phosphorylation on SPT activity was tested by creating mutants mimicking either a constitutively phosphorylated (S384D, S384E) or non-phosphorylated (S384A, Y387F, Y387F+S384A) protein. The S384D but not the S384E variant was associated with increased 1-deoxySL formation. The other mutations had no influence on activity and substrate affinity. In summary, our data show that S384F is a novel mutation in HSAN1 and that the substrate specificity of wild-type SPT might by dynamically regulated by a phosphorylation at this position.

Published
2015

29. The frequency of spinocerebellar ataxia type 23 in a UK population

Author

Fawcett, Katherine Mehrabian, Mohadeseh Liu, Yo-Tsen Hamed, Sherifa Elahi, Elahe Revesz, Tamas Koutsis, Georgios and Herscheson, Joshua Schottlaender, Lucia Wardle, Mark and Morrison, Patrick J. Morris, Huw R. Giunti, Paola Wood, Nicholas Houlden, Henry

Subjects
congenital, hereditary, and neonatal diseases and abnormalities
Abstract

Spinocerebellar ataxias (SCA) are a genetically heterogeneous group of neurodegenerative diseases characterised by progressive cerebellar ataxia, dysarthria and oculomotor abnormalities. Recently the prodynorphin (PDYN) gene was identified as the cause of SCA23 in four Dutch families displaying progressive gait and limb ataxia. In this study we aimed to assess the frequency of PDYN gene defects and extend the phenotype of SCA23 patients in a UK ataxia series and also in patients from Greece, Egypt and India. We sequenced the coding and flanking intronic regions of the PDYN gene in a total of 852 ataxia patients, of which 356 were sporadic with no family history, 320 had a positive family history, and 176 probands had a positive family history and at least one family member had also been investigated. We also analysed 190 patients with multiple-system atrophy with cerebellar features (MSA-C), a phenocopy of SCA23. We identified a novel putative pathogenic heterozygous missense variant in the PDYN gene in an early onset SCA patient with an unknown family history. This variant was not present in 570 matched British controls. This is the first study to screen for SCA23 in UK patients and confirms that PDYN mutations are a very rare cause of spinocerebellar ataxia, accounting for 0.1 % of ataxia cases but perhaps with a higher frequency in pure cerebellar ataxia. Given the rarity of PDYN mutations, front-line diagnostic evaluation of UK familial and early onset pure spinocerebellar ataxia patients should focus on other known ataxia genes.

Published
2013

30. Characterization of CADASIL among the Han Chinese in Taiwan: Distinct Genotypic and Phenotypic Profiles

Author

Liao, Yi-Chu, primary, Hsiao, Cheng-Tsung, additional, Fuh, Jong-Ling, additional, Chern, Chang-Ming, additional, Lee, Wei-Ju, additional, Guo, Yuh-Cherng, additional, Wang, Shuu-Jiun, additional, Lee, I-Hui, additional, Liu, Yo-Tsen, additional, Wang, Yen-Feng, additional, Chang, Feng-Chi, additional, Chang, Ming-Hung, additional, Soong, Bing-Wen, additional, and Lee, Yi-Chung, additional

Published
2015
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32. PDXK mutations cause polyneuropathy responsive to pyridoxal 5′‐phosphate supplementation

