Mutations in PIK3R1 Cause SHORT Syndrome
Mutations in PIK3R1 Cause SHORT Syndrome
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DOI：
10.1016/j.ajhg.2013.06.005
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发表时间：
2013-07-11
影响因子：
9.8
通讯作者：
Innes, A. Micheil
中科院分区：
文献类型：
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作者：
Dyment, David A.;Smith, Amanda C.;Innes, A. Micheil
矮综合症是一种罕见的多系统疾病，其特征是身材矮小、前房眼异常、特征性面部特征、脂肪营养不良、疝气、过度伸展和牙列延迟。作为加拿大罕见疾病基因发现联盟 (FORGE) 的一部分，我们研究了具有短路综合征临床特征的个体，以确定这种罕见疾病的遗传病因。对受影响儿童和未受影响父母的家庭三人组进行全外显子组测序，发现 PIK3R1 外显子 14 中存在从头移码插入 c.1906_1907insC (p.Asn636Thrfs*18)。随后通过桑格测序在另外三名受影响的个体和两名受影响的家庭成员中鉴定出 PIK3R1 外显子 14 的杂合突变。其中一种突变 c.1945C>T (p.Arg649Trp) 被证实是一名受影响个体的从头突变，并且还被鉴定并显示与不相关家族中的表型分离。另一种突变是从头截短突变 (c.1971T>G [p.Tyr657*])，是在另一个受影响的个体中发现的。 PIK3R1 参与磷脂酰肌醇 3 激酶 (PI3K) 信号级联，因此在细胞生长、增殖和存活中发挥重要作用。对具有 PIK3R1 c.1906_1907insC 突变的类淋巴母细胞的功能研究表明，PI3K-AKT-mTOR 通路下游 S6 靶标的磷酸化降低。我们的研究结果表明，PIK3R1 突变是短路综合征的主要原因，并表明疾病的分子机制可能涉及 PI3K-AKT-mTOR 通路的下调。
SHORT syndrome is a rare, multisystem disease characterized by short stature, anterior-chamber eye anomalies, characteristic facial features, lipodystrophy, hernias, hyperextensibility, and delayed dentition. As part of the FORGE (Finding of Rare Disease Genes) Canada Consortium, we studied individuals with clinical features of SHORT syndrome to identify the genetic etiology of this rare disease. Whole-exome sequencing in a family trio of an affected child and unaffected parents identified a de novo frameshift insertion, c.1906_1907insC (p.Asn636Thrfs*18), in exon 14 of PIK3R1. Heterozygous mutations in exon 14 of PIK3R1 were subsequently identified by Sanger sequencing in three additional affected individuals and two affected family members. One of these mutations, c.1945C>T (p.Arg649Trp), was confirmed to be a de novo mutation in one affected individual and was also identified and shown to segregate with the phenotype in an unrelated family. The other mutation, a de novo truncating mutation (c.1971T>G [p.Tyr657*]), was identified in another affected individual. PIK3R1 is involved in the phosphatidylinositol 3 kinase (PI3K) signaling cascade and, as such, plays an important role in cell growth, proliferation, and survival. Functional studies on lymphoblastoid cells with the PIK3R1 c.1906_1907insC mutation showed decreased phosphorylation of the downstream S6 target of the PI3K-AKT-mTOR pathway. Our findings show that PIK3R1 mutations are the major cause of SHORT syndrome and suggest that the molecular mechanism of disease might involve down-regulation of the PI3K-AKT-mTOR pathway.