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1. Noninvasive Monitoring of Tissue Oxygenation and Redox Status in Humans.

Author

SAINT GEORGE'S HOSPITAL MEDICAL SCHOOL LONDON (UNITED KINGDOM) DEPT OF PHYSIOLOGY, Whipp, Brian J., SAINT GEORGE'S HOSPITAL MEDICAL SCHOOL LONDON (UNITED KINGDOM) DEPT OF PHYSIOLOGY, and Whipp, Brian J.

Abstract

This report results from a contract tasking St. George's Medical School to investigate a cluster of reliable noninvasive techniques for the tracking of improvements in oxygen delivery, oxygen availability and oxygen usage within and in the vicinity of sites of injury. The investigator evaluated a range of state-of-the-art commercially available techniques designed to monitor the status of tissue hemodynamics and energetics in humans, both within and upstream of selected locations, such as the limbs and the brain. The techniques included near infrared spectroscopy and Doppler based ultrasound monitoring of regional blood velocities and flows.

Published
1997

2. Noninvasive Monitoring of Tissue Oxygenation and Redox Status in Humans.

Author

SAINT GEORGE'S HOSPITAL MEDICAL SCHOOL LONDON (UNITED KINGDOM) DEPT OF PHYSIO LOGY, Whipp, Brian J., SAINT GEORGE'S HOSPITAL MEDICAL SCHOOL LONDON (UNITED KINGDOM) DEPT OF PHYSIO LOGY, and Whipp, Brian J.

Abstract

This report results from a contract tasking St. George's Medical School as follows: The contractor will investigate a cluster of reliable noninvasive techniques for the tracking of improvements in oxygen delivery, oxygen availability and oxygen usage within and in the vicinity of sites of injury. The investigator evaluates a range of state-of-the-art commercially available techniques designed to monitor the status of tissue hemodynamics and energetics in humans, both within and upstream of selected locations, such as the limbs and the brain. Techniques will include near infrared spectroscopy and doppler based ultrasound monitoring of regional blood velocities and flows.

Published
1997

3. The Physiologic Basis of Muscular Fatigue, Pathophysiology of Exercise Intolerance, and Enhancing Exercise Tolerance in Health.

Author

SAINT GEORGE'S HOSPITAL MEDICAL SCHOOL LONDON (UNITED KINGDOM) DEPT OF PHYSIO LOGY, Steinacker, Juergen M., Ward, Susan A., SAINT GEORGE'S HOSPITAL MEDICAL SCHOOL LONDON (UNITED KINGDOM) DEPT OF PHYSIO LOGY, Steinacker, Juergen M., and Ward, Susan A.

Abstract

The Final Proceedings for The Physiology and Pathophysiology of Exercise Tolerance, 21 September 1994- 24 September 1994. The Topics covered include: the physiologic basis of muscular fatigue, pathophysiology of exercise intolerance, and enhancing exercise tolerance in health.

Published
1994

4. Analysis of X chromosome inactivation in autism spectrum disorders

Author

Christopher Gillberg, Francesca Blasi, Claudio Toma, Mari Rossi, Henrik Anckarsäter, Irma Järvelä, Agatino Battaglia, Maria Råstam, Elena Maestrini, Richard Delorme, Simona Carone, Catalina Betancur, Hany Goubran Botros, Xiaohong Gong, Elena Bacchelli, I. Carina Gillberg, Marie Christine Mouren-Simeoni, Fabien Fauchereau, Pauline Chaste, Marion Leboyer, Christelle M. Durand, Ilona Nummela, Gudrun Nygren, Thomas Bourgeron, Daniel Moreno-De-Luca, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Medical Genetics Laboratory, Policlinico S. Orsola-Malpighi, Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Department of Child and Adolescent Psychiatry, University of Gothenburg (GU), Saint George's Hospital Medical School, Department of Medical Genetics, Department of Psychiatry and Behavioral Sciences [Stanford], Stanford Medicine, Stanford University-Stanford University, Laboratory of Molecular Genetics, Helsinki University Hospital, This work was supported by the Pasteur Institute, INSERM, Assistance Publique-Hôpitaux de Paris, FP6 AUTISM MOLGEN, FP6 ENI-NET, Fondation France Télécom, Fondation de France, Fondation biomédicale de la Mairie de Paris, Fondation pour la Recherche Médicale, the Swedish Science Council, Telethon-Italy (GP030227), the Academy of Finland, and Helsinki University Hospital Research Funding. The International Molecular Genetic Study of Autism Consortium thanks the UK Medical Research Council, Wellcome Trust, BIOMED 2 (CT-97-2759), EC Fifth Framework (QLG2-CT-1999-0094), Janus Korczak Foundation, Deutsche Forschungsgemeinschaft, Conseil Regional Midi-Pyrenees, Danish Medical Research Council, Sofiefonden, Beatrice Surovell Haskells Fond for Child Mental Health Research of Copenhagen, Danish Natural Science Research Council (9802210) and the US National Institutes of Health (U19 HD35482, MO1 RR06022, K05 MH01196, K02 MH01389)., Paris Autism Research International Sib-pair (PARIS) study, International Molecular Genetic Study of Autism Consortium (IMGSAC), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Betancur, Catalina, Gong X, Bacchelli E, Blasi F, Toma C, Betancur C, Chaste P, Delorme R, Durand CM, Fauchereau F, Botros HG, Leboyer M, Mouren-Simeoni MC, Nygren G, Anckarsäter H, Rastam M, Gillberg IC, Gillberg C, Moreno-De-Luca D, Carone S, Nummela I, Rossi M, Battaglia A, Jarvela I, Maestrini E, and Bourgeron T.

Subjects
Adult, Candidate gene, Adolescent, DNA Mutational Analysis, Mothers, [SDV.GEN] Life Sciences [q-bio]/Genetics, Gene mutation, Biology, Article, X-inactivation, MECP2, Cohort Studies, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, X Chromosome Inactivation, Genetic linkage, medicine, Humans, Genetic Predisposition to Disease, Child, Skewed X-inactivation, linkage study, Genetics (clinical), X chromosome, 030304 developmental biology, Genetics, Chromosomes, Human, X, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, Middle Aged, X-linked mutation, medicine.disease, Developmental disorder, Psychiatry and Mental health, Case-Control Studies, Child, Preschool, Female, autistic disorder, skewed X-inactivation, 030217 neurology & neurosurgery
Abstract

International audience; Autism spectrum disorders (ASD) are complex genetic disorders more frequently observed in males. Skewed X chromosome inactivation (XCI) is observed in heterozygous females carrying gene mutations involved in several X-linked syndromes. In this study, we aimed to estimate the role of X-linked genes in ASD susceptibility by ascertaining the XCI pattern in a sample of 543 informative mothers of children with ASD and in a sample of 163 affected girls. The XCI pattern was also determined in two control groups (144 adult females and 40 young females) with a similar age distribution to the mothers sample and affected girls sample, respectively. We observed no significant excess of skewed XCI in families with ASD. Interestingly, two mothers and one girl carrying known mutations in X-linked genes (NLGN3, ATRX, MECP2) showed highly skewed XCI, suggesting that ascertainment of XCI could reveal families with X-linked mutations. Linkage analysis was carried out in the subgroup of multiplex families with skewed XCI (> or = 80:20) and a modest increased allele sharing was obtained in the Xq27-Xq28 region, with a peak Z-score of 1.75 close to rs719489. In summary, our results suggest that there is no major X-linked gene subject to XCI and expressed in blood cells conferring susceptibility to ASD. However, the possibility that rare mutations in X-linked genes could contribute to ASD cannot be excluded. We propose that the XCI profile could be a useful criteria to prioritize families for mutation screening of X-linked candidate genes.

