A novel MMP13 frameshift variant causes short stature via enhanced MMP13-HSPA5 interaction and activated endoplasmic reticulum stress.

backgroundShort stature (SS) is a common growth disorder with multiple aetiologies. Variants in the MMP13 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.

methodsTrio whole-exome sequencing was performed in a Chinese pedigree with SS to identify pathogenic variants, followed by Sanger sequencing validation. Patient-derived induced pluripotent stem cell model and CRISPR/Cas9-generated Mmp13

resultsA heterozygous frameshift variant, NM_002427.4:c.1372del(p.Arg458Valfs*31), was identified in the MMP13 gene. Mmp13

conclusionThis study for the first time reports the MMP13 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‒phenotype correlations of the MMP13 gene, providing a novel pathogenic mechanism of SS that is important for the precise diagnosis and treatment. KEY POINTS: The MMP13 R458fs variant is retained in the endoplasmic reticulum (ER), leading to ER expansion. Enhanced binding of variant MMP13 to HSPA5 triggers ER stress, thereby increasing chondrocyte apoptosis. This pathogenic cascade results in abnormal expansion of the growth plate hypertrophic zone, ultimately impairing long bone growth and causing short stature.