Recurrent Dominant Mutations Affecting Two Adjacent Residues in the Motor Domain of the Monomeric Kinesin KIF22 Result in Skeletal Dysplasia and Joint Laxity

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• 作者：Eric  ; D. Boyden¹ ;   ; ²⁴ ; A.  ; Belinda Campos-Xavier² ;   ; ²⁴ ; Sebastian Kalamajski¹ ;   ; ²⁴ ; Trevor  ; L. Cameron³ ; Philippe Suarez² ; Goranka Tanackovich⁴ ; Generoso Andria⁵ ; Diana Ballhausen² ; Michael  ; D. Briggs⁶ ; Claire Hartley⁶ ; Daniel  ; H. Cohn⁷ ; H.  ; Rosemarie Davidson⁸ ; Christine Hall⁹ ; Shiro Ikegawa¹⁰ ; Pierre-Simon Jouk¹¹ ; Rainer Kö ; nig¹² ; André ; Megarbané ; ¹³ ; Gen Nishimura¹⁴ ; Ralph  ; S. Lachman¹⁵ ; Geert Mortier¹⁶ ; David  ; L. Rimoin¹⁵ ;   ; ¹⁷ ; R.  ; Curtis Rogers¹⁸ ; Massimiliano Rossi⁵ ; Hirotake Sawada¹⁹ ; Richard Scott²⁰ ; Sheila Unger²¹ ; Eugenia  ; Ribeiro Valadares²² ; John  ; F. Bateman³ ;   ; ²³ ; Matthew  ; L. Warman¹ ; Andrea Superti-Furga² ; Luisa Bonafé ; ² ;   ; ^{luisa.bonafe@chuv.ch}
• 刊名：The American Journal of Human Genetics
• 出版年：2011
• 出版时间：9 December 2011
• 年：2011
• 卷：89
• 期：6
• 页码：767-772
• 全文大小：506 K

文摘

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.