Central precocious puberty caused by mutations in the imprinted gene MKRN3

Area of Science:

• Genetics
• Endocrinology
• Molecular Biology

Background:

• Central precocious puberty involves early activation of the hypothalamic-pituitary-gonadal axis.
• Genetic factors influence pubertal timing, but few molecular defects are known.
• Understanding these genetic underpinnings is crucial for diagnosing and potentially treating central precocious puberty.

Purpose of the Study:

• To identify genetic causes of central precocious puberty.
• To investigate the role of the MKRN3 gene in pubertal development.

Main Methods:

• Whole-exome sequencing was performed on 40 individuals from 15 families with central precocious puberty.
• Candidate variants were validated using Sanger sequencing.
• Messenger RNA (mRNA) levels of Mkrn3 in mouse hypothalami were analyzed at different ages.

Main Results:

• Four novel heterozygous mutations in the MKRN3 gene were identified in 5 of the 15 families.
• These MKRN3 mutations, including frameshift and missense variants, affected both males and females.
• MKRN3, a paternally expressed imprinted gene, showed high expression in prepubertal mice, decreasing as puberty onset approached.

Conclusions:

• Deficiency in the MKRN3 gene is a cause of central precocious puberty in humans.
• Inheritance patterns confirmed the role of imprinted gene mutations.
• Further research into MKRN3's function may reveal new therapeutic targets.