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.

Localization of bone morphogenetic protein 13 in human intervertebral disc and its molecular and functional effects in vitro in 3D culture

“…Mis-sense mutations in the prodomain of BMP-13, resulting in the loss of BMP-13, are associated with KFS, which is characterized by variable levels of vertebral fusion during fetal disc development. 22 Intervertebral disc cells have the ability to migrate as demonstrated during rabbit disc development 23 and in a rat degeneration model. 24,25 In addition, new findings suggest that cells derived from potential stem cell niches can also migrate into the rabbit disc.…”

A Novel GDF6 Mutation in a Family with Multiple Synostoses Syndrome without Hearing Loss

“…Since increased BMP signaling of various causes is associated with other multiple synostoses syndromes, noggin resistance of mutant GDF6s is postulated to be the major cause of SYNS4 [Wang et al, 2016;Terhal et al, 2018]. Other missense mutations in GDF6 have been reported in Klippel-Feil syndrome type 1, Leber congenital amaurosis type 17, and isolated microphthalmia [Tassabehji et al, 2008;Asai-Coakwell et al, 2009], but since several of these missense mutations are frequently found in normal control populations, their contribution to the etiology of these conditions is doubtful [Terhal et al, 2018].…”

Surgical treatment in a patient with Klippel–Feil syndrome and anterior cervical meningomyelocele: a case report and review of literature

“…Expressed in vertebrae and within the adult intervertebral disc [12], lack of GDF6 and GDF5 in mice was shown to induce osseous malformations along the vertebral column and mutations in the GDF6 gene locus have been described in both familiar and sporadic cases of KFS [11,12]. Nevertheless, reports about KFS patients lacking mutations of the GDF6 locus suggest other underlying genetic alterations [13].…”