Published
2008

5. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders

Author

Maria Råstam, I. Carina Gillberg, Eric Bieth, Marion Leboyer, Nadia Chabane, Fabien Fauchereau, Catalina Betancur, Christopher Gillberg, Delphine Héron, Tobias M. Boeckers, Gudrun Nygren, Hany Goubran-Botros, Marie-Christine Mouren-Simeoni, Philippe de Mas, Christelle M. Durand, Pauline Chaste, Richard Delorme, Eili Sponheim, Bernadette Rogé, Henrik Anckarsäter, Juergen Bockmann, Thomas Bourgeron, Lydie Burglen, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Anatomy and Cell Biology, Universität Ulm - Ulm University [Ulm, Allemagne], Université Paris Diderot - Paris 7 (UPD7), Department of Child and Adolescent Psychiatry, University of Gothenburg (GU), Centre for Child and Adolescent Psychiatry, University of Oslo (UiO), Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Department of Medical Genetics, Centre d'Etudes et de Recherches en PsychoPathologie, Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Saint George's Hospital Medical School, Département de Psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Albert Chenevier, This work was supported by the Pasteur Institute, INSERM, Assistance Publique-Hôpitaux de Paris, Fondation France Telecom, Cure Autism Now, Fondation de France, Fondation Biomédicale de la Mairie de Paris, Fondation pour la Recherche Médicale, EUSynapse European Commission FP6, AUTISM MOLGEN European Commission FP6, Fondation NRJ, the Swedish Science Council and the Deutsche Forschungsgemeinschaft DFG, SFB 497., Betancur, Catalina, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique et embryologie médicales [CHU Trousseau], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Hôpital Purpan [Toulouse], and CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]

Subjects
Male, DNA Mutational Analysis, Molecular Sequence Data, Nerve Tissue Proteins, Epigenetics of autism, 22q13 deletion syndrome, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Article, SHANK3 Gene, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Heritability of autism, Genetic Testing, Autistic Disorder, In Situ Hybridization, Fluorescence, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, Base Sequence, medicine.disease, Pedigree, Developmental disorder, Asperger syndrome, Mutation, EIF4EBP2, Autism, Female, Carrier Proteins, 030217 neurology & neurosurgery
Abstract

International audience; SHANK3 (also known as ProSAP2) regulates the structural organization of dendritic spines and is a binding partner of neuroligins; genes encoding neuroligins are mutated in autism and Asperger syndrome. Here, we report that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders. These mutations concern only a small number of individuals, but they shed light on one gene dosage-sensitive synaptic pathway that is involved in autism spectrum disorders.

Published
2006

6. Increased Rate of Twins among Affected Sibling Pairs with Autism

Author

Marion Leboyer, Catalina Betancur, Christopher Gillberg, Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Albert Chenevier, Department of Child and Adolescent Psychiatry, University of Gothenburg (GU), Saint George's Hospital Medical School, Paris Autism Research International Sibpair (PARIS) study, and Betancur, Catalina

Subjects
Concordance, Population, MESH: Autistic Disorder, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, 03 medical and health sciences, MESH: Selection Bias, 0302 clinical medicine, medicine, Genetics, Genetics(clinical), 10. No inequality, education, Letter to the Editor, MESH: Cohort Studies, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, MESH: Sample Size, 030304 developmental biology, Pervasive developmental disorder not otherwise specified, 0303 health sciences, education.field_of_study, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Twins, Heritability, medicine.disease, Zygosity, 3. Good health, Fragile X syndrome, Asperger syndrome, Autism, MESH: Diseases in Twins, 030217 neurology & neurosurgery, Demography
Abstract

To the Editor: There is consistent evidence from twin and family studies implicating genetic factors in the etiology of autism (MIM 209850), but no specific genes associated with autism have yet been identified. In a recent article in the Journal, Greenberg et al. (2001) reported a striking excess of twin pairs, both MZ and DZ, in the cohort of families with at least two siblings with autism or autism-related conditions recruited by the Autism Resource Exchange (AGRE) of the Cure Autism Now (CAN) Foundation. The proportion of twins among autistic sib pairs (18%, 30/166) was significantly higher than the expected twinning rate per sib pair (2.4%). Greenberg et al. (2001) demonstrated that to ascribe this excess of twins with autism to a sampling bias would require very large ascertainment factors, which seem unlikely. These findings suggest that being a twin represents a risk factor for autism, and they have important implications for the etiology of autism. However, as Greenberg et al. (2001) pointed out, these results need to be replicated in other data sets. We report here a similar excess of twins in a sample of affected sib pairs recruited by the Paris Autism Research International Sibpair (PARIS) study. Families with two or more children with autism or autism-related disorders (Asperger syndrome or pervasive developmental disorder not otherwise specified [PDD NOS]) were recruited by the PARIS study at specialized clinical centers in eight countries (Austria, Belgium, France, Israel, Italy, Norway, Sweden, and the United States). Patients were included after undergoing a complete clinical and neuropsychological assessment described elsewhere (Philippe et al. 1999); subjects demonstrated to suffer from organic conditions associated with autism, such as tuberous sclerosis, fragile X syndrome, or other established chromosomal disorders, were excluded from the study. We divided the affected sib pairs into two diagnostic categories: “narrow,” when both affected sibs had autism, and “broad,” when one or both of the affected sibs had either Asperger syndrome or PDD NOS. Patients in the narrow diagnostic category fulfilled the DSM-IV and ICD-10 criteria for autistic disorder/childhood autism and met the Autism Diagnostic Interview–Revised algorithm (Lord et al. 1994). All the families were white except one of mixed ethnicity (white/Asian). To make our results directly comparable to those obtained by Greenberg et al. (2001), in the current analysis we included only families having exactly two affected offspring; families with triplets or with an affected twin pair and one or more affected nontwin siblings were excluded. We also excluded families with mixed twin pairs (one affected twin, one unaffected co-twin, and a nontwin affected sib) and families with half siblings. Table 1 shows the distribution of affected sib pairs divided according to diagnostic category, twin status, and sex. Table 2 shows the observed proportion of twins in our data set compared both with the population rates reported by Greenberg et al. (2001) and with the rate observed in the AGRE families. In agreement with the results of Greenberg et al. (2001), we observed a remarkably high proportion of MZ twin pairs among affected sib pairs. Of 79 affected sib pairs (narrow + broad diagnoses), 11 were twin pairs (2 DZ and 9 MZ). This represents a 14-fold increase for MZ twins, compared with the population frequency, and is statistically significant (P

Published
2002
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7. Mutation screening of NOS1AP gene in a large sample of psychiatric patients and controls

