Abstract
Proximal symphalangism (SYM1) is an autosomal dominant disorder, mainly characterized by bony fusions of the proximal phalanges of the hands and feet. GDF5 and NOG were identified to be responsible for SYM1. We have previously reported on a p.Leu373Arg mutation in the GDF5 proregion present in a Chinese family with SYM1. Here, we investigated the effects of the GDF-L373R mutation. The variant caused proteolysis efficiency of GDF5 increased in ATDC5 cells. The variant also caused upregulation of SMAD1/5/8 phosphorylation and increased expression of target genes SMURF1, along with COL2A1 and SOX9 which are factors associated with chondrosis. Furthermore, we developed a human-relevant SYM1 mouse model by making a Gdf5L367R (the orthologous position for L373R in humans) knock-in mouse. Gdf5L367R/+ and Gdf5L367R/L367R mice displayed stiffness and adhesions across the proximal phalanx joint which were in complete accord with SYM1. It was also confirmed the joint formation and development was abnormal in Gdf5L367R/+ and Gdf5L367R/L367R mice, including the failure to develop the primary ossification center and be hypertrophic chondrocytes during embryonic development. This knock-in mouse model offers a tool for assessing the pathogenesis of SYM1 and the function of the GDF5 proregion.
Highlights
Proximal symphalangism (SYM1, OMIM 185800), known as “straight hands”, is a dominant hereditary developmental disorder
Increased Duolink staining in GDF5L373R than GDF5WT cells indicated that the L373R mutation might increase the interaction between growth differentiation factor 5 (GDF5) and BMPR1B (Figure 1B)
The SMAD signaling cascade is known to be activated upon binding of GDF5 to its receptors, and SMAD1/5/8 phosphorylation was seen at a higher level in cells infected with GDF5L373R than with GDF5WT (Figure 1C)
Summary
Proximal symphalangism (SYM1, OMIM 185800), known as “straight hands”, is a dominant hereditary developmental disorder. The disease manifests as fusions of the proximal interphalangeal joints, typically on the third to fifth digits of the hand, and affects the thumb, making it impossible to make a fist. The bony fusions occur on metacarpophalangeal joints as well as on the auditory ossicles, leading to conductive hearing loss in some affected individuals [1, 2]. The disease results from mutations of the growth differentiation factor 5 (GDF5) or NOG genes [1]. The GDF5 gene, called CDMP1, is located on 20q11.22. GDF5 belongs to the transforming growth factor beta (TGFβ) superfamily. It has a similar conserved structure and shares the same signal transduction mechanism with other family members in the TGFβ superfamily [5]. GDF5 contains an N terminal signal peptide domain, a large proregion comprised of 354 residues, and a 120 amino acid mature peptide at the carboxyl terminus [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
