Heterozygous FA2H mutations in autism spectrum disorders

BMC Medical Genetics

Richard Delorme⁵  Thomas Bourgeron^1,12  Edwin H Cook¹  Hiroko Hama⁷  Mary Coleman²  Catalina Betancur⁴  Christopher Gillberg³  Marion Leboyer⁶  Monique Elmaleh⁸  I Carina Gillberg^1,10  Fréderique Amsellem⁶  Maria Rastam⁹  Anita Beggiato^1,11  Henrik Anckarsäter⁹  Gudrun Nygren^1,10  Claire S Leblond^1,12  Guillaume Huguet^1,12  Anna Maruani⁵  Isabelle Scheid⁵ 

[1]Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Illinois, USA

[2]Foundation for Autism Research, Sarasota, Florida 34235-7117, USA

[3]Institute of Child Health, University College London, London, UK

[4]UPMC Univ Paris 06, Paris, France

[5]APHP, Robert Debré Hospital, Child and Adolescent Psychiatry, Paris, France

[6]INSERM U955, Psychiatry Genetics, Créteil, France

[7]Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA

[8]APHP, Robert Debré Hospital Paediatric Imaging, Paris, France

[9]Department of Clinical Sciences, Lund University, Lund, Sweden

[10]Gillberg Neuropsychiatry Centre, Gothenburg University, Göteborg, Sweden

[11]Fondation FondaMental, French National Science Foundation, Creteil, France

[12]CNRS URA2182, Paris, France

关键词: Myelin;    Gene;    Brain;    Autism;   

Others  :  1122565
DOI  :  10.1186/1471-2350-14-124

 received in 2013-05-17, accepted in 2013-11-18,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Scheid et al.; licensee BioMed Central Ltd.

【 图 表 】

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