Author

Isabelle Scheid, Stéphane Jamain, Catalina Betancur, Marion Leboyer, Evelyn Herbrecht, Henrik Anckarsäter, Anne Dumaine, Richard Delorme, Christopher Gillberg, Maria Råstam, Pauline Chaste, Gudrun Nygren, Franck Schuroff, Thomas Bourgeron, Marie Christine Mouren, Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Child and Adolescent Psychiatry, University of Gothenburg (GU), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Saint George's Hospital Medical School, Université Paris Diderot - Paris 7 (UPD7), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, and Guellaen, Georges

Subjects
Male, Obsessive-Compulsive Disorder, MESH: Amino Acid Sequence, MESH: Protein Isoforms, Bioinformatics, medicine.disease_cause, MESH: Child Development Disorders, Pervasive, MESH: Genotype, 0302 clinical medicine, Gene Frequency, NOS1AP, MESH: Child, Genotype, Protein Isoforms, Genetics(clinical), Child, Genetics (clinical), Genetics, MESH: Aged, 0303 health sciences, Mutation, MESH: Middle Aged, Middle Aged, MESH: Amino Acid Substitution, 3. Good health, Pedigree, Schizophrenia, Female, Research Article, Adult, medicine.medical_specialty, lcsh:Internal medicine, MESH: Mutation, lcsh:QH426-470, MESH: Pedigree, Molecular Sequence Data, Biology, behavioral disciplines and activities, 03 medical and health sciences, mental disorders, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, MESH: Gene Frequency, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Allele, Psychiatry, lcsh:RC31-1245, Allele frequency, Alleles, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Aged, MESH: Adaptor Proteins, Signal Transducing, MESH: Obsessive-Compulsive Disorder, MESH: Humans, MESH: Molecular Sequence Data, MESH: Alleles, MESH: Adult, medicine.disease, Human genetics, MESH: Male, MESH: Schizophrenia, lcsh:Genetics, Amino Acid Substitution, Child Development Disorders, Pervasive, Autism, MESH: Female, 030217 neurology & neurosurgery
Abstract

Background The gene encoding carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase (NOS1AP) is located on chromosome 1q23.3, a candidate region for schizophrenia, autism spectrum disorders (ASD) and obsessive-compulsive disorder (OCD). Previous genetic and functional studies explored the role of NOS1AP in these psychiatric conditions, but only a limited number explored the sequence variability of NOS1AP. Methods We analyzed the coding sequence of NOS1AP in a large population (n = 280), including patients with schizophrenia (n = 72), ASD (n = 81) or OCD (n = 34), and in healthy volunteers controlled for the absence of personal or familial history of psychiatric disorders (n = 93). Results Two non-synonymous variations, V37I and D423N were identified in two families, one with two siblings with OCD and the other with two brothers with ASD. These rare variations apparently segregate with the presence of psychiatric conditions. Conclusions Coding variations of NOS1AP are relatively rare in patients and controls. Nevertheless, we report the first non-synonymous variations within the human NOS1AP gene that warrant further genetic and functional investigations to ascertain their roles in the susceptibility to psychiatric disorders.

Published
2010

8. Abnormal melatonin synthesis in autism spectrum disorders

Author

Christopher Gillberg, Henrik Anckarsäter, Richard Delorme, Thomas Bourgeron, X Drouot, J.M. Launay, I. C. Gillberg, H Goubran Botros, Maria Råstam, Jonas Melke, Gudrun Nygren, Nadia Chabane, M-C Mouren-Simeoni, Pauline Chaste, F Chevalier, Catalina Betancur, Marion Leboyer, Ola Ståhlberg, Fabien Fauchereau, Christelle M. Durand, Corinne Collet, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Child and Adolescent Psychiatry, University of Gothenburg (GU), Institute of Clinical Sciences, Lund University [Lund], Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de physiologie, explorations fonctionnelles [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de Biochimie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-EA3621, Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Saint George's Hospital Medical School, Université Paris Diderot - Paris 7 (UPD7), This work was supported by the Pasteur Institute, INSERM, Assistance Publique-Hôpitaux de Paris, Fondation France Télécom, Cure Autism Now, Fondation de France, Fondation biomédicale de la Mairie de Paris, Fondation pour la Recherche Médicale, Fondation NRJ and the Swedish Medical Research Council., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Betancur, Catalina

Subjects
Male, melatonin, [SDV.GEN] Life Sciences [q-bio]/Genetics, Pineal gland, Exon, 0302 clinical medicine, Reference Values, Child, Promoter Regions, Genetic, Genetics, 0303 health sciences, Middle Aged, HIOMT, Pedigree, Psychiatry and Mental health, medicine.anatomical_structure, Female, medicine.drug, Acetylserotonin O-Methyltransferase, Adult, circadian rhythm, medicine.medical_specialty, Adolescent, Matched-Pair Analysis, autism, Biology, Article, Melatonin, 03 medical and health sciences, Cellular and Molecular Neuroscience, ASMT, Internal medicine, mental disorders, medicine, Humans, Circadian rhythm, Autistic Disorder, Allele, sleep, Molecular Biology, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Polymorphism, Genetic, medicine.disease, Developmental disorder, Endocrinology, Acetylserotonin O-methyltransferase, Case-Control Studies, Autism, 030217 neurology & neurosurgery
Abstract

International audience; Melatonin is produced in the dark by the pineal gland and is a key regulator of circadian and seasonal rhythms. A low melatonin level has been reported in individuals with autism spectrum disorders (ASD), but the underlying cause of this deficit was unknown. The ASMT gene, encoding the last enzyme of melatonin synthesis, is located on the pseudo-autosomal region 1 of the sex chromosomes, deleted in several individuals with ASD. In this study, we sequenced all ASMT exons and promoters in individuals with ASD (n=250) and compared the allelic frequencies with controls (n=255). Non-conservative variations of ASMT were identified, including a splicing mutation present in two families with ASD, but not in controls. Two polymorphisms located in the promoter (rs4446909 and rs5989681) were more frequent in ASD compared to controls (P=0.0006) and were associated with a dramatic decrease in ASMT transcripts in blood cell lines (P=2 x 10(-10)). Biochemical analyses performed on blood platelets and/or cultured cells revealed a highly significant decrease in ASMT activity (P=2 x 10(-12)) and melatonin level (P=3 x 10(-11)) in individuals with ASD. These results indicate that a low melatonin level, caused by a primary deficit in ASMT activity, is a risk factor for ASD. They also support ASMT as a susceptibility gene for ASD and highlight the crucial role of melatonin in human cognition and behavior.Molecular Psychiatry (2008) 13, 90-98; doi:10.1038/sj.mp.4002016; published online 15 May 2007.

