A GDF5 Point Mutation Strikes Twice - Causing BDA1 and SYNS2

Abstract

Growth and Differentiation Factor 5 (GDF5) is a secreted growth factor that belongs to the Bone Morphogenetic Protein (BMP) family and plays a pivotal role during limb development. GDF5 is a susceptibility gene for osteoarthritis (OA) and mutations in GDF5 are associated with a wide variety of skeletal malformations ranging from complex syndromes such as acromesomelic chondrodysplasias to isolated forms of brachydactylies or multiple synostoses syndrome 2 (SYNS2). Here, we report on a family with an autosomal dominant inherited combination of SYNS2 and additional brachydactyly type A1 (BDA1) caused by a single point mutation in GDF5 (p.W414R). Functional studies, including chondrogenesis assays with primary mesenchymal cells, luciferase reporter gene assays and Surface Plasmon Resonance analysis, of the GDF5W414R variant in comparison to other GDF5 mutations associated with isolated BDA1 (p.R399C) or SYNS2 (p.E491K) revealed a dual pathomechanism characterized by a gain- and loss-of-function at the same time. On the one hand insensitivity to the main GDF5 antagonist NOGGIN (NOG) leads to a GDF5 gain of function and subsequent SYNS2 phenotype. Whereas on the other hand, a reduced signaling activity, specifically via the BMP receptor type IA (BMPR1A), is likely responsible for the BDA1 phenotype. These results demonstrate that one mutation in the overlapping interface of antagonist and receptor binding site in GDF5 can lead to a GDF5 variant with pathophysiological relevance for both, BDA1 and SYNS2 development. Consequently, our study assembles another part of the molecular puzzle of how loss and gain of function mutations in GDF5 affect bone development in hands and feet resulting in specific types of brachydactyly and SYNS2. These novel insights into the biology of GDF5 might also provide further clues on the pathophysiology of OA.

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

“…Within the BMP family, growth and differentiation factor (GDF) 5 and GDF6 are known to have critical roles in joint formation, the process by which skeletal elements separate and develop the articulations that allow for ambulation, consistent with the observation that BMP signaling imbalances can lead to abnormal joint morphogenesis . As would be predicted from the skeletal anomalies found in mice lacking Gdf5 , human mutations in GDF5 result in joint anomalies; proximal symphalangism (SYM) and multiple synostoses syndromes (SYNS) are caused by increased GDF5 activity, whereas brachydactyly (BDA and BDC) results from reduced GDF5 activity . Although Gdf6 mutations in mice specifically affect joint morphogenesis, to date, human loss‐of‐function GDF6 mutations underlie Klippel‐Feil syndrome (KFS; MIM 118100), Leber congenital amaurosis‐17 (LCA17, MIM 615360), and isolated microphthalmia (MCOP4, MIM 613094), diseases whose skeletal involvement is not specific to joint formation .…”

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

“…SYM1 is caused by gain-of-function mutations in GDF5 that strongly increase ligand affinity for the BMPRIA receptor and result in loss of binding specificity for BMPRIB (Nickel et al 2005;Seemann et al 2005). Increased BMP signaling activity also follows from GDF5 mutations that render GDF-5 resistant to noggin and cause SYNS2 (Schwaerzer et al 2012;Degenkolbe et al 2013). SYNS1 and SYM1 can also result from heterozygous missense mutations in the gene coding for the BMP inhibitor noggin.…”

Expression analysis of limb element markers during mouse embryonic development

“…Meech et al, (2005) reported Gdf5 expression in digit rays at E11.5 and in developing cartilage condensations by E13.5; however, we do not see Gdf5 expression exclusively across developing joint sites until E14.5 (Meech et al, 2005; Ota et al, 2007; Seemann et al, 2005). This difference may be due to strain differences in embryonic development, which can exhibit differences in gestation periods (Degenkolbe et al, 2013; Huang et al, 2016). Gdf5 is expressed across developing joint sites, including interphalangeal joints, from E14.5 (Chen et al, 2016; Houweling et al, 2001; Huang et al, 2016; Sohaskey et al, 2009).…”

“…Distinct aspects of Gdf5 expression have been reported in several publications that combined have shown Gdf5 expression between E11.5 and E14.5 in the presumptive sites of joint development and the forming joint interzone (Chen et al, 2016; Degenkolbe et al, 2013; Hellman et al, 2012; Houweling et al, 2001; Huang et al, 2016; Meech et al, 2005; Ota et al, 2007; Perez et al, 2010; Seemann et al, 2005; Sohaskey et al, 2008). Uniquely, we have shown side‐by‐side Gdf5 expression across a range of key stages of development in both the forelimb and hindlimb.…”