NEK1 Mutations Cause Short-Rib Polydactyly Syndrome Type Majewski

Abstract

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.

Nek1 kinase associates with ATR–ATRIP and primes ATR for efficient DNA damage signaling

“…Similar to some Seckel patients, Nek +/− mutant mice developed lymphoma (38,39). Interestingly, loss of Nek1 has been linked to defective ciliogenesis and progressive kidney failure in both mouse and human (40)(41)(42)(43). Several other genes involved in the DNA damage response were recently linked to similar cellular and tissue defects (44)(45)(46), raising the possibility that the function of Nek1 in DNA damage signaling is critical in specific tissues.…”

Cell cycle regulation by the NEK family of protein kinases

“…A typical characteristic of these disorders is polycystic kidney disease (PKD), and studies on two mouse PKD models have led to the identification of mutations in the Nek1 and Nek8 genes (Liu et al, 2002;Upadhya et al, 2000;Vogler et al, 1999). Since then, mutations in NEK1 and NEK8 have also been identified in human ciliopathy patients; these NEKs are thought to have roles in the post-mitotic process of cilia assembly and/or function (Otto et al, 2008;Quarmby and Mahjoub, 2005;Thiel et al, 2011). Interestingly, NEK4 has also recently been implicated in cilium stability (Coene et al, 2011).…”

Abnormalities in Embryogenesis of Urinary System (Review of Literature)

“…Ці синдроми відносяться до групи ціліопатій і хара-ктеризуються наявністю коротких ребер і кінці-вок, дисплазією нирок, полідактилією і смертніс-тю в ранньому віці внаслідок дихальної недостат-ності. Найбільш вивчені мутації в гені NEK1 і TTC21B, які асоційовані із синдромом короткого ребра [23].…”