Published
2008

9. Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly

Author

Eric Hollander, Pauline Chaste, Marion Leboyer, Gudrun Nygren, Maria Råstam, Juliet Goldsmith, Henrik Anckarsäter, Jennifer Reichert, Guiqing Cai, Joseph D. Buxbaum, Christopher J. Smith, Alain Verloes, Catalina Betancur, Christopher Gillberg, Jeremy M. Silverman, Laboratory of Molecular Neuropsychiatry, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Department of Child and Adolescent Psychiatry, University of Gothenburg (GU), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Saint George's Hospital Medical School, Unité fonctionnelle de génétique clinique, This research was supported by the Seaver Autism Research Center, NIH (grants MH066673 and NS-042165), INSERM, Assistance Publique-Hôpitaux de Paris, Fondation pour la Recherche Médicale, Fondation France Télécom, Fondation de France, and the Swedish Science Council., Paris Autism Research International Sibpair (PARIS) study, Autism Genetic Resource Exchange (AGRE), and Betancur, Catalina

Subjects
Male, Bannayan-Riley-Ruvalcaba syndrome, sequence analysis, DNA Mutational Analysis, [SDV.GEN] Life Sciences [q-bio]/Genetics, Craniofacial Abnormalities, 0302 clinical medicine, Bannayan–Riley–Ruvalcaba syndrome, Missense mutation, Child, multiplex ligation-dependent probe amplification, Genetics (clinical), Genetics, 0303 health sciences, Polydactyly, Cowden syndrome, Exons, Syndrome, polydactyly, 3. Good health, Psychiatry and Mental health, Child, Preschool, Female, Asparagine, medicine.symptom, Adult, Adolescent, Molecular Sequence Data, Biology, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, medicine, Humans, PTEN, Abnormalities, Multiple, Amino Acid Sequence, Genetic Testing, Multiplex ligation-dependent probe amplification, Autistic Disorder, 030304 developmental biology, Aspartic Acid, [SDV.GEN]Life Sciences [q-bio]/Genetics, PTEN Phosphohydrolase, Macrocephaly, medicine.disease, Introns, Developmental disorder, Mutation, biology.protein, 030217 neurology & neurosurgery
Abstract

Mutations in the PTEN gene are associated with a broad spectrum of disorders, including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Lhermitte-Duclos disease. In addition, PTEN mutations have been described in a few patients with autism spectrum disorders (ASDs) and macrocephaly. In this study, we screened the PTEN gene for mutations and deletions in 88 patients with ASDs and macrocephaly (defined as >/=2 SD above the mean). Mutation analysis was performed by direct sequencing of all exons and flanking regions, as well as the promoter region. Dosage analysis of PTEN was carried out using multiplex ligation-dependent probe amplification (MLPA). No partial or whole gene deletions were observed. We identified a de novo missense mutation (D326N) in a highly conserved amino acid in a 5-year-old boy with autism, mental retardation, language delay, extreme macrocephaly (+9.6 SD) and polydactyly of both feet. Polydactyly has previously been described in two patients with Lhermitte-Duclos disease and CS and is thus likely to be a rare sign of PTEN mutations. Our findings suggest that PTEN mutations are a relatively infrequent cause of ASDs with macrocephaly. Screening of PTEN mutations is warranted in patients with autism and pronounced macrocephaly, even in the absence of other features of PTEN-related tumor syndromes. (c) 2007 Wiley-Liss, Inc.

Published
2007

10. Mutation screening of the ARX gene in patients with autism

Author

Henrik Anckarsäter, Maria Råstam, Catalina Betancur, Mary Coleman, Pauline Chaste, Christopher Gillberg, Marion Leboyer, Gudrun Nygren, Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Department of Child and Adolescent Psychiatry, University of Gothenburg (GU), Department of Pediatrics, Georgetown University School of Medicine, Département de Psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Albert Chenevier, Saint George's Hospital Medical School, This research was supported by Fondation Jérôme Lejeune, INSERM, Assistance Publique-Hôpitaux de Paris, Fondation pour la Recherche Médicale, Fondation France Télécom, Fondation de France, and the Swedish Medical Research Council., Paris Autism Research International Sibpair (PARIS) study, and Betancur, Catalina

Subjects
Male, DNA Mutational Analysis, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, mental retardation, Article, X chromosome, 03 medical and health sciences, Cellular and Molecular Neuroscience, Epilepsy, Exon, 0302 clinical medicine, medicine, Humans, Genetic Testing, Autistic Disorder, education, Genetics (clinical), 030304 developmental biology, Genetic testing, Genetics, Homeodomain Proteins, 0303 health sciences, Mutation, education.field_of_study, [SDV.GEN]Life Sciences [q-bio]/Genetics, medicine.diagnostic_test, business.industry, medicine.disease, Developmental disorder, Psychiatry and Mental health, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Aristaless related homeobox, Autism, epilepsy, Female, business, 030217 neurology & neurosurgery, Transcription Factors
Abstract

International audience; Mutations in the Aristaless related homeobox (ARX) gene are associated with a broad spectrum of disorders, including nonsyndromic X-linked mental retardation, sometimes associated with epilepsy, as well as syndromic forms with brain abnormalities and abnormal genitalia. Furthermore, ARX mutations have been described in a few patients with autism or autistic features. In this study, we screened the ARX gene in 226 male patients with autism spectrum disorders and mental retardation; 42 of the patients had epilepsy. The mutation analysis was performed by direct sequencing of all exons and flanking regions. No ARX mutations were identified in any of the patients tested. These findings indicate that mutations in the ARX gene are very rare in autism. (c) 2006 Wiley-Liss, Inc.

Published
2007

11. Expression and genetic variability of PCDH11Y, a gene specific to Homo sapiens and candidate for susceptibility to psychiatric disorders

Author

Hany Goubran-Botros, Richard Delorme, Christopher Gillberg, Henrik Anckarsäter, Caroline Kappeler, Maria Råstam, Franck Bellivier, Christelle M. Durand, Franck Schürhoff, Nadia Chabane, Hélène Quach, Jonas Melke, Andrei Szöke, Marion Leboyer, Catalina Betancur, Thomas Bourgeron, Gudrun Nygren, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Child and Adolescent Psychiatry, University of Gothenburg (GU), Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Département de Psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Albert Chenevier, Department of Psychiatry, Saint George's Hospital Medical School, Université Paris Diderot - Paris 7 (UPD7), This work was funded by the Pasteur Institute, INSERM (Institut National de la Santé et la Recherche Médicale), Assistance Publique Hopitaux de Paris, Fondation France Télécom, Fondation de France, Cure Autism Now, Fondation NRJ and the Swedish Medical Research Council., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Betancur, Catalina

Subjects
Male, Bipolar Disorder, MESH: Menta, DNA Mutational Analysis, Gene Expression, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Amino Acid Sequence, MESH: Cadherins, 0302 clinical medicine, Gene Frequency, MESH: Bipolar Disorder, MESH: DNA Mutational Analysis, Genetics (clinical), PCDH11X, Genetics, 0303 health sciences, synaptogenesis, Reverse Transcriptase Polymerase Chain Reaction, Mental Disorders, MESH: Genetic Predisposition to Disease, Brain, Cadherins, obsessive-compulsive disorder, Psychiatry and Mental health, Schizophrenia, France, MESH: Gene Expression, Molecular Sequence Data, MESH: Autistic Disorder, Mutation, Missense, Protocadherin, autism, MESH: Attention Deficit Disorder with Hyperactivity, Biology, Y chromosome, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, MESH: Brain, medicine, MESH: Gene Frequency, Humans, Genetic Predisposition to Disease, Genetic variability, Bipolar disorder, Amino Acid Sequence, Autistic Disorder, Gene, 030304 developmental biology, Sweden, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Polymorphism, Genetic, Sequence Homology, Amino Acid, MESH: Haplotypes, medicine.disease, MESH: Male, Protocadherins, schizophrenia, MESH: France, Haplotypes, Attention Deficit Disorder with Hyperactivity, Mutation, Autism, RNA, 030217 neurology & neurosurgery
Abstract

