Sequencing ASMT identifies rare mutations in Chinese Han patients with autism

Abstract

Melatonin is involved in the regulation of circadian and seasonal rhythms and immune function. Prior research reported low melatonin levels in autism spectrum disorders (ASD). ASMT located in pseudo-autosomal region 1 encodes the last enzyme of the melatonin biosynthesis pathway. A previous study reported an association between ASD and single nucleotide polymorphisms (SNPs) rs4446909 and rs5989681 located in the promoter of ASMT. Furthermore, rare deleterious mutations were identified in a subset of patients. To investigate the association between ASMT and autism, we sequenced all ASMT exons and its neighboring region in 398 Chinese Han individuals with autism and 437 healthy controls. Although our study did not detect significant differences of genotypic distribution and allele frequencies of the common SNPs in ASMT between patients with autism and healthy controls, we identified new rare coding mutations of ASMT. Among these rare variants, 4 were exclusively detected in patients with autism including a stop mutation (p.R115W, p.V166I, p.V179G, and p.W257X). These four coding variants were observed in 6 of 398 (1.51%) patients with autism and none in 437 controls (Chi-Square test, Continuity Correction p = 0.032, two-sided). Functional prediction of impact of amino acid showed that p.R115W might affect protein function. These results indicate that ASMT might be a susceptibility gene for autism. Further studies in larger samples are needed to better understand the degree of variation in this gene as well as to understand the biochemical and clinical impacts of ASMT/melatonin deficiency.

Figure 1. Linkage disequilibrium (LD) block of 4 common SNPs in promoter of ASMT.

Markers with Linkage disequilibrium (LD) (D′<1 and LOD>2) are shown in red through pink (color intensity decreases with decreasing D′ value). D′ value shown within each square represents a pairwise LD relationship between the two polymorphisms. This LD plot was generated with the Haploview.

Figure 2. Localization of rare nonsynonymous variants or splite site identified in patients with autism.

Upper: SNPs were associated with autism and rare variants identified in children with autism in other researches. Lower: rare nonsynonymous only identified in children with autism not in controls in our research.