Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland; Institute of Medical Genetics, University of Zurich, 8603 Zurich, Switzerland.
Am J Hum Genet. 2014 Jan 2;94(1):62-72. doi: 10.1016/j.ajhg.2013.11.019. Epub 2013 Dec 19.
Joubert syndrome (JBTS) is a recessive ciliopathy in which a subset of affected individuals also have the skeletal dysplasia Jeune asphyxiating thoracic dystrophy (JATD). Here, we have identified biallelic truncating CSPP1 (centrosome and spindle pole associated protein 1) mutations in 19 JBTS-affected individuals, four of whom also have features of JATD. CSPP1 mutations explain ∼5% of JBTS in our cohort, and despite truncating mutations in all affected individuals, the range of phenotypic severity is broad. Morpholino knockdown of cspp1 in zebrafish caused phenotypes reported in other zebrafish models of JBTS (curved body shape, pronephric cysts, and cerebellar abnormalities) and reduced ciliary localization of Arl13b, further supporting loss of CSPP1 function as a cause of JBTS. Fibroblasts from affected individuals with CSPP1 mutations showed reduced numbers of primary cilia and/or short primary cilia, as well as reduced axonemal localization of ciliary proteins ARL13B and adenylyl cyclase III. In summary, CSPP1 mutations are a major cause of the Joubert-Jeune phenotype in humans; however, the mechanism by which these mutations lead to both JBTS and JATD remains unknown.
杰伯综合征（JBTS）是一种隐性纤毛病，其中一部分受影响的个体还具有骨骼发育不良的杨氏窒息性胸肌营养不良症（JATD）。在这里，我们在 19 名受 JBTS 影响的个体中发现了双等位基因截断的 CSPP1（中心体和纺锤极相关蛋白 1）突变，其中 4 名个体也具有 JATD 的特征。CSPP1 突变解释了我们队列中约 5%的 JBTS，尽管所有受影响的个体都存在截断突变，但表型严重程度的范围很广。在斑马鱼中，cspp1 的形态发生抑制导致了其他斑马鱼 JBTS 模型中报告的表型（弯曲的体型、肾前囊肿和小脑异常），并减少了 Arl13b 的纤毛定位，进一步支持 CSPP1 功能丧失是 JBTS 的原因。来自 CSPP1 突变个体的成纤维细胞显示初级纤毛数量减少和/或初级纤毛短小，以及纤毛蛋白 ARL13B 和腺苷酸环化酶 III 的轴突定位减少。总之，CSPP1 突变是人类杰伯-杨氏表型的主要原因；然而，这些突变导致 JBTS 和 JATD 的机制尚不清楚。
