Loss-of-Function Mutations in RAB18 Cause Warburg Micro Syndrome
Loss-of-Function Mutations in RAB18 Cause Warburg Micro Syndrome
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DOI：
10.1016/j.ajhg.2011.03.012
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发表时间：
2011-04-08
影响因子：
9.8
通讯作者：
Aligianis, Irene A.
中科院分区：
文献类型：
--
作者：
Bem, Danai;Yoshimura, Shin-Ichiro;Aligianis, Irene A.
Warburg Micro综合征和Martsolf综合征是一种以脑、眼和内分泌异常为特征的异质性常染色体隐性发育障碍。此前，在这两种综合征中都发现了RAB3GAP1和RAB3GAP2的突变，这表明RAB3周期(控制神经递质和激素的钙介导的胞吐)在疾病发病机制中存在失调。RAB3GAP1和RAB3GAP2编码RAB3GAP(RAB3GTP酶激活蛋白)的催化和非催化亚基，RAB3GAP是RAB3循环的关键调节因子。我们在五个没有RAB3GAP1/2突变的血缘关系家族中进行了自合作图，发现了Rab18的功能缺失突变。在四个巴基斯坦家系中发现了c.71T>；A(p.Leu24Gln)创始人突变，在第五个家系中发现了外显子2纯合子缺失(预计会导致移码)。通过对另外58个家系进行基因直接测序和多重连接依赖的探针扩增(MLPA)，发现了一个成员为终止密码子C.619T>；C(p.X207QextX20)和亚精氨酸缺失c.277_279 del(p.Arg93 del)的复合杂合子的单一家系。与Rab18(Leu24Gln)和Rab18(Arg93del)的核苷酸结合分析表明，这些突变蛋白不能与鸟氨酸结合，因此在功能上是零的。具有RAB3GAP1或RAB3GAP2突变和Rab18突变的Warburg Micro综合征患者的临床特征无法区分，尽管Rab18在贩运中的作用仍在出现，并且以前没有与RAB3通路相关联。在斑马鱼中敲除rob 18表明它可能具有保守的发育作用。我们的发现表明，Rab18在人类中起着关键作用。大脑和眼睛发育和神经退化。
Warburg Micro syndrome and Martsolf syndrome are heterogenous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Previously, identification of mutations in RAB3GAP1 and RAB3GAP2 in both these syndromes implicated dysregulation of the RAB3 cycle (which controls calcium-mediated exocytcsis of neurotransmitters and hormones) in disease pathogenesis. RAB3GAP1 and RAB3GAP2 encode the catalytic and noncatalytic subunits of the hetrodimeric enzyme RAB3GAP (RAB3GTPase-activating protein), a key regulator of the RAB3 cycle. We performed autozygosity mapping in five consanguineous families without RAB3GAP1/2 mutations and identified loss-of-function mutations in RAB18. A c.71T > A (p.Leu24Gln) founder mutation was identified in four Pakistani families, and a homozygous exon 2 deletion (predicted to result in a frameshift) was found in the fifth family. A single family whose members were compound heterozygotes for an anti-termination mutation of the stop codon c.619T > C (p.X207QextX20) and an inframe arginine deletion c.277_279 del (p.Arg93 del) were identified after direct gene sequencing and multiplex ligation-dependent probe amplification (MLPA) of a further 58 families. Nucleotide binding assays for RAB18(Leu24Gln) and RAB18(Arg93del) showed that these mutant proteins were functionally null in that they were unable to bind guanine. The clinical features of Warburg Micro syndrome patients with RAB3GAP1 or RAB3GAP2 mutations and RAB18 mutations are indistinguishable, although the role of RAB18 in trafficking is still emerging, and it has not been linked previously to the RAB3 pathway. Knockdown of rob 18 in zebrafish suggests that it might have a conserved developmental role. Our findings imply that RAB18 has a critical role in human. brain and eye development and neurodegeneration.