Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome.
Klippel-Feil syndrome (KFS) is a congenital disorder of spinal segmentation distinguished by the bony fusion of anterior/cervical vertebrae. Scoliosis, mirror movements, otolaryngological, kidney, ocular, cranial, limb, and/or digit anomalies are often associated. Here we report mutations at the GDF6 gene locus in familial and sporadic cases of KFS including the recurrent missense mutation of an extremely conserved residue c.866T>C (p.Leu289Pro) in association with mirror movements and an inversion breakpoint downstream of the gene in association with carpal, tarsal, and vertebral fusions. GDF6 is expressed at the boundaries of the developing carpals, tarsals, and vertebrae and within the adult vertebral disc. GDF6 knockout mice are best distinguished by fusion of carpals and tarsals and GDF6 knockdown in Xenopus results in a high incidence of anterior axial defects consistent with a role for GDF6 in the etiology, diversity, and variability of KFS.
Tassabehji
May
M
Academic Unit of Medical Genetics and Regional Genetics Service, University of Manchester, St Mary's Hospital, Manchester, United Kingdom.
Fang
Zhi Ming
ZM
Hilton
Emma N
EN
McGaughran
Julie
J
Zhao
Zhongming
Z
de Bock
Charles E
CE
Howard
Emma
E
Malass
Michael
M
Donnai
Dian
D
Diwan
Ashish
A
Manson
Forbes D C
FD
Murrell
Dédée
D
Clarke
Raymond A
RA
D000595:Amino Acid Sequence; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000737:chemistry / Q000235:genetics*; D007446:Chromosome Inversion; D004252:DNA Mutational Analysis; D005260:Female; D055431:Growth Differentiation Factor 6; D006801:Humans; D007714:Klippel-Feil Syndrome / Q000235:genetics*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D016415:Sequence Alignment; D013131:Spine / Q000002:abnormalities; D014982:Xenopus laevis
D019485:Bone Morphogenetic Proteins; C525906:GDF6 protein, human; C525907:Gdf6 protein, mouse; D055431:Growth Differentiation Factor 6