Ciliary Abnormalities Due to Defects in the Retrograde Transport Protein DYNC2H1 in Short-Rib Polydactyly Syndrome

被引：122

作者：

Merrill, Amy E. ^{[1
,2
]}

Merriman, Barry ^{[3
]}

Farrington-Rock, Claire ^{[1
]}

Camacho, Natalia ^{[2
]}

Sebald, Eiman T. ^{[1
]}

Funari, Vincent A. ^{[1
,4
]}

Schibler, Matthew J. ^{[7
,8
]}

Firestein, Marc H. ^{[2
]}

Cohn, Zachary A. ^{[1
]}

Priore, Mary Ann ^{[1
]}

Thompson, Alicia K. ^{[9
]}

Rimoin, David L. ^{[1
,3
,4
,5
]}

Nelson, Stanley F. ^{[3
]}

Cohn, Daniel H. ^{[1
,3
,4
]}

Krakow, Deborah ^{[1
,2
,3
,6
]}

机构：

[1] Cedars Sinai Med Ctr, Med Genet Res Inst, Los Angeles, CA 90048 USA

[2] Univ Calif Los Angeles, Dept Orthoped Surg, David Geffen Sch Med, Los Angeles, CA 90024 USA

[3] Univ Calif Los Angeles, Dept Human Genet, David Geffen Sch Med, Los Angeles, CA 90024 USA

[4] Univ Calif Los Angeles, Dept Pediat, David Geffen Sch Med, Los Angeles, CA 90024 USA

[5] Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, Los Angeles, CA 90024 USA

[6] Univ Calif Los Angeles, Dept Obstet & Gynecol, David Geffen Sch Med, Los Angeles, CA 90024 USA

[7] Univ Calif Los Angeles, Brain Res Inst, David Geffen Sch Med, Los Angeles, CA 90024 USA

[8] Univ Calif Los Angeles, Calif NanoSyst Inst, David Geffen Sch Med, Los Angeles, CA 90024 USA

[9] Univ So Calif, Ctr Electron Microscopy, Los Angeles, CA 90089 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2009年 / 84卷 / 04期

关键词：

ASPHYXIATING THORACIC DYSTROPHY; CHONDROCYTE PRIMARY CILIUM; VAN-CREVELD-SYNDROME; INTRAFLAGELLAR TRANSPORT; CONTINUOUS-SPECTRUM; DYNEIN; MOUSE; MOTOR; LOCALIZATION; DISORDERS;

D O I：

10.1016/j.ajhg.2009.03.015

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The short-rib polydactyly (SRP) syndromes are a heterogenous group of perinatal lethal skeletal disorders with polydactyly and multisystem organ abnormalities. Homozygosity by descent mapping in a consanguineous SRP family identified a genomic region that contained DYNC2H1, a cytoplasmic dynein involved in retrograde transport in the cilium. Affected individuals in the family were homozygous for an exon 12 missense mutation that predicted the amino acid substitution R587C. Compound heterozygosity for one missense and one null mutation was identified in two additional nonconsanguineous SRP families. Cultured chondrocytes from affected individuals showed morphologically abnormal, shortened cilia. In addition, the chondrocytes showed abnormal cytoskeletal microtubule architecture, implicating an altered microtubule network as part of the disease process. These findings establish SRP as a cilia disorder and demonstrate that DYNC2H1 is essential for skeletogenesis and growth.

引用

页码：542 / 549

页数：8

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