title: 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.
authors.affiliation: Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany. christian.thiel@uk-erlangen.de
authors.forename: Christian
authors.initials: C
authors.lastname: Thiel
authors.forename: Kristin
authors.initials: K
authors.lastname: Kessler
authors.forename: Andreas
authors.initials: A
authors.lastname: Giessl
authors.forename: Arno
authors.initials: A
authors.lastname: Dimmler
authors.forename: Stavit A
authors.initials: SA
authors.lastname: Shalev
authors.forename: Sigrun
authors.initials: S
authors.lastname: von der Haar
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.forename: Diana
authors.initials: D
authors.lastname: Zahnleiter
authors.forename: Hartmut
authors.initials: H
authors.lastname: Stöss
authors.forename: Ernst
authors.initials: E
authors.lastname: Beinder
authors.forename: Rami
authors.initials: R
authors.lastname: Abou Jamra
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.forename: Nadja
authors.initials: N
authors.lastname: Schröder-Kress
authors.forename: Thomas
authors.initials: T
authors.lastname: Aigner
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirchner
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Johann H
authors.initials: JH
authors.lastname: Brandstätter
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D002923:Cilia / Q000235:genetics* / Q000502:physiology; D056445:Cytoplasmic Dyneins / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D000072380:NIMA-Related Kinase 1; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011859:Radiography; D017422:Sequence Analysis, DNA; D012720:Severity of Illness Index; D012779:Short Rib-Polydactyly Syndrome / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology
chemical_list: D018797:Cell Cycle Proteins; C099883:DYNC2H1 protein, human; C000606914:NEK1 protein, human; D000072380:NIMA-Related Kinase 1; D017346:Protein Serine-Threonine Kinases; D056445:Cytoplasmic Dyneins