Zahnleiter Diana, Hauer Nadine N, Kessler Kristin, Uebe Steffen, Sugano Yuya, Neuhauss Stephan C F, Giessl Andreas, Ekici Arif B, Blessing Holger, Sticht Heinrich, Dörr Helmuth-Günther, Reis André, Thiel Christian T
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Hum Mutat. 2015 Jan;36(1):87-97. doi: 10.1002/humu.22711. Epub 2014 Nov 28.
Numerous genes are involved in human growth regulation. Recently, autosomal-recessive inherited variants in centrosomal proteins have been identified in Seckel syndrome, primary microcephaly, or microcephalic osteodysplastic primary dwarfism. Common hallmarks of these syndromic forms are severe short stature and microcephaly. In a consanguineous family with two affected children with severe growth retardation and normocephaly, we used homozygosity mapping and next-generation sequencing to identify a homozygous MAP4 variant. MAP4 is a major protein for microtubule assembly during mitosis. High-expression levels in the somite boundaries of zebrafish suggested a role in growth and body segment patterning. The identified variant affects binding sites of kinases necessary for dynamic instability of microtubule formation. We found centrosome amplifications in mitotic fibroblast cells in vivo and in vitro. These numeric centrosomal aberrations were also present during interphase resulting in aberrant ciliogenesis. Furthermore, affected cells showed a dysfunction of the microtubule-dependent assembly of the Golgi apparatus, indicated by a significant lack of compactness of Golgi membranes. These observations demonstrated that MAP4 mutations contribute to the clinical spectrum of centrosomal defects and confirmed the complex role of a centrosomal protein in centrosomal, ciliary, and Golgi regulation associated with severe short stature.
许多基因参与人类生长调节。最近，在塞克尔综合征、原发性小头畸形或小头畸形骨发育不良性原发性侏儒症中，已鉴定出中心体蛋白的常染色体隐性遗传变异。这些综合征形式的共同特征是严重身材矮小和小头畸形。在一个有两个患有严重生长发育迟缓且头部正常的患病儿童的近亲家庭中，我们使用纯合性定位和下一代测序来鉴定一个纯合的MAP4变异。MAP4是有丝分裂期间微管组装的主要蛋白质。斑马鱼体节边界中的高表达水平表明其在生长和身体节段模式形成中起作用。所鉴定的变异影响微管形成动态不稳定性所需激酶的结合位点。我们在体内和体外的有丝分裂成纤维细胞中发现了中心体扩增。这些数量上的中心体畸变在间期也存在，导致异常的纤毛发生。此外，受影响的细胞显示出高尔基体微管依赖性组装功能障碍，这表现为高尔基体膜明显缺乏紧密性。这些观察结果表明，MAP4突变导致了中心体缺陷的临床症状，并证实了一种中心体蛋白在与严重身材矮小相关的中心体、纤毛和高尔基体调节中的复杂作用。
