Missense mutations in MKRN3 and central precocious puberty: a mutational approach to understanding protein function

Loss-of-function mutations in MKRN3 are the most common monogenic cause of central precocious puberty (CPP), yet the functional consequences of missense variants, which account for the majority of such cases, remain incompletely understood. A growing body of genetic, biochemical, computational, and in vivo studies now allows a domain-by-domain dissection of how missense mutations impair MKRN3 function, offering mechanistic insight into pubertal regulation that extends beyond individual variant reporting.

Missense mutations in the C3HC4 RING finger domain consistently reduce ubiquitin ligase activity and impair MKRN3-mediated repression of neurokinin B, kisspeptin, and GnRH, while mutations in C3H zinc finger domains paradoxically enhance auto-ubiquitination or disrupt RNA binding, revealing distinct pathogenic mechanisms. Computational stability analysis shows that destabilizing and stabilizing variants can both be pathogenic, underscoring the limitations of in silico tools alone. Phenotypic variability is shaped by the classes of mutations, sexually dimorphic neuroendocrine sensitivity, epigenetic regulation of MKRN3 promoter activity, and polygenic modifiers of pubertal timing.

Understanding the domain-specific effects of MKRN3 missense mutations refines genotype-phenotype correlations and improves variant interpretation in clinical practice. Integration of functional assays with polygenic risk assessment is essential for accurate genetic counseling in families with CPP.