title: Identification of a Ninein (NIN) mutation in a family with spondyloepimetaphyseal dysplasia with joint laxity (leptodactylic type)-like phenotype.
abstract: Spondyloepimetaphyseal dysplasia with joint laxity-leptodactylic type (SEMDJL2) is an autosomal dominant skeletal dysplasia which is characterized by midface hypoplasia, short stature, joint laxity with dislocations, genua valga, progressive scoliosis, and slender fingers. Recently, heterozygous missense mutations in KIF22, a gene which encodes a member of the kinesin-like protein family, have been identified in sporadic as well as familial cases of SEMDJL2. In the present study homozygosity mapping and whole-exome sequencing were combined to analyze a consanguineous family with a phenotype resembling SEMDJL2. We identified homozygous missense mutations in the two nearby genes NIN (Ninein) and POLE2 (DNA polymerase epsilon subunit B) which segregate with the disease in the family and were not present in 500 healthy control individuals and in the 1094 control individuals contained within the 1000-genomes database. We present several lines of evidence that mutant Ninein is most likely causative for the SEMDJL2-like phenotype. The centrosomal protein NIN shows a functional relationship with KIF22 and other proteins associated with chromosome congression/movement, centrosomal function, and ciliogenesis, which have been associated with skeletal dysplasias. Moreover, compound heterozygous missense mutations at more N-terminal positions of Ninein have very recently been identified in a family with microcephalic primordial dwarfism. Together with the present report this strongly supports a fundamental role of Ninein in skeletal development.
authors.affiliation: Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Grosch
authors.forename: Barbara
authors.initials: B
authors.lastname: Grüner
authors.forename: Stephanie
authors.initials: S
authors.lastname: Spranger
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Stütz
authors.forename: Tobias
authors.initials: T
authors.lastname: Rausch
authors.forename: Jan O
authors.initials: JO
authors.lastname: Korbel
authors.forename: Dominik
authors.initials: D
authors.lastname: Seelow
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Lausch
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zabel
authors.forename: Andreas
authors.initials: A
authors.lastname: Winterpacht
authors.forename: Andreas
authors.initials: A
authors.lastname: Tagariello
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002874:Chromosome Mapping; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004257:DNA Polymerase II / Q000235:genetics; D040461:Gene Components; D006801:Humans; D007593:Joint Instability / Q000235:genetics* / Q000473:pathology*; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000473:pathology*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
chemical_list: D003598:Cytoskeletal Proteins; C512806:NIN protein, human; D009687:Nuclear Proteins; D020033:Protein Isoforms; D004257:DNA Polymerase II
keywords: Centrosome; Ninein; SEMD; Spondyloepimetaphyseal dysplasia; Whole-exome sequencing