Author

Chelban, Viorica, Wilson, Matthew P., Warman Chardon, Jodi, Vandrovcova, Jana, Zanetti, M. Natalia, Zamba‐Papanicolaou, Eleni, Efthymiou, Stephanie, Pope, Simon, Conte, Maria R., Abis, Giancarlo, Liu, Yo‐Tsen, Tribollet, Eloise, Haridy, Nourelhoda A., Botía, Juan A., Ryten, Mina, Nicolaou, Paschalis, Minaidou, Anna, Christodoulou, Kyproula, Kernohan, Kristin D., Eaton, Alison, Osmond, Matthew, Ito, Yoko, Bourque, Pierre, Jepson, James E. C., Bello, Oscar, Bremner, Fion, Cordivari, Carla, Reilly, Mary M., Foiani, Martha, Heslegrave, Amanda, Zetterberg, Henrik, Heales, Simon J. R., Wood, Nicholas W., Rothman, James E., Boycott, Kym M., Mills, Philippa B., Clayton, Peter T., Houlden, Henry, Kriouile, Yamna, Khorassani, Mohamed El, Aguennouz, Mhammed, Groppa, Stanislav, Marinova Karashova, Blagovesta, Van Maldergem, Lionel, Nachbauer, Wolfgang, Boesch, Sylvia, Arning, Larissa, Timmann, Dagmar, Cormand, Bru, Pérez‐Dueñas, Belen, Di Rosa, Gabriella, Goraya, Jatinder S., Sultan, Tipu, Mine, Jun, Avdjieva, Daniela, Kathom, Hadil, Tincheva, Radka, Banu, Selina, Pineda‐Marfa, Mercedes, Veggiotti, Pierangelo, Ferrari, Michel D., van den Maagdenberg, Arn M J M, Verrotti, Alberto, Marseglia, Giangluigi, Savasta, Salvatore, García‐Silva, Mayte, Ruiz, Alfons Macaya, Garavaglia, Barbara, Borgione, Eugenia, Portaro, Simona, Sanchez, Benigno Monteagudo, Boles, Richard, Papacostas, Savvas, Vikelis, Michail, Rothman, James, Giunti, Paola, Salpietro, Vincenzo, Oconnor, Emer, Kullmann, Dimitri, Kaiyrzhanov, Rauan, Sullivan, Roisin, Khan, Alaa Matooq, Yau, Wai Yan, Hostettler, Isabel, Papanicolaou, Eleni Zamba, Dardiotis, Efthymios, Maqbool, Shazia, Ibrahim, Shahnaz, Kirmani, Salman, Rana, Nuzhat Noureen, Atawneh, Osama, Lim, Shen‐Yang, Shaikh, Farooq, Koutsis, George, Breza, Marianthi, Mangano, Salvatore, Scuderi, Carmela, Morello, Giovanna, Stojkovic, Tanya, Torti, Erin, Zollo, Massimi, Heimer, Gali, Dauvilliers, Yves A., Striano, Pasquale, Al‐Khawaja, Issam, Al‐Mutairi, Fuad, Alkuraya, Fowzan S, Sherifa, Hamed, Rizig, Mie, Okubadejo, Njideka U., Ojo, Oluwadamilola O., Oshinaike, Olajumoke O., Wahab, Kolawole, Bello, Abiodun H., Abubakar, Sanni, Obiabo, Yahaya, Nwazor, Ernest, Ekenze, Oluchi, Williams, Uduak, Iyagba, Alagoma, Taiwo, Lolade, Komolafe, Morenikeji, Oguntunde, Olapeju, Pchelina, Sofya, Senkevich, Konstantin, Haridy, Nourelhoda, Shashkin, Chingiz, Zharkynbekova, Nazira, Koneyev, Kairgali, Manizha, Ganieva, Isrofilov, Maksud, Guliyeva, Ulviyya, Salayev, Kamran, Khachatryan, Samson, Rossi, Salvatore, Silvestri, Gabriella, Bourinaris, Thomas, Xiromerisiou, Georgia, Fidani, Liana, Spanaki, Cleanthe, Tucci, Arianna, University College London Hospitals (UCLH), Université d'Ottawa [Ontario] (uOttawa), King‘s College London, University College of London [London] (UCL), University of Cyprus [Nicosia], UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, Institute of Psychiatry, Psychology & Neuroscience, King's College London, National Yang Ming University (NYMU), Department of Information and Communications Engineering [Murcia], Universidad de Murcia, Guy's Hospital [London], Cyprus Institute of Neurology and Genetics, University of Ottawa [Ottawa], The Ottawa Hospital, University of British Columbia (UBC), Ottawa Hospital Research Institute [Ottawa] (OHRI), Institute of Neurology, Queen Square, London, Sahlgrenska University Hospital, Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health, Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Department of Human Genetics, Ruhr University Bochum (RUB), Universitat de Barcelona (UB), Department of Medical and Surgical Pediatrics, University Hospital, Fondazione, Departments of Human Genetics & Neurology, Leiden University Medical Center (LUMC), University of Laquila, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Yale University School of Medicine, Department of Microbiology, Università degli studi di Catania [Catania], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Gene Dx, Partenaires INRAE, Tel Aviv University Sackler School of Medicine [Tel Aviv, Israël], Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Universita degli studi di Genova, Fondazione 'Policlinico Universitario A. Gemelli' [Rome], UCL Institute of neurology, UCL Institute of Neurology, Chelban V., Wilson M.P., Warman Chardon J., Vandrovcova J., Zanetti M.N., Zamba-Papanicolaou E., Efthymiou S., Pope S., Conte M.R., Abis G., Liu Y.-T., Tribollet E., Haridy N.A., Botia J.A., Ryten M., Nicolaou P., Minaidou A., Christodoulou K., Kernohan K.D., Eaton A., Osmond M., Ito Y., Bourque P., Jepson J.E.C., Bello O., Bremner F., Cordivari C., Reilly M.M., Foiani M., Heslegrave A., Zetterberg H., Heales S.J.R., Wood N.W., Rothman J.E., Boycott K.M., Mills P.B., Clayton P.T., Houlden H., Kriouile Y., Khorassani M.E., Aguennouz M., Groppa S., Marinova Karashova B., Van Maldergem L., Nachbauer W., Boesch S., Arning L., Timmann D., Cormand B., Perez-Duenas B., Di Rosa G., Goraya J.S., Sultan T., Mine J., Avdjieva D., Kathom H., Tincheva R., Banu S., Pineda-Marfa M., Veggiotti P., Ferrari M.D., van den Maagdenberg A.M.J.M., Verrotti A., Marseglia G., Savasta S., Garcia-Silva M., Ruiz A.M., Garavaglia B., Borgione E., Portaro S., Sanchez B.M., Boles R., Papacostas S., Vikelis M., Rothman J., Giunti P., Salpietro V., Oconnor E., Kullmann D., Kaiyrzhanov R., Sullivan R., Khan A.M., Yau W.Y., Hostettler I., Papanicolaou E.Z., Dardiotis E., Maqbool S., Ibrahim S., Kirmani S., Rana N.N., Atawneh O., Lim S.-Y., Shaikh F., Koutsis G., Breza M., Mangano S., Scuderi C., Morello G., Stojkovic T., Torti E., Zollo M., Heimer G., Dauvilliers Y.A., Striano P., Al-Khawaja I., Al-Mutairi F., Alkuraya F.S., Sherifa H., Rizig M., Okubadejo N.U., Ojo O.O., Oshinaike O.O., Wahab K., Bello A.H., Abubakar S., Obiabo Y., Nwazor E., Ekenze O., Williams U., Iyagba A., Taiwo L., Komolafe M., Oguntunde O., Pchelina S., Senkevich K., Haridy N., Shashkin C., Zharkynbekova N., Koneyev K., Manizha G., Isrofilov M., Guliyeva U., Salayev K., Khachatryan S., Rossi S., Silvestri G., Bourinaris T., Xiromerisiou G., Fidani L., Spanaki C., and Tucci A.

