title: Recurrent dominant mutations affecting two adjacent residues in the motor domain of the monomeric kinesin KIF22 result in skeletal dysplasia and joint laxity.
abstract: Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type (lepto-SEMDJL, aka SEMDJL, Hall type), is an autosomal dominant skeletal disorder that, in spite of being relatively common among skeletal dysplasias, has eluded molecular elucidation so far. We used whole-exome sequencing of five unrelated individuals with lepto-SEMDJL to identify mutations in KIF22 as the cause of this skeletal condition. Missense mutations affecting one of two adjacent amino acids in the motor domain of KIF22 were present in 20 familial cases from eight families and in 12 other sporadic cases. The skeletal and connective tissue phenotype produced by these specific mutations point to functions of KIF22 beyond those previously ascribed functions involving chromosome segregation. Although we have found Kif22 to be strongly upregulated at the growth plate, the precise pathogenetic mechanisms remain to be elucidated.
authors.affiliation: Children's Hospital Boston, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Boyden
authors.forename: A Belinda
authors.initials: AB
authors.lastname: Campos-Xavier
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kalamajski
authors.forename: Trevor L
authors.initials: TL
authors.lastname: Cameron
authors.forename: Philippe
authors.initials: P
authors.lastname: Suarez
authors.forename: Goranka
authors.initials: G
authors.lastname: Tanackovic
authors.forename: Goranka
authors.initials: G
authors.lastname: Tanackovich
authors.forename: Generoso
authors.initials: G
authors.lastname: Andria
authors.forename: Diana
authors.initials: D
authors.lastname: Ballhausen
authors.forename: Michael D
authors.initials: MD
authors.lastname: Briggs
authors.forename: Claire
authors.initials: C
authors.lastname: Hartley
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cohn
authors.forename: H Rosemarie
authors.initials: HR
authors.lastname: Davidson
authors.forename: Christine
authors.initials: C
authors.lastname: Hall
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
authors.forename: Pierre-Simon
authors.initials: PS
authors.lastname: Jouk
authors.forename: Rainer
authors.initials: R
authors.lastname: König
authors.forename: André
authors.initials: A
authors.lastname: Megarbané
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Lachman
authors.forename: Geert
authors.initials: G
authors.lastname: Mortier
authors.forename: David L
authors.initials: DL
authors.lastname: Rimoin
authors.forename: R Curtis
authors.initials: RC
authors.lastname: Rogers
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Rossi
authors.forename: Hirotake
authors.initials: H
authors.lastname: Sawada
authors.forename: Richard
authors.initials: R
authors.lastname: Scott
authors.forename: Sheila
authors.initials: S
authors.lastname: Unger
authors.forename: Eugenia Ribeiro
authors.initials: ER
authors.lastname: Valadares
authors.forename: John F
authors.initials: JF
authors.lastname: Bateman
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Warman
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonafé
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D002648:Child; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D059472:Exome; D015870:Gene Expression; D005799:Genes, Dominant; D056726:Genetic Association Studies; D006132:Growth Plate / Q000378:metabolism; D006801:Humans; D004204:Joint Dislocations / Q000151:congenital* / Q000235:genetics; D007593:Joint Instability / Q000235:genetics*; D016547:Kinesins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D010009:Osteochondrodysplasias / Q000235:genetics*; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA; D013977:Tibia / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C098764:KIF22 protein, human; D016547:Kinesins