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- Title
Identification of kinesin family member (KIF22) homozygous variants in spondyloepimetaphyseal dysplasia with joint laxity, lepdodactylic type and demonstration of proteoglycan biosynthesis impairment.
- Authors
Dubail, Johanne; Rondeau, Sophie; Michot, Caroline; Baujat, Geneviève; Capri, Yline; Thévenon, Julien; Charpie, Maelle; Pejin, Zagorka; Phan, Gilles; Huber, Céline; Cormier-Daire, Valérie
- Abstract
Heterozygous variants in KIF22 , encoding a kinesin-like protein, are responsible for spondyloepimetaphyseal dysplasia with joint laxity, leptodactilic type (lepto-SEMDJL), characterized by short stature, flat face, generalized joint laxity with multiple dislocations, and progressive scoliosis and limb deformity. By targeted gene sequencing analysis, we identified a homozygous KIF22 variant (NM_007317.3: c.146G>A, p.Arg49Gln) in 3 patients from 3 unrelated families. The clinical features appeared similar to those of patients carrying heterozygous KIF22 variant (c.443C>T or c.446G>A), although the spinal involvement appeared later and was less severe in patients with a recessive variant. Relatives harboring the c.146G>A variant at the heterozygous state were asymptomatic. The homozygous KIF22 variant c.146G>A affected a conserved residue located in the active site and potentially destabilized ATP binding. RT-PCR and western blot analyses demonstrated that both dominant and recessive KIF22 variants do not affect KIF22 mRNA and protein expression in patient fibroblasts compared to controls. As lepto-SEMDJL presents phenotypic overlap with chondrodysplasias with multiple dislocations (CMD), related to defective proteoglycan biosynthesis, we analyzed proteoglycan synthesis in patient skin fibroblasts. Compared to controls, DMMB assay showed a significant decrease of total sulfated proteoglycan content in culture medium but not in the cell layer, and immunofluorescence demonstrated a strong reduction of staining for chondroitin sulfates but not for heparan sulfates, similarly in patients with recessive or dominant KIF22 variants. These data identify a new recessive KIF22 pathogenic variant and link for the first time KIF22 pathogenic variants to altered proteoglycan biosynthesis and place the lepto-SEMDJL in the CMD spectrum.
- Subjects
JOINT hypermobility; GLYCANS; CHONDROITIN sulfate proteoglycan; DYSPLASIA; KINESIN; CHONDROITIN sulfates; BIOSYNTHESIS; GENETIC variation; WESTERN immunoblotting
- Publication
Journal of Bone & Mineral Research, 2024, Vol 39, Issue 3, p287
- ISSN
0884-0431
- Publication type
Article
- DOI
10.1093/jbmr/zjad020