International audience; Synaptogenesis, the formation of functional synapses, is a crucial step for the development of the central nervous system. Among the genes involved in this process are cell adhesion molecules, such as protocadherins and neuroligins, which are essential factors for the identification of the appropriate partner cell and the formation of synapses. In this work, we studied the expression and the genetic variability of two closely related members of the protocadherin family PCDH11X/Y, located on the X and the Y chromosome, respectively. PCDH11Y is one of the rare genes specific to the hominoid lineage, being absent in other primates. Expression analysis indicated that transcripts of the PCDH11X/Y genes are mainly detected in the cortex of the human brain. Mutation screening of 30 individuals with autism identified two PCDH11Y polymorphic amino acid changes, F885V and K980N. These variations are in complete association, appeared during human evolution approximately 40,000 years ago and represent informative polymorphisms to study Y chromosome variability in populations. We studied the frequency of these variants in males with autism spectrum disorders (n = 110), attention deficit hyperactivity disorder (ADHD; n = 61), bipolar disorder (n = 61), obsessive-compulsive disorder (n = 51), or schizophrenia (n = 61) and observed no significant differences when compared to ethnically-matched control populations. These findings do not support the role of PCDH11Y, or more generally of a frequent specific Y chromosome, in the susceptibility to these neuropsychiatric disorders.

Published
2005

12. Support for the association between the rare functional variant I425V of the serotonin transporter gene and susceptibility to obsessive compulsive disorder

Author

P. Pickering, Christopher Gillberg, Marie-Christine Mouren-Simeoni, Claudia Reck, Richard Delorme, Michael Wagner, Isabelle Roy, Philip Gorwood, Nadia Chabane, Catalina Betancur, Marie-Odile Krebs, Gudrun Nygren, Bruno Millet, Thomas Bourgeron, Friederike Buhtz, Phillip L. Pearl, Marion Leboyer, Jonas Melke, Henrik Anckarsäter, Christelle M. Durand, Stephan Ruhrmann, Amélie Kipman, Wolfgang Maier, Maria Råstam, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Department of Psychiatry, Rheinische Friedrich-Wilhelms-Universität Bonn, Physiopathologie des Maladies Psychiatriques, Développement et Vulnérabilité, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Analyse Phenotypique, Developpementale et Genetique des Comportements Addictifs, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Children's National Medical Center, The George Washington University (GW), Department of Child and Adolescent Psychiatry, University of Gothenburg (GU), University of Greifwald, Department of Psychiatry and Psychotherapy, University of Cologne, Département de Psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Albert Chenevier, Saint George's Hospital Medical School, Université Paris Diderot - Paris 7 (UPD7), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Bonn Universität [Bonn], Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), George Washington University ( GW ), University of Gothenburg ( GU ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Albert Chenevier, Université Paris Diderot - Paris 7 ( UPD7 ), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Betancur, Catalina

Subjects
Male, Proband, Obsessive-Compulsive Disorder, Anorexia Nervosa, MESH : Polymorphism, Genetic, Drug Resistance, Alcohol abuse, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Child Development Disorders, Pervasive, 0302 clinical medicine, MESH : Child, Reference Values, MESH: Child, MESH : Obsessive-Compulsive Disorder, MESH : Female, Family history, Child, Serotonin transporter, ComputingMilieux_MISCELLANEOUS, Serotonin Plasma Membrane Transport Proteins, 0303 health sciences, MESH: Middle Aged, biology, MESH: Genetic Predisposition to Disease, Middle Aged, MESH : Adult, Pedigree, 3. Good health, Alcoholism, Psychiatry and Mental health, Anorexia nervosa (differential diagnoses), MESH : Anorexia Nervosa, MESH: Drug Resistance, Female, Psychology, MESH: Anorexia Nervosa, Selective Serotonin Reuptake Inhibitors, Clinical psychology, Adult, medicine.medical_specialty, Adolescent, MESH: Pedigree, MESH : Male, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, MESH: Alcoholism, MESH : Adolescent, mental disorders, MESH: Polymorphism, Genetic, Pervasive developmental disorder, medicine, Humans, MESH : Child Development Disorders, Pervasive, Family, Genetic Predisposition to Disease, MESH : Middle Aged, Rare functional variant, Psychiatry, Molecular Biology, MESH: Family, 030304 developmental biology, MESH: Adolescent, MESH: Obsessive-Compulsive Disorder, MESH : Drug Resistance, [SDV.GEN]Life Sciences [q-bio]/Genetics, Polymorphism, Genetic, MESH: Humans, MESH : Alcoholism, MESH : Humans, Schedule for Affective Disorders and Schizophrenia, MESH: Adult, medicine.disease, MESH: Male, Child Development Disorders, Pervasive, MESH : Pedigree, biology.protein, MESH : Family, MESH : Genetic Predisposition to Disease, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Female, 030217 neurology & neurosurgery
Abstract

