Abstract
BackgroundWidespread 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.MethodsWe 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.ResultsOne 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.ConclusionsWhile 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.
Highlights
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 of the fatty-acid 2-hydroxylase (FA2H) gene in humans are associated with three neurodegenerative disorders involving a wide variety of symptoms: complicated spastic paraplegia (SPG35) [8], leukodystrophy with spastic paraparesis and dystonia [9,10], and neurodegeneration associated with brain iron accumulation [11]
Molecular findings A rare Copy number variant (CNV) is identified in the Paris Autism Research International Sibpair Study (PARIS) ASD patient cohort Among the 1256 independent patients with ASD genotyped using Illumina Single nucleotide polimorphism (SNP) arrays [996 from the AGP [12] and 260 from the PARIS study [13]], we detected a heterozygous 167.1 kb deletion within 16q22.3q23.1 [chr16: 73258900-73426000_hg18] in one patient (AUR139_7) with autism and moderate intellectual disability
Summary
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. Autism spectrum disorders (ASD) are characterized by impairments in reciprocal social interactions, language impairments and repetitive, stereotyped and ritualistic verbal and non-verbal behaviors Beyond this unifying definition lies an extreme degree of clinical heterogeneity, ranging from mild to profound impairments [1,2]. FA2H gene codes for fatty acid 2-hydroxylase (FA2H) [2], an enzyme that produces 2-hydroxylated fatty acids for incorporation into 2-hydroxydihydroceramide and 2hydroxyceramide [7] These ceramides, in turn, serve as precursors for the synthesis of galactosylceramide and sulfatides, essential lipid components of myelin sheaths. We sequenced the FA2H gene in 186 patients with ASD and 353 controls, finding one non-synonymous mutation (R113W) shared by the affected siblings and transmitted by the mother who may carry a somatic mosaicism
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