{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T09:09:16Z","timestamp":1774429756137,"version":"3.50.1"},"reference-count":43,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"vor","delay-in-days":23,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82270837"],"award-info":[{"award-number":["82270837"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical & Translational Med"],"published-print":{"date-parts":[[2026,3]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n \n Short stature (SS) is a common growth disorder with multiple aetiologies. Variants in the\n MMP13<\/jats:italic>\n gene can result in varying degrees of SS, typically accompanied by pronounced skeletal abnormalities. This study aimed to investigate the genetic basis of SS in a family lacking significant imaging abnormalities and elucidate the underlying pathogenic mechanism.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Trio whole\u2010exome sequencing was performed in a Chinese pedigree with SS to identify pathogenic variants, followed by Sanger sequencing validation. Patient\u2010derived induced pluripotent stem cell model and CRISPR\/Cas9\u2010generated Mmp13\n R459fs<\/jats:sup>\n homologous mutant mouse model were established to verify the pathogenicity of the variant. Western blotting, immunofluorescence staining, co\u2010immunoprecipitation coupled with mass spectrometry (Co\u2010IP\/MS), histological staining and transmission electron microscopy were used to evaluate the effects of the variant on MMP13 protein function and chondrocyte development.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A heterozygous frameshift variant, NM_002427.4:c.1372del(p.Arg458Valfs*31), was identified in the\n MMP13<\/jats:italic>\n gene. Mmp13\n R459fs<\/jats:sup>\n mutant mice recapitulated the SS phenotype in patients, with growth plate abnormalities that were present only during the growth phase and resolved earlier than those in\n Mmp13<\/jats:italic>\n knockout mice. Co\u2010IP\/MS in HEK293T cells revealed significantly increased HSPA5 expression in the mutant, and enhanced interaction between MMP13 mutant and HSPA5 was confirmed, leading to their retention within the endoplasmic reticulum (ER). In patient\u2010derived chondrocytes, misfolded MMP13 protein upregulated HSPA5 expression, induced significant ER dilation, activated unfolded protein response and increased chondrocyte apoptosis, ultimately contributing to\n MMP13<\/jats:italic>\n \u2010related SS.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n This study for the first time reports the\n MMP13<\/jats:italic>\n c.1372del (p.Arg458Valfs*31) variant causes autosomal dominant SS without obvious skeletal abnormalities. The variant is associated with defective MMP13 protein secretion and ER stress. These findings expand the mutational spectrum and genotype\u2012phenotype correlations of the\n MMP13<\/jats:italic>\n gene, providing a novel pathogenic mechanism of SS that is important for the precise diagnosis and treatment.\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n The MMP13 R458fs variant is retained in the endoplasmic reticulum (ER), leading to ER expansion.<\/jats:p>\n <\/jats:list-item>\n \n Enhanced binding of variant MMP13 to HSPA5 triggers ER stress, thereby increasing chondrocyte apoptosis.<\/jats:p>\n <\/jats:list-item>\n \n This pathogenic cascade results in abnormal expansion of the growth plate hypertrophic zone, ultimately impairing long bone growth and causing short stature.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n 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