Molecular screening of PROKR2 gene in girls with idiopathic central precocious puberty

Francesca Aiello,Emanuele Miraglia Del Giudice,Raffaella Di Mase,Gianluca Tornese,Alessandra Cassio,Giuseppina R Umano,Grazia Cirillo,Anna Grandone

doi:10.1186/s13052-020-00951-z

Abstract

BackgroundProkineticin receptor 2 (PROKR2) loss of function mutations have been described as cause of hypogonadotropic hypogonadism. In 2017, a first case of central precocious puberty (CPP) caused by PROKR2 heterozygous gain of function mutation was described in a 3.5 years-old girl. No other cases have been reported yet. This study performs a molecular screening in girls with early onset CPP (breast budding before 6 years of age) to identify possible alterations in PROKR2.MethodsWe analysed DNA of 31 girls with idiopathic CPP diagnosed via basal LH levels > 0.3 IU/L or peak-LH > 5 IU/L after stimulation, without any MKRN3 mutations. The Fisher exact test was used to compare polymorphism allele frequency to corresponding ones in genome aggregation database (gnomAD).ResultsNo rare variants were identified. Five polymorphisms were found (rs6076809, rs8116897, rS3746684, rs3746682, rs3746683). All except one (i.e. rs3746682) had a minor allele frequency (MAF) similar to that reported in literature. rs3746682 presented a MAF higher than that described in the gnomAD (0.84 in our cohort vs 0.25 from gnomAD).ConclusionsAs for other G protein-coupled receptors (i.e. GPR54), mutations in PROKR2 do not seem to be a frequent cause of CPP in girls.

Highlights

Prokineticin receptor 2 (PROKR2) loss of function mutations have been described as cause of hypogonadotropic hypogonadism
DLK1 loss-of-function mutations determine a more complex, yet uncommon, phenotype characterized by central precocious puberty (CPP), overweight, early onset Type 2 Diabetes, hyperlipidemia, and Polycystic Ovary Syndrome [7]
This study aimed to perform a molecular screening of PROKR2 variations in a cohort of girls with CPP

Summary

Introduction

Prokineticin receptor 2 (PROKR2) loss of function mutations have been described as cause of hypogonadotropic hypogonadism. In 2017, a first case of central precocious puberty (CPP) caused by PROKR2 heterozygous gain of function mutation was described in a 3.5 years-old girl. This study performs a molecular screening in girls with early onset CPP (breast budding before 6 years of age) to identify possible alterations in PROKR2. MKRN3 loss-of-function mutations are the most frequently identified monogenic cause of CPP [3, 4]. Heterozygous activating mutations in KISS1 and KISS1R genes have been reported as causes of few cases of CPP [5, 6]. DLK1 loss-of-function mutations determine a more complex, yet uncommon, phenotype characterized by CPP, overweight, early onset Type 2 Diabetes, hyperlipidemia, and Polycystic Ovary Syndrome [7]. Rare cases of CPP patients primarily related to clinical syndromes or chromosomal abnormalities have been identified [8]

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