Subjects
0301 basic medicine, Male, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, LOCAL TRANSLATION, Medizin, medicine.disease_cause, DISEASE, chemistry.chemical_compound, 0302 clinical medicine, polineuropathy, Cinètica enzimàtica, Gene Regulatory Networks, Pyridoxal phosphate, Child, Pyridoxal Kinase, Adenosine triphosphate (ATP), Research Articles, Aged, 80 and over, Mutation, Gene Regulatory Network, PLASMA, Autosomal recessive axonal polyneuropathy, Disease gene identification, Pyridoxal kinase, 3. Good health, Settore MED/26 - NEUROLOGIA, Neuropaties perifèriques, Treatment Outcome, Polyneuropathie, Neurology, Child, Preschool, Pyridoxal Phosphate, RELIABILITY, Vitamin B Complex, Female, Life Sciences & Biomedicine, Polyneuropathy, Human, Research Article, Adult, Adolescent, PDXK, Clinical Neurology, CHARCOT-MARIE-TOOTH, CHARCOT-MARIE-TOOTH, CMT NEUROPATHY SCORE, LOCAL TRANSLATION, DISEASE, RELIABILITY, MECHANISMS, DISCOVERY, FRAMEWORK, KINASE, PLASMA, MECHANISMS, 03 medical and health sciences, Polyneuropathies, Atrophy, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], KINASE, medicine, Humans, CMT NEUROPATHY SCORE, PDXK mutations, Pyridoxal, Dietary Supplement, Aged, Peripheral neuropathies, Science & Technology, [SCCO.NEUR]Cognitive science/Neuroscience, Enzyme kinetics, Neurosciences, FRAMEWORK, medicine.disease, Molecular biology, 030104 developmental biology, chemistry, DISCOVERY, Dietary Supplements, Neurosciences & Neurology, Neurology (clinical), Adenosine triphosphate, 030217 neurology & neurosurgery
Abstract

