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

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Mutations in MKRN3 are the leading genetic cause of central precocious puberty (CPP).
• Missense variants constitute the majority of MKRN3 mutations, but their functional impact is not fully understood.
• Understanding MKRN3 function is crucial for deciphering pubertal regulation.

Purpose of the Study:

• To dissect the domain-specific functional consequences of MKRN3 missense variants.
• To provide mechanistic insights into how these variants cause central precocious puberty.
• To improve the interpretation of MKRN3 variants in clinical settings.

Main Methods:

• Domain-by-domain analysis of MKRN3 missense variants.
• Biochemical assays to assess ubiquitin ligase activity.
• In vivo studies and computational stability analysis.
• Evaluation of genotype-phenotype correlations and polygenic modifiers.

Main Results:

• Missense mutations in the C3HC4 RING finger domain impair MKRN3's repressive function on neurokinin B, kisspeptin, and GnRH.
• Mutations in C3H zinc finger domains disrupt RNA binding or alter auto-ubiquitination.
• Both destabilizing and stabilizing variants can be pathogenic, highlighting the need for integrated analysis.
• Phenotypic variability is influenced by mutation type, neuroendocrine sensitivity, epigenetics, and polygenic factors.

Conclusions:

• Domain-specific effects of MKRN3 mutations clarify genotype-phenotype correlations for central precocious puberty.
• Functional assays combined with polygenic risk assessment are vital for accurate genetic counseling in CPP families.
• Improved variant interpretation aids clinical management of patients with central precocious puberty.