PDF(Pubmed)
Abstract：
Spondylo-epi-metaphyseal dysplasias with joint laxity, type 3 (SEMDJL3) is a genetic skeletal disorder characterized by multiple joint dislocations, caused by biallelic pathogenic variants in the EXOC6B gene. Only four individuals from two families have been reported to have this condition to date. The molecular pathogenesis related to primary ciliogenesis has not been enumerated in subjects with SEMDJL3. In this study, we report two additional affected individuals from unrelated families with biallelic pathogenic variants, c.2122+15447_2197-59588del and c.401T>G in EXOC6B identified by exome sequencing. One of the affected individuals had an intellectual disability and central nervous system anomalies, including hydrocephalus, hypoplastic mesencephalon, and thin corpus callosum. Using the fibroblast cell lines, we demonstrate the primary evidence for the abrogation of exocytosis in an individual with SEMDLJ3 leading to impaired primary ciliogenesis. Osteogenesis differentiation and pathways related to the extracellular matrix were also found to be reduced. Additionally, we provide a review of the clinical and molecular profile of all the mutation-proven patients reported hitherto, thereby further characterizing SEMDJL3. SEMDJL3 with biallelic pathogenic variants in EXOC6B might represent yet another ciliopathy with central nervous system involvement and joint dislocations.
摘要：
脊椎-epi-meta端发育不良伴关节松弛，3型（SEMDJL3）是一种以多个关节脱位为特征的遗传性骨骼疾病，由EXOC6B基因的双等位基因致病变异引起。据报道，到目前为止，只有来自两个家庭的四个人患有这种疾病。在患有SEMDJL3的受试者中尚未列举与原发性纤毛发生相关的分子发病机理。在这项研究中,我们报告了另外两名来自具有双等位基因致病变异的无关家庭的受影响个体，通过外显子组测序鉴定的EXOC6B中的c.2122+15447_2197-59588del和c.401T>G。其中一个受影响的人有智力残疾和中枢神经系统异常，包括脑积水,中脑发育不良,和薄的call体。使用成纤维细胞系，我们证明了SEMDLJ3患者胞吐作用的消除导致原发性纤毛发生受损的主要证据.还发现与细胞外基质相关的成骨分化和途径减少。此外,我们提供了迄今为止报道的所有经突变证实的患者的临床和分子概况的综述，从而进一步表征SEMDJL3。在EXOC6B中具有双等位基因致病性变异的SEMDJL3可能代表另一种中枢神经系统受累和关节脱位的纤毛病。
