Parvari Ruti, Hershkovitz Eli, Grossman Nili, Gorodischer Rafael, Loeys Bart, Zecic Alexandra, Mortier Geert, Gregory Simon, Sharony Reuven, Kambouris Marios, Sakati Nadia, Meyer Brian F, Al Aqeel Aida I, Al Humaidan Abdul Karim, Al Zanhrani Fatma, Al Swaid Abdulrahman, Al Othman Johara, Diaz George A, Weiner Rory, Khan K Tahseen S, Gordon Ronald, Gelb Bruce D
Department of Developmental Molecular Genetics, Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel.
Nat Genet. 2002 Nov;32(3):448-52. doi: 10.1038/ng1012. Epub 2002 Oct 21.
The syndrome of congenital hypoparathyroidism, mental retardation, facial dysmorphism and extreme growth failure (HRD or Sanjad-Sakati syndrome; OMIM 241410) is an autosomal recessive disorder reported almost exclusively in Middle Eastern populations. A similar syndrome with the additional features of osteosclerosis and recurrent bacterial infections has been classified as autosomal recessive Kenny-Caffey syndrome (AR-KCS; OMIM 244460). Both traits have previously been mapped to chromosome 1q43-44 (refs 5,6) and, despite the observed clinical variability, share an ancestral haplotype, suggesting a common founder mutation. We describe refinement of the critical region to an interval of roughly 230 kb and identification of deletion and truncation mutations of TBCE in affected individuals. The gene TBCE encodes one of several chaperone proteins required for the proper folding of alpha-tubulin subunits and the formation of alpha-beta-tubulin heterodimers. Analysis of diseased fibroblasts and lymphoblastoid cells showed lower microtubule density at the microtubule-organizing center (MTOC) and perturbed microtubule polarity in diseased cells. Immunofluorescence and ultrastructural studies showed disturbances in subcellular organelles that require microtubules for membrane trafficking, such as the Golgi and late endosomal compartments. These findings demonstrate that HRD and AR-KCS are chaperone diseases caused by a genetic defect in the tubulin assembly pathway, and establish a potential connection between tubulin physiology and the development of the parathyroid.
先天性甲状旁腺功能减退、智力发育迟缓、面部畸形及严重生长发育障碍综合征（HRD或Sanjad-Sakati综合征；OMIM 241410）是一种常染色体隐性疾病，几乎仅在中东人群中报道。一种具有骨硬化和反复细菌感染等额外特征的类似综合征已被归类为常染色体隐性Kenny-Caffey综合征（AR-KCS；OMIM 244460）。这两种病症此前均已被定位到1号染色体的1q43 - 44区域（参考文献5、6），并且尽管观察到临床变异性，但共享一个祖传单倍型，提示存在一个共同的奠基者突变。我们描述了将关键区域精细定位到大约230 kb的区间，并在受影响个体中鉴定出TBCE的缺失和截断突变。基因TBCE编码α-微管蛋白亚基正确折叠以及α-β微管蛋白异二聚体形成所需的几种伴侣蛋白之一。对患病成纤维细胞和淋巴母细胞的分析显示，在微管组织中心（MTOC）微管密度降低，且患病细胞中微管极性受到干扰。免疫荧光和超微结构研究显示，在需要微管进行膜运输的亚细胞器（如高尔基体和晚期内体区室）中存在紊乱。这些发现表明，HRD和AR-KCS是由微管蛋白组装途径中的遗传缺陷引起的伴侣蛋白疾病，并在微管蛋白生理学与甲状旁腺发育之间建立了潜在联系。
