RAB23 mutations in carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity
RAB23 mutations in carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity
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DOI：
10.1086/518047
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发表时间：
2007-06-01
影响因子：
9.8
通讯作者：
Wilkie, Andrew O. M.
中科院分区：
文献类型：
--
作者：
Jenkins, Dagan;Seelow, Dominik;Wilkie, Andrew O. M.
卡彭特综合征是一种常染色体隐性遗传的多效性疾病，其主要特征包括颅缝闭合、多指畸形、肥胖和心脏缺陷。通过纯合子作图，我们发现了与染色体6p12.1-q12的连锁，并在15个独立家族中鉴定出RAB23的5个不同突变（4个截断和1个错义），RAB23编码RAB鸟苷三磷酸酶（GTPase）家族的一个成员，并作为hedgehog （HH）信号传导的负调控因子。在10例患者中，这种疾病是由同一无义突变L145X的纯合性引起的，该突变位于一个共同的单倍型上，表明北欧血统患者存在奠基者效应。令人惊讶的是，开放脑小鼠中Rab23的无义突变会导致隐性胚胎致死性和神经管缺陷，这表明在早期发育过程中对Rab23的需求存在物种差异。RAB23突变在卡彭特综合征患者中的发现暗示了HH信号在颅缝生物发生中的作用，这是一个意想不到的发现，因为颅缝闭合通常与其他HH通路组分的突变无关，并且为肥胖研究提供了一个新的分子靶点。
Carpenter syndrome is a pleiotropic disorder with autosomal recessive inheritance, the cardinal features of which include craniosynostosis, polysyndactyly, obesity, and cardiac defects. Using homozygosity mapping, we found linkage to chromosome 6p12.1-q12 and, in 15 independent families, identified five different mutations (four truncating and one missense) in RAB23, which encodes a member of the RAB guanosine triphosphatase (GTPase) family of vesicle transport proteins and acts as a negative regulator of hedgehog (HH) signaling. In 10 patients, the disease was caused by homozygosity for the same nonsense mutation, L145X, that resides on a common haplotype, indicative of a founder effect in patients of northern European descent. Surprisingly, nonsense mutations of Rab23 in open brain mice cause recessive embryonic lethality with neural-tube defects, suggesting a species difference in the requirement for RAB23 during early development. The discovery of RAB23 mutations in patients with Carpenter syndrome implicates HH signaling in cranial-suture biogenesis-an unexpected finding, given that craniosynostosis is not usually associated with mutations of other HH-pathway components-and provides a new molecular target for studies of obesity.