NEK1 Mutations Cause Short-Rib Polydactyly Syndrome Type Majewski

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• 作者：Christian Thiel¹ ; ^{christian.thiel@uk-erlangen.de} ; Kristin Kessler¹ ; Andreas Giessl² ; Arno Dimmler³ ; Stavit A. Shalev⁴ ; ⁵ ; Sigrun von der Haar⁶ ; Martin Zenker⁷ ; Diana Zahnleiter¹ ; Hartmut Stö ; ss⁸ ; Ernst Beinder⁹ ; Rami Abou Jamra¹ ; Arif B. Ekici¹ ; Nadja Schrö ; der-Kre&#xdf ; ² ; Thomas Aigner¹⁰ ; Thomas Kirchner¹¹ ; André ; Reis¹ ; Johann H. Brandstä ; tter² ; Anita Rauch¹²
• 刊名：The American Journal of Human Genetics
• 出版年：2011
• 出版时间：7 January 2011
• 年：2011
• 卷：88
• 期：1
• 页码：106-114
• 全文大小：1929 K

文摘

Defects of ciliogenesis have been implicated in a wide range of human phenotypes and play a crucial role in signal transduction and cell-cycle coordination. We used homozygosity mapping in two families with autosomal-recessive short-rib polydactyly syndrome Majewski type to identify mutations in NEK1 as an underlying cause of this lethal osteochondrodysplasia. NEK1 encodes a serine/threonine kinase with proposed function in DNA double-strand repair, neuronal development, and coordination of cell-cycle-associated ciliogenesis. We found that absence of functional full-length NEK1 severely reduces cilia number and alters ciliar morphology in vivo. We further substantiate a proposed digenic diallelic inheritance of ciliopathies by the identification of heterozygous mutations in NEK1 and DYNC2H1 in an additional family. Notably, these findings not only increase the broad spectrum of ciliar disorders, but suggest a correlation between the degree of defective microtubule or centriole elongation and organization and the severity of the resulting phenotype.