生物谷报道:最新研究结果显示,最少一半的男性自闭症(autism)病例是由自发遗传突变引起的。遗传有这些突变的个体,其子女罹患自闭症的风险很高。详细内容刊登于PNAS。
自闭症患者有社交障碍,兴趣范围狭窄。每1000人中就有3-6名有自闭症倾向,但病因不明,专家推测其可能与遗传有关。纽约Albert Einstein医学院神经学家Isabelle Rapin说:“遗传在自闭症中发挥主要作用,这是20多年来的共识……遗传学证据也并不矛盾。”但弄清基因影响自闭症的确切机制却并非易事。自闭症是一种复杂疾病,症状范围广泛且很严重。由于某种未知原因,男性患者是女性患者的四倍。
自发突变
今年早期进行一次基因组范围内扫描,将某些自闭症病例与某些基因的拷贝数突变联系起来。10%的自闭症患者有其余患者中不存在的拷贝数突变,说明突变是自发的。但文章第一作者、冷泉港实验室遗传学家Michael Wigler强调,可能此研究错失了一些拷贝数突变。“我们可以肯定,10%这个数字是低估了。”因此,Wigler与其同事转向一个记录家庭中有两个或者两个以上自闭症儿童的家谱数据库,试图弄清头两个孩子患有自闭症的家庭,第三个孩子患有自闭症的几率有多大。所调查的86个家庭中,头两个孩子是自闭症患者,第三个孩子是男性,结果其中42个排行第三的孩子有自闭症症状。这说明患者将突变传给后代的几率为1/2。另一个数据库研究得到了相似的结论。
利用数学模型,Wigler小组发现描述这种自闭症遗传的最为简单的方法是将患者分为两个风险级别,携带一个之前存在的自闭症诱发突变的人群和不携带此突变的人群。该模型强调,大约一半的自闭症儿童来的父母,之前没有明显的自闭症遗传学特征,说明这些儿童的自闭症是由自发突变引起的。倾向于有自闭症子女的高龄母亲,也可归为此列。高龄母亲的卵子有更多的机会积累突变。
这些自发突变一旦传递下去,其后代——特别是女性后代,毫无症状地携带突变——更有可能得到自闭症子女。携带此突变的男性,也应该有遗传给后代的可能,但也许因为自闭症而不会有后代。最新研究模式提示,约1/4的自闭症儿童从其父母处获得一个拷贝数突变。
“这是观察数据的一种新方式,”Papin说,但该模型还需要经过更多数据的检验。自闭症也可能与其它因素如妊娠期并发症以及多重基因的影响有关。
原始出处:
Published online before print July 25, 2007
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0705803104
OPEN ACCESS ARTICLE
Genetics
A unified genetic theory for sporadic and inherited autism
( human genetics | neurodevelopmental disorders | population genetics )
Xiaoyue Zhao *, Anthony Leotta *, Vlad Kustanovich , Clara Lajonchere , Daniel H. Geschwind , Kiely Law , Paul Law , Shanping Qiu ¶, Catherine Lord ¶, Jonathan Sebat *, Kenny Ye ||**, and Michael Wigler ***
*Cold Spring Harbor Laboratory, 1 Bungtown Road, P.O. Box 100, Cold Spring Harbor, NY 11724; Autism Genetic Resource Exchange, Cure Autism Now, 5455 Wilshire Boulevard, Suite 2250, Los Angeles, CA 90036; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1769; Department of Medical Informatics, and Interactive Autism Network, Kennedy Krieger Institute, Baltimore, MD 21205; ¶University of Michigan Autism and Communication Disorders Center, 1111 East Catherine Street, Ann Arbor, MI 48109-2054; and ||Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461
Contributed by Michael Wigler, June 20, 2007 (sent for review June 1, 2007)
Autism is among the most clearly genetically determined of all cognitive-developmental disorders, with males affected more often than females. We have analyzed autism risk in multiplex families from the Autism Genetic Resource Exchange (AGRE) and find strong evidence for dominant transmission to male offspring. By incorporating generally accepted rates of autism and sibling recurrence, we find good fit for a simple genetic model in which most families fall into two types: a small minority for whom the risk of autism in male offspring is near 50%, and the vast majority for whom male offspring have a low risk. We propose an explanation that links these two types of families: sporadic autism in the low-risk families is mainly caused by spontaneous mutation with high penetrance in males and relatively poor penetrance in females; and high-risk families are from those offspring, most often females, who carry a new causative mutation but are unaffected and in turn transmit the mutation in dominant fashion to their offspring.