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MED-4 is caused by homozygous or compound heterozygous pathogenic variants in the <jats:italic>SLC26A2<\/jats:italic> gene. However, the underlying pathogenic mechanisms in chondrocytes remains unknown. This study aimed to identify the pathogenic variants within a MED-4 family and explore the molecular etiology of this condition in human primary chondrocyte cells.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Clinical data were recorded and peripheral blood samples were collected for analysis. Whole exome sequencing (WES) and bioinformatic analyses were performed to determine causative variants. Wild-type <jats:italic>SLC26A2<\/jats:italic> and corresponding mutant expression plasmids were constructed and transfected into human primary chondrocytes. The expression and subcellular distribution of SLC26A2 protein in chondrocytes were detected by immunoblotting and immunofluorescence. Effects of these variants on chondrocytes viability and apoptosis were measured by Cell Counting Kit-8 (CCK-8) assay. Expression of genes related to cartilage homeostasis was subsequently analyzed by quantitative real-time polymerase chain reaction (qRT-PCR).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We identified two compound heterozygous variants c.1020_1022delTGT(p.Val341del) and c.1262\u00a0T\u2009&gt;\u2009C(p.Ile421Thr) in the <jats:italic>SLC26A2<\/jats:italic> gene in the patients. Mutant SLC26A2<jats:sup>Val341del<\/jats:sup> and SLC26A2<jats:sup>Ile421Thr<\/jats:sup> proteins were distributed in relatively few cells and were observed only within the nucleus. The viability of chondrocytes with the <jats:italic>SLC26A2<\/jats:italic> variant group was similar to the wild-type (WT) group. However, the protein expressions of SLC26A2<jats:sup>Val341del<\/jats:sup> and SLC26A2<jats:sup>Ile421Thr<\/jats:sup> were decreased compared with SLC26A2<jats:sup>WT<\/jats:sup>. Expression levels of matrix metallopeptidase 13 (<jats:italic>MMP13<\/jats:italic>), \u03b1-1 chain of type X collagen <jats:italic>(COL10A1<\/jats:italic>), and Runt-related transcription factor 2 (<jats:italic>RUNX2<\/jats:italic>) were significantly decreased in the variant group. However, aggrecan (<jats:italic>ACAN<\/jats:italic>) expression was higher in the variant group than the WT group.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Overall, our data demonstrate that the variants p.Val341del and p.Ile421Thr in <jats:italic>SLC26A2<\/jats:italic> cause MED-4 and that these two variants promote chondrocyte proliferation while inhibiting chondrocyte differentiation.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13023-024-03228-4","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T13:02:28Z","timestamp":1719925348000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Biallelic variants in SLC26A2 cause multiple epiphyseal dysplasia-4 by disturbing chondrocyte homeostasis"],"prefix":"10.1186","volume":"19","author":[{"given":"Shan","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yueyang","family":"Sheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qianqian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanzhuo","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6366-4758","authenticated-orcid":false,"given":"Chengai","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,7,2]]},"reference":[{"key":"3228_CR1","unstructured":"Superti-Furga A, Unger S. 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