与昼夜节律相关的基因在自闭症谱系障碍患者中具有高度多态性。

Circadian-relevant genes are highly polymorphic in autism spectrum disorder patients.

作者信息

Yang Zhiliang, Matsumoto Ayumi, Nakayama Kazuhiro, Jimbo Eriko F, Kojima Karin, Nagata Koh-ichi, Iwamoto Sadahiko, Yamagata Takanori

机构信息

Department of Pediatrics, Jichi Medical University, Shimotsuke, Tochigi, Japan.

Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.

出版信息

Brain Dev. 2016 Jan;38(1):91-9. doi: 10.1016/j.braindev.2015.04.006. Epub 2015 May 6.

DOI:10.1016/j.braindev.2015.04.006

PMID:25957987

Abstract

BACKGROUND

The genetic background of autism spectrum disorder (ASD) is considered a multi-genetic disorder with high heritability. Autistic children present with a higher prevalence of sleep disorders than has been observed in children with normal development. Some circadian-relevant genes have been associated with ASD (e.g., PER1, PER2, NPAS2, MTNR1A, and MTNR1B).

METHODS

We analyzed 28 ASD patients (14 with sleep disorders and 14 without) and 23 control subjects of Japanese descent. The coding regions of 18 canonical clock genes and clock-controlled genes were sequenced. Detected mutations were verified by direct sequencing analysis, and additional control individuals were screened.

RESULTS

Thirty-six base changes with amino acid changes were detected in 11 genes. Six missense changes were detected only in individuals with ASD with sleep disturbance: p.F498S in TIMELESS, p.S20R in NR1D1, p.R493C in PER3, p.H542R in CLOCK, p.L473S in ARNTL2, and p.A325V in MTNR1B. Six missense changes were detected only in individuals with ASD without sleep disturbance: p.S1241N in PER1, p.A325T in TIMELESS, p.S13T in ARNTL, p.G24E in MTNR1B, p.G24E in PER2, and p.T1177A in PER3. The p.R493C mutation in PER3 was detected in both groups. One missense change, p.P932L in PER2, was detected only in the control group. Mutations in NR1D1, CLOCK, and ARNTL2 were detected only in individuals with ASD with sleep disorder. The prevalence of the mutations detected only single time differed significantly among all ASD patients and controls (p=0.003). Two kinds of mutations detected only in individuals with ASD with sleep disorder, p.F498S in TIMELESS and p.R366Q in PER3, were considered to affect gene function by three different methods: PolyPhen-2, scale-invariant feature transform (SIFT) prediction, and Mutation Taster (www.mutationtaster.org). The mutations p.S20R in NR1D1, p.H542R in CLOCK, p.L473S in ARNTL2, p.A325T in TIMELESS, p.S13T in ARNTL, and p.G24E in PER2 were diagnosed to negatively affect gene function by more than one of these methods.

CONCLUSION

Mutations in circadian-relevant genes affecting gene function are more frequent in patients with ASD than in controls. Circadian-relevant genes may be involved in the psychopathology of ASD.

摘要

背景

自闭症谱系障碍（ASD）的遗传背景被认为是一种具有高遗传度的多基因疾病。与正常发育儿童相比，自闭症儿童睡眠障碍的患病率更高。一些与昼夜节律相关的基因已被证实与ASD有关（例如，PER1、PER2、NPAS2、MTNR1A和MTNR1B）。

方法

我们分析了28名ASD患者（14名有睡眠障碍，14名无睡眠障碍）以及23名日本血统的对照受试者。对18个典型生物钟基因和生物钟调控基因的编码区进行测序。通过直接测序分析验证检测到的突变，并对额外的对照个体进行筛查。

结果

在11个基因中检测到36个碱基变化且伴有氨基酸变化。仅在有睡眠障碍的ASD个体中检测到6个错义变化：在TIMLESS基因中的p.F498S、在NR1D1基因中的p.S20R、在PER3基因中的p.R493C、在CLOCK基因中的p.H542R、在ARNTL2基因中的p.L473S以及在MTNR1B基因中的p.A325V。仅在无睡眠障碍的ASD个体中检测到6个错义变化：在PER1基因中的p.S1241N、在TIMLESS基因中的p.A325T、在ARNTL基因中的p.S13T、在MTNR1B基因中的p.G24E、在PER2基因中的p.G24E以及在PER3基因中的p.T1177A。在两组中均检测到PER3基因中的p.R493C突变。仅在对照组中检测到一个错义变化，即PER2基因中的p.P932L。仅在有睡眠障碍的ASD个体中检测到NR1D1、CLOCK和ARNTL2基因的突变。在所有ASD患者和对照中，仅单次检测到的突变患病率存在显著差异（p = 0.003）。仅在有睡眠障碍的ASD个体中检测到的两种突变，即TIMLESS基因中的p.F498S和PER3基因中的p.R366Q，被认为通过三种不同方法影响基因功能：PolyPhen - 2、尺度不变特征变换（SIFT）预测和Mutation Taster（www.mutationtaster.org）。NR1D1基因中的p.S20R、CLOCK基因中的p.H542R、ARNTL2基因中的p.L473S、TIMLESS基因中的p.A325T、ARNTL基因中的p.S13T以及PER2基因中的p.G24E等突变通过不止一种上述方法被诊断为对基因功能有负面影响。