SIR—Recently, a rare functional variant, I425V, in the serotonin transporter gene (SLC6A4) has been reported to be associated with a complex neuropsychiatric phenotype that includes obsessive-compulsive disorder (OCD), alcohol abuse/dependence, anorexia nervosa, and pervasive developmental disorder (PDD).1 Our study, performed in a large population of patients with these disorders, confirms the occurrence and the segregation of V425 in OCD. The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has been implicated in numerous psychiatric disorders, mostly because of the efficacy of serotonin reuptake inhibitors (SRIs). Among the polymorphisms identified in SLC6A4, three have been shown to be functional. The rare I425V variation, located in exon 9, increases the transport activity of the protein2, whereas the two more frequent polymorphisms, 5-HTTLPR located in the 5′-UTR of the gene, and STin2 located in intron 2, modify the transcriptional activity of the gene3,4. Despite a large number of studies, the functional implications of the two frequent SLC6A4 polymorphisms in psychiatric disorders are still a matter of debate. In the present study, we sought to further explore the influence of the rare but clearly functional I425V variant in a large sample of patients with OCD and other psychiatric conditions previously reported in the two families carrying I425V, i.e., FDD, anorexia nervosa, and alcohol abuse/dependence. To be included in the study, patients had to meet the DSM-IV criteria for OCD, anorexia nervosa, alcohol abuse/dependence, or FDD. The diagnosis of FDD was confirmed using the Autism Diagnostic Interview-Revised.5 For the other disorders, lifetime psychiatric evaluation was carried out using the Diagnostic Interview for Genetic Studies (DIGS)6 for adult patients, or the Kiddie Schedule for Affective Disorders and Schizophrenia for children.7 Healthy controls were included after being interviewed with the DIGS and the Family Interview for Genetic Studies8 to confirm the absence of both personal and family history of major psychiatric disorders. The local Research Ethics Boards reviewed and approved the study. The V425 was found in 3/254 probands with OCD, 1/284 with PDD, 1/124 with anorexia nervosa, in 1/285 healthy controls, but not in alcohol abusers/dependents (0/128) (Table 1). In OCD family 1, V425 was transmitted by the father who also had a lifetime history of OCD and single phobia. The paternal grandfather was alcoholic and tobacco dependant. No genotypic information was available for the paternal grandparents since the grandfather died of throat cancer and the grandmother of breast cancer. In OCD family 2, the mother and two siblings of the proband had committed suicide and the father was also dead, so no genotypic information was available for these individuals. OCD case 1 had only one brother, who committed suicide some years ago, so no genotypic information was available for him. No other clinical data were available concerning the first-degree relatives of OCD case 1. In FDD family 1, V425 was transmitted by the father and was present in the proband and two brothers. The father and one of the brothers carrying the V425 were both alcohol dependent. However, the youngest brother (19 years old), also carrying the V425 variant, did not suffer from alcoholism or any other psychiatric disorder at the time of evaluation. Table 1 SCL6A4 genotypes and clinical features of the subjects included in the study Our results are in accordance with those previously reported by Ozaki et al1 on four points. First, we report a possibly higher occurrence of the V425 variant in OCD compared to controls. Although the variant is rare, the combined results of the two studies indicate a significantly higher frequency of V425 in OCD compared to controls1,9 (5/457 vs. 2/884, Fisher exact test, P= 0.02). Second, despite the limited clinical and genotypic information on the families carrying the V425 variant, our results suggest a possible co-segregation between the V425 and neuropsychiatric phenotypes, specifically in OCD. Third, Ozaki et al. hypothesized that the V425 variant may confer treatment-resistance to SRIs. This was indirectly supported by our findings since all OCD probands carrying the V425 variant in our study were considered resistant to SRIs, i.e., the severity of their obsessive and compulsive symptoms decreased less than 25% with multiple trials of a high dose of SRIs and a good compliance. Specifically, the three probands with OCD carrying the variant showed poor or no response to multiple trials of SRIs at adequate doses over several years. Fourth, the analysis of the two additional polymorphisms of the SCL6A4 gene indicated that the V425 polymorphism might be associated with the L allele of 5-HTTLPR. However, our results do not confirm the hypothesis of a combined gain of function effect of both V425 and L/L genotype as a genetic risk for OCD, since this combined genotype was not present in all affected patients and, by contrast, was present in the control subject carrying the V425 variant. In conclusion, our results are similar to those of the original report by Ozaki et al. and, therefore, lend support for a role of SLC6A4 V425 in the susceptibility to complex neuropsychiatric phenotypes. However, due to its global low frequency and to the fact that it was detected in a few controls, the role of V425 remains uncertain and should be interpreted with caution. We encourage other investigators, especially in the field of OCD, to screen for V425 in their samples. Indeed, the replication of these findings could ultimately implicate SLC6A4 as a true susceptibility gene to complex neuropsychiatric disorders, and consequently shed further light on the results obtained with the more frequent polymorphisms.

Published
2005

13. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism

Author

Catalina Betancur, Marion Leboyer, Stéphane Jamain, Hélène Quach, Catherine Colineaux, Thomas Bourgeron, Bruno Giros, Henrik Soderstrom, Maria Råstam, I. Carina Gillberg, Christopher Gillberg, Betancur, Catalina, Génomique fonctionnelle et développement, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Child and Adolescent Psychiatry, University of Gothenburg (GU), Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Département de Psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Albert Chenevier, Department of Psychiatry, Saint George's Hospital Medical School, This work was funded by the French Research Ministry (Actions Concertées Incitatives), the INSERM (Institut National de la Santé et la Recherche Médicale), France Télécom, and the Swedish Medical Research Council., Paris Autism Research International Sibpair (PARIS) study, and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, CNTNAP2, Genetic Linkage, Neurexin, Neuroligin, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Amino Acid Sequence, MESH: Base Sequence, medicine.disease_cause, 0302 clinical medicine, Heritability of autism, Genetics, 0303 health sciences, Mutation, Brain, Pedigree, Female, MESH: Membrane Proteins, DNA, Complementary, MESH: Mutation, Cell Adhesion Molecules, Neuronal, Molecular Sequence Data, MESH: Autistic Disorder, Epigenetics of autism, LRRTM1, Nerve Tissue Proteins, MESH: Carrier Proteins, Biology, behavioral disciplines and activities, Article, MESH: Chromosomes, Human, X, 03 medical and health sciences, MESH: Brain, MESH: Gene Expression Profiling, mental disorders, medicine, Humans, Amino Acid Sequence, RNA, Messenger, Autistic Disorder, 030304 developmental biology, Chromosomes, Human, X, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Molecular Sequence Data, MESH: Humans, Base Sequence, Sequence Homology, Amino Acid, Gene Expression Profiling, Membrane Proteins, MESH: DNA, Complementary, medicine.disease, MESH: Male, MESH: Nerve Tis, Autism, Carrier Proteins, MESH: Linkage (Genetics), MESH: Female, 030217 neurology & neurosurgery
Abstract

Many studies have supported a genetic etiology for autism. Here we report mutations in two X-linked genes encoding neuroligins NLGN3 and NLGN4 in siblings with autism-spectrum disorders. These mutations affect cell-adhesion molecules localized at the synapse and suggest that a defect of synaptogenesis may predispose to autism.

Published
2003

14. Marfan database (third edition) : new mutations and new routines for the software

Author

Gwenaëlle Collod-Béroud, Claudine Junien, Ana Beatriz Alvarez Perez, Leena Peltonen, Maureen Boxer, Ulrich Grau, David J. H. Brock, Uta Francke, Terhi Rantamäki, H. G. Klein, Caroline Hayward, Catherine Boileau, Lesley C. Adès, Wanguo Liu, Lieve Nuytinck, Anne De Paepe, Cheryl Black, Christophe Béroud, Katherine Holman, Génétique, chromosome et cancer, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pharmacie, Hôpital Broussais, Department of Medical Genetics5, Royal Alexandra Children's Hospital, Department of Paediatrics and Child Health, Molecular Genetics Laboratory, Department of Molecular and Cellular Pathology, Ninewells Hospital and Medical School [Dundee], North Thames (East) Clinical Molecular Genetics Laboratory, Unit of Clinical Genetics and Fetal Medicine, Institute of Child Health, Human Genetics Unit, Department of Medicine (WGH), University of Edinburgh, Cardiological Sciences, Saint George's Hospital Medical School, Department of Genetics [Stanford], Stanford Medicine, Stanford University-Stanford University, Howard Hughes Medical Institute (HHMI), Department of Cardiovascular Surgery, Klinikum GroBhadern, University of Munnich, Institute of Clinical Chemistry, Klinikum GroBhadern, OK5, Center for Medical Genetics, University Hospital Gent, Department of Human Molecular Genetics, National Public Health Institute, UNIFESP-EPM, Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM), University of Edinburgh, Western General Hospital, Department of Genetics and Pediatrics, Stanford University [Stanford], Howard Hughes Medical Institute, Service de biochimie, d'hormonologie et de génétique moléculaire, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ) - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Ambroise Paré, and COLLOD-BEROUD, Gwenaëlle

Subjects
Marfan syndrome, Databases, Factual, Fibrillin-1, DNA Mutational Analysis, [SDV.GEN] Life Sciences [q-bio]/Genetics, NON-CALCIUM-BINDING, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, computer.software_genre, PHENOTYPE, Marfan Syndrome, 0302 clinical medicine, Software, Medicine and Health Sciences, MESH: DNA Mutational Analysis, skin and connective tissue diseases, Computer communication networks, MESH: Computer Communication Networks, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 0303 health sciences, Database, integumentary system, MICROFIBRILS, Microfilament Proteins, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, CYSTEINE, EXONS, CHROMOSOME-15, Research Article, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Mutation, EGF-LIKE DOMAINS, Biology, Fibrillins, ECTOPIA LENTIS, MESH: Marfan Syndrome, Computer Communication Networks, 03 medical and health sciences, MESH: Microfilament Proteins, MESH: Software, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MISSENSE MUTATION, Genetics, medicine, Humans, cardiovascular diseases, 030304 developmental biology, FIBRILLIN GENE FBN1, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, business.industry, De novo mutation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: Databases, Factual, Mutation, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, computer, 030217 neurology & neurosurgery
Abstract

The Marfan database is a software that contains routines for the analysis of mutations identified in the FBN1 gene that encodes fibrillin-1. Mutations in this gene are associated not only with Marfan syndrome but also with a spectrum of overlapping disorders. The third version of the Marfan database contains 137 entries. The software has been modified to accommodate four new routines and is now accessible on the World Wide Web at http://www.umd.necker.fr.

