1. Recurrent dominant mutations affecting two adjacent residues in the motor domain of the monomeric kinesin KIF22 result in skeletal dysplasia and joint laxity.
- Author
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Boyden ED, Campos-Xavier AB, Kalamajski S, Cameron TL, Suarez P, Tanackovic G, Andria G, Ballhausen D, Briggs MD, Hartley C, Cohn DH, Davidson HR, Hall C, Ikegawa S, Jouk PS, König R, Megarbané A, Nishimura G, Lachman RS, Mortier G, Rimoin DL, Rogers RC, Rossi M, Sawada H, Scott R, Unger S, Valadares ER, Bateman JF, Warman ML, Superti-Furga A, and Bonafé L
- Subjects
- Amino Acid Sequence, Animals, Base Sequence, Cells, Cultured, Child, DNA-Binding Proteins chemistry, DNA-Binding Proteins metabolism, Exome, Gene Expression, Genetic Association Studies, Growth Plate metabolism, Humans, Joint Dislocations genetics, Kinesins chemistry, Kinesins metabolism, Male, Mice, Protein Structure, Tertiary, Sequence Analysis, DNA, Tibia metabolism, Abnormalities, Multiple genetics, DNA-Binding Proteins genetics, Genes, Dominant, Joint Dislocations congenital, Joint Instability genetics, Kinesins genetics, Mutation, Missense, Osteochondrodysplasias genetics
- 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., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
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