University of Illinois at Chicago
1471-2350-14-124.pdf (1.88 MB)

Heterozygous FA2H mutations in autism spectrum disorders

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posted on 2016-04-12, 00:00 authored by Isabelle Scheid, Anna Maruani, Guillaume Huguet, Claire S. Leblond, Gudrun Nygren, Henrik Anckarsaeter, Anita Beggiato, Maria Rastam, Frederique Amsellem, I. Carina Gillberg, Monique Elmaleh, Marion Leboyer, Christopher Gillberg, Catalina Betancur, Mary Coleman, Hiroko Hama, Edwin H. Cook, Thomas Bourgeron, Richard Delorme
Background 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.


The Institut Pasteur, INSERM, CNRS, ANR, Fondation FondaMentale, PHRC and Fondation Orange supported this work.


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© 2013 Scheid et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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