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Heterozygous FA2H mutations in autism spectrum disorders.

By Isabelle Scheid, Anna Maruani, Guillaume Huguet, Claire Leblond, Gudrun Nygren, Henrik Anckarsäter, Anita Beggiato, Maria Rastam, Fréderique Amsellem, Carina Gillberg, Monique Elmaleh, Marion Leboyer, Christopher Gillberg, Catalina Betancur, Mary Coleman, Hiroko Hama, Edwin Cook, Thomas Bourgeron and Richard Delorme


International audienceBACKGROUND: Widespread abnormalities in white matter development are frequently reported in cases of autism spectrum disorders (ASD) and could be involved in the disconnectivity suggested in these disorders. Homozygous mutations in the gene coding for fatty-acid 2-hydroxylase (FA2H), an enzyme involved in myelin synthesis, are associated with complex leukodystrophies, but little is known about the functional impact of heterozygous FA2H mutations. We hypothesized that rare deleterious heterozygous mutations of FA2H might constitute risk factors for ASD. METHODS: We searched deleterious mutations affecting FA2H, by genotyping 1256 independent patients with ASD genotyped using Genome Wide SNP arrays, and also by sequencing in independent set of 186 subjects with ASD and 353 controls. We then explored the impact of the identified mutations by measuring FA2H enzymatic activity and expression, in transfected COS7 cells. RESULTS: One heterozygous deletion within 16q22.3-q23.1 including FA2H was observed in two siblings who share symptoms of autism and severe cognitive impairment, axial T2-FLAIR weighted MRI posterior periventricular white matter lesions. Also, two rare non-synonymous mutations (R113W and R113Q) were reported. Although predictive models suggested that R113W should be a deleterious, we did not find that FA2H activity was affected by expression of the R113W mutation in cultured COS cells. CONCLUSIONS: While our results do not support a major role for FA2H coding variants in ASD, a screening of other genes related to myelin synthesis would allow us to better understand the role of non-neuronal elements in ASD susceptibility

Topics: Autism, Brain, Gene, Myelin, [ SDV.MHEP.PSM ] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health
Publisher: BioMed Central
Year: 2013
DOI identifier: 10.1186/1471-2350-14-124
OAI identifier: oai:HAL:inserm-00918083v1
Provided by: Hal-Diderot

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