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Immunoprecipitation, cytogenetic analysis, fluorescence activated cell sorting (FACS) and electron microscopy were used to elucidate the cellular consequences of patient's cells. smc5 knockout (KO) zebrafish and Smc5<jats:sup>K371del<\/jats:sup> knock\u2010in mouse models were generated by CRISPR\u2010Cas9. RNA\u2010seq, quantitative real\u2010time PCR (qPCR), western blot, microquantitative computed tomography (microCT) and histology were used to explore phenotypic characteristics and potential mechanisms of the animal models. The effects of Smc5 knockdown on mitotic clonal expansion (MCE) during adipogenesis were investigated through Oil Red O staining, proliferation and apoptosis assays in vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified a homozygous in\u2010frame deletion of Arg372 in <jats:italic>SMC5<\/jats:italic>, one of the core subunits of the SMC5\/6 complex, from an adult patient with microcephalic primordial dwarfism, chromosomal instability and insulin resistance. SMC5 mutation disrupted its interaction with its interacting protein NSMCE2, leading to defects in DNA repair and chromosomal instability in patient fibroblasts. Smc5 KO zebrafish showed microcephaly, short length and disturbed glucose metabolism. Smc5 depletion triggers a p53\u2010related apoptosis, as concomitant deletion of the p53 rescued growth defects phenotype in zebrafish. An smc5<jats:sup>K371del<\/jats:sup> knock\u2010in mouse model exhibited high mortality, severe growth restriction and fat loss. In 3T3\u2010L1 cells, the knockdown of smc5 results in impaired MCE, a crucial step in adipogenesis. This finding implies that defective cell survival and differentiation is an important mechanism linking growth disorders and metabolic homeostasis imbalance.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.1007","type":"journal-article","created":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T05:12:31Z","timestamp":1673413951000},"source":"Crossref","is-referenced-by-count":12,"title":["In\u2010frame deletion of SMC5 related with the phenotype of primordial dwarfism, chromosomal instability and insulin resistance"],"prefix":"10.1002","volume":"13","author":[{"given":"Wenjiao","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Endocrinology Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanping","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changrun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajie","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueyue","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Molecular Diagnostics &amp; 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