Analysis of MKRN3 gene in patients with central precocious puberty

Abstract

Central Precocious puberty (CPP) is clinically defined by the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. Most of CPP cases affect girls and keep idiopathic. Genetic alterations associated to CPP was first describe in kisspeptin system genes (KISS1 and KISS1R) Loss-of-function mutations in imprinted MKRN3 gene is describing to be responsible to most CPP cases, special familial cases. The MKRN3 is the first imprinted gene associated to pubertal disorders. Through whole-exome sequencing analysis in 15 families with CPP, 5 families have loss of function mutations in MKRN3. Three frameshift mutations (Arg213Glyfs*73, Tyr391*, and Ala162Glyfs*14) and one missense mutation (Arg365Ser) in ring zinc finger important for protein function. In all families the study shows an autosomal dominant inheritance with complete penetrance and exclusive transmission through the paternal allele. Recently a study of the promoter region of MKRN3 was developed. Mutations in the coding region of the MKRN3 were excluded in all patients. A rare heterozygous four nucleotides deletion in the proximal promoter region of MKRN3 (c.-150_-147delTCAG) in a girl with onset of puberty in 6.6 yrs was found. This mutation can be associated with reductions of MKRN3 expression. The objective of this study is identified mutations or polymorphisms in MKRN3 gene (condign and promoter region) in patients with familial CPP. (AU)