A New Subtype of Multiple Synostoses Syndrome Is Caused by a Mutation in GDF6 That Decreases Its Sensitivity to Noggin and Enhances Its Potency as a BMP Signal

Abstract

Growth and differentiation factors (GDFs) are secreted signaling molecules within the BMP family that have critical roles in joint morphogenesis during skeletal development in mice and humans. Using genetic data obtained from a six-generation Chinese family, we identified a missense variant in GDF6 (NP_001001557.1; p.Y444N) that fully segregates with a novel autosomal dominant synostoses (SYNS) phenotype, which we designate as SYNS4. Affected individuals display bilateral wrist and ankle deformities at birth and progressive conductive deafness after age 40 years. We find that the Y444N variant affects a highly conserved residue of GDF6 in a region critical for binding of GDF6 to its receptor(s) and to the BMP antagonist NOG, and show that this mutant GDF6 is a more potent stimulator of the canonical BMP signaling pathway compared with wild-type GDF6. Further, we determine that the enhanced BMP activity exhibited by mutant GDF6 is attributable to resistance to NOG-mediated antagonism. Collectively, our findings indicate that increased BMP signaling owing to a GDF6 gain-of-function mutation is responsible for loss of joint formation and profound functional impairment in patients with SYNS4. More broadly, our study highlights the delicate balance of BMP signaling required for proper joint morphogenesis and reinforces the critical role of BMP signaling in skeletal development.

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

“…3 a), in line with the notion that SYNS4 is caused by gain-of-function mutations making GDF6 noggin resistant [Wang et al, 2016;Terhal et al, 2018]. When comparing the carpal and tarsal synostoses in our patients to the 2 previously reported families, 1 Dutch and 1 Chinese [Wang et al, 2016;Terhal et al, 2018], the skeletal phenotype is highly similar. Synostoses in fingers, knees, elbows, or vertebrae have not been reported, which makes SYNS4 different from SYNS1, SYNS2, and SYNS3.…”

“…The skeletal phenotype of symmetrical carpal and tarsal synostoses is similar to the skeletal phenotype found in the 2 previous families [Wang et al, 2016;Terhal et al, 2018]. However, unlike these families, none of the 9 affected individuals in our family have mechanical hearing loss, and we speculate that this may be related to GDF6-N399K having no effect on receptor dimerization.…”

“…In the Chinese family [Wang et al, 2016], some of the patients had progressive conductive hearing loss after age 40, and in the Dutch family [Terhal et al, 2018], at least 6 of 10 patients had hearing loss, and severe stapes fixation was detected as early as age 6 years. Although we cannot completely rule out late-onset otosclerosis in our family, this seems unlikely as audiometric testing in individual II-3 at 73 years of age was not indicative of otosclerosis, and other affected family members (including II-1 and III-1) are reported to hear well.…”

“…Just as GDF5, GDF6 is a secreted growth factor of the BMP family that plays an important role in joint formation [Settle et al, 2003]. 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].…”

“…SYNS4 is caused by gain-of-function mutations in GDF6 , encoding growth/differentiation factor 6 [Wang et al, 2016;Terhal et al, 2018]. The SYNS4 phenotype comprises variable carpal and tarsal synostoses, and some patients have otosclerosis and conductive hearing loss.…”