OBJECTIVE: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. METHODS: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. RESULTS: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5'-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. INTERPRETATION: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225-240. ispartof: ANNALS OF NEUROLOGY vol:86 issue:2 pages:225-240 ispartof: location:United States status: published

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33. Novel HSAN1 Mutation in Serine Palmitoyltransferase Resides at a Putative Phosphorylation Site That Is Involved in Regulating Substrate Specificity

Author

Ernst, Daniela, Murphy, Sinéad, Sathiyanadan, Karthik, Wei, Yu, Othman, Alaa, Laurá, Matilde, Liu, Yo-Tsen, Penno, Anke, Blake, Julian, Donaghy, Michael, Houlden, Henry, Reilly, Mary, Hornemann, Thorsten, Ernst, Daniela, Murphy, Sinéad, Sathiyanadan, Karthik, Wei, Yu, Othman, Alaa, Laurá, Matilde, Liu, Yo-Tsen, Penno, Anke, Blake, Julian, Donaghy, Michael, Houlden, Henry, Reilly, Mary, and Hornemann, Thorsten

Abstract

1-Deoxysphingolipids (1-deoxySL) are atypical sphingolipids that are formed by the enzyme serine palmitoyltransferase (SPT) due to a promiscuous use of l-alanine over its canonical substrate l-serine. Several mutations in SPT are associated with the hereditary sensory and autonomic neuropathy type I (HSAN1). The current hypothesis is that these mutations induce a permanent shift in the affinity from l-serine toward l-alanine which results in a pathologically increased 1-deoxySL formation in HSAN1 patients. Also, wild-type SPT forms 1-deoxySL under certain conditions, and elevated levels were found in individuals with the metabolic syndrome and diabetes. However, the molecular mechanisms which control the substrate shift of the wild-type enzyme are not understood. Here, we report a novel SPTLC2-S384F variant in two unrelated HSAN1 families. Affected patients showed elevated plasma 1-deoxySL levels and expression of the S384F mutant in HEK293 cells increased 1-deoxySL formation. Previously, S384 has been reported as one of the two (S384 and Y387) putative phosphorylation sites in SPTLC2. The phosphorylation of wild-type SPTLC2 was confirmed by isoelectric focusing. The impact of an S384 phosphorylation on SPT activity was tested by creating mutants mimicking either a constitutively phosphorylated (S384D, S384E) or non-phosphorylated (S384A, Y387F, Y387F+S384A) protein. The S384D but not the S384E variant was associated with increased 1-deoxySL formation. The other mutations had no influence on activity and substrate affinity. In summary, our data show that S384F is a novel mutation in HSAN1 and that the substrate specificity of wild-type SPT might by dynamically regulated by a phosphorylation at this position.

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