Published
1998

15. Effect of Mutation Type and Location on Clinical Outcome in 1,013 Probands with Marfan Syndrome or Related Phenotypes and FBN1 Mutations: An International Study

Author

Nicola Marziliano, H. Plauchu, Peter N. Robinson, Catherine Boileau, Bert Callewaert, Uta Francke, P Comeglio, Christine Binquet, J. De Backer, Guillaume Jondeau, Dorothy Halliday, Christophe Béroud, Paul Coucke, A. De Paepe, Katherine Holman, Kenneth H. Mayer, B. Benetts, Andrew Biggin, Eloisa Arbustini, Hal Dietz, Anne H. Child, Gwenaëlle Collod-Béroud, Christine Muti, Laurence Faivre, Mireille Claustres, A Kiotsekoglou, Lesley C. Adès, Mine Arslan-Kirchner, Maggie Brett, Bart Loeys, Claire Bonithon-Kopp, Elodie Gautier, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Medical Genetics [Ghent], Ghent University Hospital, Howard Hughes Medical Institute (HHMI), Sonalee Laboratory for Marfan syndrome and related disorders, Department of Cardiological Sciences, St. George's Hospital Medical School, Centre for Inherited Cardiovacular Diseases, Foundation IRCCS Policlinico San Matteo, Center for Human Genetics and Laboratory Medicine, Center of Human Genetics and Laboratory Medicine, Institut für Humagenetik, Hannover Medical School [Hannover] (MHH)-Institut für Humagenetik, Department of Biochemistry [Oxford], University of Oxford [Oxford], Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, Service de Génétique, Hôtel Dieu, Institut für Medizinische Genetik, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Marfan Research Group, Westmead Hospital [Sydney], Department of Clinical Genetics, Discipline of Paediatrics and Child Health, The University of Sydney, Department of Molecular Genetics, Department of Genetics [Stanford], Stanford Medicine, Stanford University-Stanford University, Cardiological Sciences, Saint George's Hospital Medical School, Service de cardiologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Institute of Genetic Medicine and the Howard Hugues Medical Institute, Johns Hopkins University School of Medicine, Hannover Medical School [Hannover] ( MHH ) -Institut für Humagenetik, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bichat, Universitätsmedizin Charité, The Children's Hospital at Westmead, The University of Sydney [Sydney], The Children's Hospital ant Westmead, Department of Genetics and Pediatrics, Stanford University [Stanford], Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Service de biochimie, d'hormonologie et de génétique moléculaire, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), University of Oxford, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), and COLLOD-BEROUD, Gwenaëlle

Subjects
Marfan syndrome, Proband, Male, MESH: Epidermal Growth Factor, Fibrillin-1, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030204 cardiovascular system & hematology, Bioinformatics, Severity of Illness Index, Marfan Syndrome, MESH: Protein Structure, Tertiary, MESH : Exons, 0302 clinical medicine, Transforming Growth Factor beta, Genotype, Missense mutation, MESH : Female, Genetics(clinical), Ectopia lentis, Genetics (clinical), MESH : Epidermal Growth Factor, Genetics, 0303 health sciences, MESH : Prognosis, Microfilament Proteins, Exons, MESH : Adult, Prognosis, 3. Good health, MESH : Phenotype, Phenotype, Mutation (genetic algorithm), MESH : Severity of Illness Index, Female, MESH : Mutation, Haploinsufficiency, MESH : Protein Structure, Tertiary, Adult, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Mutation, MESH : Microfilament Proteins, Adolescent, MESH : Male, Biology, MESH: Phenotype, Fibrillins, MESH: Prognosis, Article, MESH: Marfan Syndrome, MESH: Microfilament Proteins, 03 medical and health sciences, MESH : Adolescent, MESH: Severity of Illness Index, medicine, Humans, MESH: Transforming Growth Factor beta, 030304 developmental biology, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH : Marfan Syndrome, MESH: Humans, Epidermal Growth Factor, MESH : Humans, MESH: Adult, medicine.disease, MESH: Male, Protein Structure, Tertiary, MESH : Transforming Growth Factor beta, Inframe Mutation, Mutation, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Exons, MESH: Female
Abstract

International audience; Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.

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16. 11q24.2-25 micro-rearrangements in autism spectrum disorders: Relation to brain structures.

Author

Maruani A, Huguet G, Beggiato A, ElMaleh M, Toro R, Leblond CS, Mathieu A, Amsellem F, Lemière N, Verloes A, Leboyer M, Gillberg C, Bourgeron T, and Delorme R

Subjects
Adult, Brain abnormalities, Brain physiopathology, Case-Control Studies, DNA Copy Number Variations, Female, GPI-Linked Proteins genetics, Genetic Predisposition to Disease, Humans, Jacobsen Distal 11q Deletion Syndrome etiology, Jacobsen Distal 11q Deletion Syndrome genetics, Magnetic Resonance Imaging, Male, Megalencephaly genetics, Mutation, Polymorphism, Single Nucleotide, Pregnancy, Autism Spectrum Disorder genetics, Chromosome Aberrations, Chromosomes, Human, Pair 11, Neural Cell Adhesion Molecules genetics
Abstract

Jacobsen syndrome (JS) is characterized by intellectual disability and higher risk for autism spectrum disorders (ASD). All patients with JS are carriers of contiguous de novo deletions of 11q24.2-25, but the causative genes remain unknown. Within the critical interval, we hypothesized that haploinsufficiency of the neuronal cell adhesion molecule Neurotrimin (NTM) might increase the risk for ASD and could affect brain structure volumes. We searched for deleterious mutations affecting NTM in 1256 ASD patients and 1287 controls, using SNP arrays, and by direct sequencing of 250 ASD patients and 180 controls. We compared our results to those obtained from independent cohorts of ASD patients and controls. We identified two patients with Copy Number Variants (CNV) encompassing NTM, one with a large de novo deletion, and a clinical phenotype of JS (including macrocephaly), and a second with a paternally inherited duplication, not consistent with JS. Interestingly, no similar CNVs were observed in controls. We did not observe enrichment for deleterious NTM mutations in our cohort. We then explored if the macrocephaly in the patient with JS was associated with a homogeneous increase of brain structures volumes using automatic segmentation. Compared to subjects without NTM micro-rearrangements (n=188), the patient had an increased volume of the sub-cortical structures but a decrease of the occipital gray matter. Finally our explorations could not incriminate NTM as a susceptibility gene for ASD, but provides new information on the impact of the 11q24.2-25 deletion on brain anatomy., (© 2015 Wiley Periodicals, Inc.)

