Circadian-relevant genes are highly polymorphic in autism spectrum disorder patients
Circadian-relevant genes are highly polymorphic in autism spectrum disorder patients
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DOI：
10.1016/j.braindev.2015.04.006
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发表时间：
2016-01-01
影响因子：
1.7
通讯作者：
Yamagata, Takanori
中科院分区：
文献类型：
--
作者：
Yang, Zhiliang;Matsumoto, Ayumi;Yamagata, Takanori
背景：自闭症谱系障碍(ASD)的遗传背景被认为是一种遗传率较高的多基因疾病。与发育正常的儿童相比，自闭症儿童的睡眠障碍发生率更高。一些与昼夜节律相关的基因(如PER1、PER2、NPAS2、MTNR1A和MTNR1B)与ASD相关。方法：我们分析了28例ASD患者(14例有睡眠障碍，14例没有)和23名日裔对照受试者。对18个典型时钟基因和钟控基因的编码区进行了测序。结果：在11个基因中检测到36个碱基变化并伴有氨基酸变化。仅在伴有睡眠障碍的ASD患者中才检测到6个错义改变：无时间的p.F498S、NR1D1的p.S20R、PER3的p.R493C、时钟的p.H542R、ARNTL2的p.L473S和MTNR1B的p.A325V。仅在无睡眠障碍的ASD患者中检测到6个错义改变：PER1中的p.S1241N，永恒中的p.A325T，ARNTL中的p.S13T，MTNR1B中的p.G24E，PER2中的p.G24E，以及PER3中的p.T1177A。两组均检测到PER3基因p.R493C突变。仅在对照组中检测到PER2中的一个错义突变p.P932L。仅在伴有睡眠障碍的ASD患者中检测到NR1D1、CLOCK和ARNTL2的突变。在所有自闭症患者和对照组中，仅检测到一次突变的发生率显著不同(p=0.003)。通过三种不同的方法：PolyPhen-2、尺度不变特征变换(SIFT)预测和突变尝试者(www.matationtaster.org)，仅在伴有睡眠障碍的ASD患者中检测到的两种突变，即永恒的p.F498S和PER3的p.R366Q，被认为影响了基因功能。NR1D1中的p.S20R突变、Clock中的p.H542R突变、ARNTL2中的p.L473S突变、Timeless中的p.A325T突变、ARNTL中的p.S13T突变以及PER2中的p.G24E突变可通过多种方法对基因功能产生负面影响。昼夜节律相关基因可能参与ASD的精神病理过程。(C)2015年日本儿童神经病学学会。爱思唯尔出版，版权所有。
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 (wwvv.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. (c) 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.