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. 2014 Apr 29:5:31.
doi: 10.1186/2040-2392-5-31. eCollection 2014.

Rare deleterious mutations of the gene EFR3A in autism spectrum disorders

Abha R Gupta  1 , Michelle Pirruccello  2 , Feng Cheng  3 , Hyo Jung Kang  4 , Thomas V Fernandez  5 , Jeremy M Baskin  6 , Murim Choi  7 , Li Liu  8 , Adife Gulhan Ercan-Sencicek  9 , John D Murdoch  10 , Lambertus Klei  11 , Benjamin M Neale  12 , Daniel Franjic  13 , Mark J Daly  12 , Richard P Lifton  7 , Pietro De Camilli  6 , Hongyu Zhao  14 , Nenad Sestan  13 , Matthew W State  15
Affiliations

Rare deleterious mutations of the gene EFR3A in autism spectrum disorders

Abha R Gupta et al. Mol Autism. .

Abstract

Background: Whole-exome sequencing studies in autism spectrum disorder (ASD) have identified de novo mutations in novel candidate genes, including the synaptic gene Eighty-five Requiring 3A (EFR3A). EFR3A is a critical component of a protein complex required for the synthesis of the phosphoinositide PtdIns4P, which has a variety of functions at the neural synapse. We hypothesized that deleterious mutations in EFR3A would be significantly associated with ASD.

Methods: We conducted a large case/control association study by deep resequencing and analysis of whole-exome data for coding and splice site variants in EFR3A. We determined the potential impact of these variants on protein structure and function by a variety of conservation measures and analysis of the Saccharomyces cerevisiae Efr3 crystal structure. We also analyzed the expression pattern of EFR3A in human brain tissue.

Results: Rare nonsynonymous mutations in EFR3A were more common among cases (16 / 2,196 = 0.73%) than matched controls (12 / 3,389 = 0.35%) and were statistically more common at conserved nucleotides based on an experiment-wide significance threshold (P = 0.0077, permutation test). Crystal structure analysis revealed that mutations likely to be deleterious were also statistically more common in cases than controls (P = 0.017, Fisher exact test). Furthermore, EFR3A is expressed in cortical neurons, including pyramidal neurons, during human fetal brain development in a pattern consistent with ASD-related genes, and it is strongly co-expressed (P < 2.2 × 10(-16), Wilcoxon test) with a module of genes significantly associated with ASD.

Conclusions: Rare deleterious mutations in EFR3A were found to be associated with ASD using an experiment-wide significance threshold. Synaptic phosphoinositide metabolism has been strongly implicated in syndromic forms of ASD. These data for EFR3A strengthen the evidence for the involvement of this pathway in idiopathic autism.

Keywords: Autism spectrum disorder; EFR3A; Genetics; Phosphoinositide metabolism; Rare variants; Synapse.

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Figures

Figure 1
Figure 1
Ribbon diagram of S. cerevisiae Efr3 crystal structure. Crystallization of Efr3 revealed a series of HEAT repeats, as we had predicted bioinformatically. Alignment of yeast Efr3 and human EFR3A was reliable to amino acid 451. Blinded to case/control status, the human mutations were mapped and analyzed for their potential to disrupt protein structure and function given the three-dimensional crystal structure. Mutations in red are deleterious and found in cases. (R161* in a control and G216Sfs*12 in a case are not shown but presumed to be deleterious.) Mutations in green are benign and found in cases. Mutations in blue are benign and found in controls.
Figure 2
Figure 2
Expression analysis of human EFR3A. (A) Spatio-temporal mRNA expression of EFR3A in the human brain. Line plots show log2-transformed exon-array signal intensity during prenatal to adult stages. (B)In situ hybridization of EFR3A, using antisense and sense (negative control) probes, in the dorsolateral prefrontal cortex of 40-year-old human brain. Scale bar, 20 μm. (C) Functional annotation of top 100 genes correlated with EFR3A expression. The dashed line is the threshold for significance, P = 0.05. (D) Distribution of expression correlation coefficients of EFR3A and ASD genes with M12 genes (n = 356) [20]. (E) Distribution of expression correlation coefficients of EFR3A and ASD genes with all brain-expressed genes (n = 15,132) [19]. The homologue EFR3B is shown for comparison and ACTB, a housekeeping gene, is included as a negative control.
Figure 3
Figure 3
ASD-related molecules at the synapse. Mutations in proteins in green have been demonstrated to carry risk for idiopathic ASD, and mutations in proteins in blue cause syndromic forms of ASD. EFR3A has been linked to phosphoinositide metabolism [8].
See this image and copyright information in PMC

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