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Heterozygous FA2H mutations in autism spectrum disorders

Scheid, Isabelle; Maruani, Anna; Huguet, Guillaume; Leblond, Claire S; Nygren, Gudrun; Anckarsäter, Henrik LU ; Beggiato, Anita; Råstam, Maria LU ; Amsellem, Frédederique and Gillberg, I Carina, et al. (2013) In BMC Medical Genetics 14.
Abstract
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Autism, Brain, Gene, Myelin
in
BMC Medical Genetics
volume
14
publisher
BioMed Central
external identifiers
  • wos:000328505900001
  • scopus:84888784847
ISSN
1471-2350
DOI
10.1186/1471-2350-14-124
language
English
LU publication?
yes
id
9fa8921e-8f2d-4177-a064-170a4fd1f6d0 (old id 4248627)
date added to LUP
2014-01-16 15:17:30
date last changed
2019-04-23 02:08:53
@article{9fa8921e-8f2d-4177-a064-170a4fd1f6d0,
  abstract     = {Background<br/><br>
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. <br/><br>
<br/><br>
Methods<br/><br>
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. <br/><br>
<br/><br>
Results<br/><br>
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. <br/><br>
<br/><br>
Conclusions<br/><br>
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.},
  articleno    = {124},
  author       = {Scheid, Isabelle and Maruani, Anna and Huguet, Guillaume and Leblond, Claire S and Nygren, Gudrun and Anckarsäter, Henrik and Beggiato, Anita and Råstam, Maria and Amsellem, Frédederique and Gillberg, I Carina and Elmaleh, Monique and Leboyer, Marion and Gillberg, Christopher and Betancur, Catalina and Coleman, Mary and Hama, Hiroko and Cook, Edwin H and Bourgeron, Thomas and Delorme, Richard},
  issn         = {1471-2350},
  keyword      = {Autism,Brain,Gene,Myelin},
  language     = {eng},
  publisher    = {BioMed Central},
  series       = {BMC Medical Genetics},
  title        = {Heterozygous FA2H mutations in autism spectrum disorders},
  url          = {http://dx.doi.org/10.1186/1471-2350-14-124},
  volume       = {14},
  year         = {2013},
}