{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:09:40Z","timestamp":1790820580370,"version":"4.1.0"},"reference-count":15,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2024,1,4]],"date-time":"2024-01-04T00:00:00Z","timestamp":1704326400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-18-CE14\u20130040"],"award-info":[{"award-number":["ANR-18-CE14\u20130040"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,4,19]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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&amp;gt;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&amp;gt;T or c.446G&amp;gt;A), although the spinal involvement appeared later and was less severe in patients with a recessive variant. Relatives harboring the c.146G&amp;gt;A variant at the heterozygous state were asymptomatic. The homozygous KIF22 variant c.146G&amp;gt;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.<\/jats:p>","DOI":"10.1093\/jbmr\/zjad020","type":"journal-article","created":{"date-parts":[[2024,1,4]],"date-time":"2024-01-04T22:04:32Z","timestamp":1704405872000},"page":"287-297","source":"Crossref","is-referenced-by-count":3,"title":["Identification of<i>kinesin family member (KIF22)<\/i>homozygous variants in spondyloepimetaphyseal dysplasia with joint laxity, lepdodactylic type and demonstration of proteoglycan biosynthesis impairment"],"prefix":"10.1093","volume":"39","author":[{"given":"Johanne","family":"Dubail","sequence":"first","affiliation":[{"name":"Paris Cit\u00e9 University , INSERM UMR 1163, , Paris 75015 , France"},{"name":"Imagine Institute , INSERM UMR 1163, , Paris 75015 , 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75015 , France"},{"name":"Imagine Institute , INSERM UMR 1163, , Paris 75015 , France"},{"name":"Reference Center for Skeletal Dysplasia, Necker-Enfants Malades Hospital, AP-HP , Paris 75015 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yline","family":"Capri","sequence":"additional","affiliation":[{"name":"D\u00e9partement de G\u00e9n\u00e9tique, H\u00f4pital Robert Debr\u00e9, APHP-Nord , Paris 75019 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Th\u00e9venon","sequence":"additional","affiliation":[{"name":"Service de G\u00e9n\u00e9tique , G\u00e9nomique et Procr\u00e9ation, , Grenoble 38700 , France"},{"name":"H\u00f4pital Couple-Enfant CHU Grenoble Alpes , G\u00e9nomique et Procr\u00e9ation, , Grenoble 38700 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maelle","family":"Charpie","sequence":"additional","affiliation":[{"name":"Paris Cit\u00e9 University , INSERM UMR 1163, , Paris 75015 , France"},{"name":"Imagine Institute , INSERM UMR 1163, , Paris 75015 , France"},{"name":"Reference Center for Skeletal Dysplasia, Necker-Enfants Malades Hospital, AP-HP , Paris 75015 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zagorka","family":"Pejin","sequence":"additional","affiliation":[{"name":"Paris Cit\u00e9 University , INSERM UMR 1163, , Paris 75015 , France"},{"name":"Imagine Institute , INSERM UMR 1163, , Paris 75015 , France"},{"name":"Service de chirurgie orthop\u00e9dique, Necker-Enfants Malades Hospital, AP-HP , Paris 75015 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"Phan","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, CNRS , CiTCoM, Paris 75006 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Huber","sequence":"additional","affiliation":[{"name":"Paris Cit\u00e9 University , INSERM UMR 1163, , Paris 75015 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