title: Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome.
abstract: 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.
authors.affiliation: Academic Unit of Medical Genetics and Regional Genetics Service, University of Manchester, St Mary's Hospital, Manchester, United Kingdom.
authors.forename: May
authors.initials: M
authors.lastname: Tassabehji
authors.forename: Zhi Ming
authors.initials: ZM
authors.lastname: Fang
authors.forename: Emma N
authors.initials: EN
authors.lastname: Hilton
authors.forename: Julie
authors.initials: J
authors.lastname: McGaughran
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhao
authors.forename: Charles E
authors.initials: CE
authors.lastname: de Bock
authors.forename: Emma
authors.initials: E
authors.lastname: Howard
authors.forename: Michael
authors.initials: M
authors.lastname: Malass
authors.forename: Dian
authors.initials: D
authors.lastname: Donnai
authors.forename: Ashish
authors.initials: A
authors.lastname: Diwan
authors.forename: Forbes D C
authors.initials: FD
authors.lastname: Manson
authors.forename: Dédée
authors.initials: D
authors.lastname: Murrell
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Clarke
mesh_terms: 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
chemical_list: D019485:Bone Morphogenetic Proteins; C525906:GDF6 protein, human; C525907:Gdf6 protein, mouse; D055431:Growth Differentiation Factor 6