Published
2015
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17. Measurement of NO synthesis in humans by L-[15N2]arginine: application to the response to vaccination.

Author

Macallan DC, Smith LM, Ferber J, Milne E, Griffin GE, Benjamin N, and McNurlan MA

Subjects
Adult, Humans, Male, Nitrates metabolism, Nitrates urine, Nitrogen Isotopes, Pilot Projects, Typhoid-Paratyphoid Vaccines, Arginine pharmacokinetics, Nitric Oxide biosynthesis, Vaccination
Abstract

Induction of nitric oxide (NO) synthesis is a key element of the inflammatory response in humans. We describe a sensitive gas isotope ratio mass spectrometric (GIRMS) method for measuring urinary [15N]nitrate production during intravenous infusion of L-[guanidino-15N2]arginine and its application to investigate the effects of a controlled inflammatory stimulus, typhoid vaccination, on NO synthesis in humans. Intravenous infusion of L-[15N2]arginine at 5-12 mumol.kg-1.h-1 for 24 h in three subjects was used to determine arginine and nitrate pool kinetics. Eight subjects received primed constant infusion of 2.5 mumol.kg-1.h-1 of L-[15N2]arginine for 12 h once before and again after typhoid vaccination. NO synthesis was calculated from 15N enrichment of plasma arginine and urinary nitrate, measured by gas chromatography mass spectrometry and GIRMS, respectively, and total urinary nitrate excretion. Baseline NO synthesis was 298 +/- 44 nmol.h-1.kg lean body mass-1, representing 0.41% of arginine flux. After vaccination, NO synthesis (267 +/- 77 nmol.h-1.kg-1) was not increased (P = 0.18), despite demonstration of an acute phase response. Typhoid vaccination is not accompanied by accelerated NO synthesis.

Published
1997
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18. Radiofrequency current delivery by way of a bipolar tricuspid annulus-mitral annulus electrode configuration for ablation of posteroseptal accessory pathways.

Author

Bashir Y, Heald SC, O'Nunain S, Katritsis D, Camm AJ, and Ward DE

Subjects
Adolescent, Adult, Atrial Fibrillation surgery, Atrial Flutter surgery, Catheter Ablation methods, Electrocardiography, Electrodes, Female, Follow-Up Studies, Humans, Male, Middle Aged, Mitral Valve surgery, Treatment Outcome, Tricuspid Valve surgery, Wolff-Parkinson-White Syndrome physiopathology, Wolff-Parkinson-White Syndrome surgery, Catheter Ablation instrumentation, Heart Conduction System surgery, Tachycardia, Atrioventricular Nodal Reentry surgery
Abstract

Objectives: This report describes a novel technique for ablation of "difficult" posteroseptal pathways., Background: Although radiofrequency ablation of accessory atrioventricular (AV) pathways is successful in > or = 90% of cases, particular difficulty may be encountered with some bypass tracts in the posteroseptal region., Methods: In eight patients with posteroseptal accessory pathways (two concealed), radiofrequency catheter ablation using conventional unipolar current applications from favorable sites along the tricuspid or mitral annulus, or both, was unsuccessful. Subsequently, a bipolar technique was adopted, with current application between the distal electrodes of two catheters positioned against the septal region at sites of early activation along both mitral and tricuspid annuli., Results: The bipolar configuration proved effective in all cases. The number of bipolar lesions required for success was one (five patients), five (two patients) and nine (one patient). In five patients, bipolar current application abolished pathway conduction using positions at which delivery of unipolar lesions had been ineffective or caused transient block. The AV or ventriculoatrial interval at successful sites varied from 20 to 65 ms, and the time from delta wave onset to local ventricular activation was zero or negative. There were no complications attributable to the bipolar technique. During follow-up of 8 to 36 weeks, pathway conduction has not recurred in any patient., Conclusions: Bipolar radiofrequency current delivery across the septal region using a tricuspid annulus-mitral annulus electrode configuration may abolish accessory pathway conduction when conventional unipolar applications have proved ineffective. The technique may reduce procedure duration, radiation exposure and overall failure rate in these problematic cases.

Published
1993
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19. Development of the left-right axis.

Author

Brown NA, McCarthy A, and Seo J

Subjects
Animals, Culture Techniques, Female, Male, Mice, Sex Ratio, Embryonic and Fetal Development, Functional Laterality
Abstract

Left-right is not an axis in the conventional sense but rather two mirror-image proximodistal axes, upon which a quantal piece of positional information (leftness or rightness) is superimposed for laterally asymmetric organ development. We are attempting to establish the stages at which left-right is specified and determined, but this is complicated by the apparent loss of normal handed development in embryos that are cultured from pre-neural plate stages. Experiments suggest that left-right is determined by the first somite stage. The loss of normal left-right development in early cultures is probably not due to removal of some maternal signal, even though embryos do develop in vivo with their axes in a specific orientation relative to the uterus. The fact that there are two random embryonic axis orientations, 180 degrees opposed to one another, and that the axes of the two uterine horns are mirror-images of each other make it unlikely that the uterus could impart a sense of left-right to the embryo. The right ovary produces more eggs than the left one; this is reversed in iv/iv situs inversus mice. Analysis of iv/iv mice shows a correlation of left-right abnormalities with sex and close relationships between the abnormal left-right development of some organs, for example the heart and spleen, that have no obvious developmental connection.

Published
1992
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20. The development of handed asymmetry in aggregation chimeras of situs inversus mutant and wild-type mouse embryo.

Author

Brown NA, McCarthy A, and Wolpert L

Subjects
Animals, Embryo Transfer, Genotype, Mice, Mice, Inbred Strains, Mutation, Chimera, Functional Laterality genetics
Abstract

Mutant iv/iv mice develop as if they have no sense of left and right, so the development of asymmetry is random: half normal, half as a mirror-image of normal, situs inversus. We have made aggregation chimeras of 8-cell stage iv/iv and +/+ embryos, transferred them into pseudopregnant mice, and examined their phenotype on day 10 of gestation. The contribution of mutant and wild-type cells to tissues of the embryo was estimated by strain-specific isozyme (GPI-1) analysis. We have also performed reciprocal embryo transfers, iv/iv blastocysts into +/+ mice, and vice versa. These transfers show that the development of handed asymmetry is determined by embryonic genotype, and is unaffected by the maternal environment (at least after day 3), or by the procedures of embryo collection, culture and transfer. Our observations on the development of 21 viable chimeric embryos show that neither iv/iv nor +/+ cells are dominant. All embryos (12) with less than 50% contribution of iv/iv cells to the heart developed with normal situs. Of 9 embryos with greater than 50% iv/iv cells, only 2 developed with inverted situs. These findings suggests that there was partial 'rescue' of embryos by some influence of normal over mutant cells. However, we cannot, statistically, exclude an alternative interpretation that cells are behaving autonomously. Interestingly, the embryos that developed with inverted situs were unique in having greater than two thirds contribution of iv/iv cells to both the heart and the visceral yolk-sac.

Published
1990
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