MKRN3 and KISS1R mutations in precocious and early puberty

Sara Pagani,Manuela Gasparri,Mauro Bozzola,Alberto Villani,Pietro Ferrara,Valeria Calcaterra,Elena Bozzola,Chiara Montalbano,Gloria Acquafredda

doi:10.1186/s13052-020-0808-6

Abstract

BackgroundPubertal timing is known to be influenced by interactions among various genetic, nutritional, environmental and socio-economic factors, although the ultimate mechanisms underlying the increase in pulsatile GnRH secretion at puberty have yet to be fully elucidated. The aim of our research was to verify the role of KISSR1 (previously named GPR54) and MKRN3 genes on pubertal timing.MethodsWe analyzed the DNA sequence of these genes in 13 girls affected by central precocious puberty (CPP) who showed onset of puberty before 8 years of age, and in 6 girls affected by early puberty (EP) between 8 and 10 years of age.ResultsDirect sequencing of the KISS1R (GPR54) gene revealed two SNPs. One SNP is a missense variant (rs 350,132) that has been previously reported in connection to CPP in Korean girls. The other variant that we found in the GPR54 gene (rs764046557) was a missense SNP located in exon 5 at position 209 of the aminoacid. We identified this variant in only one CPP patient. Automatic sequencing of MKRN3 in all patients revealed three variants in eight subjects. In 6 out of 19 (31.5%) patients (3/13 CPP patients and 3/6 EP patients) we found the synonymous variant c.663C > T (rs2239669). Another synonymous variant (rs140467331) was found in one of our CPP patients, as well as one missense variant (rs760981395) in another CPP patient.ConclusionIn conclusion, we identified sequence variations of the KISS1R and MKRN3 genes, two of the most frequent genetic causes of ICPP. Our results suggest that these variants might be inducible factors in the pathogenesis of CPP.

Highlights

Puberty is a complex biological process of sexual development, controlled at hypothalamic level by activation of pulsatile gonadotropin-releasing hormone (GnRH) secretion, which stimulates hormonal cascade and gonadal activation [1].Pubertal timing is known to be influenced by interactions among various genetic, nutritional, environmentalCentral precocious puberty (CPP) is clinically identified by the development of secondary sexual characteristics such as breast development before 8 years of age in females (B2 according to Tanner classification) and the increase of testicular volume before 9 years of age in boys
The other variant that we found in the G-protein 54 (GPR54) gene was a missense SNP located in exon 5 at position 209 of the aminoacid
We identified this variant in only one central precocious puberty (CPP) patient

Summary

Introduction

Puberty is a complex biological process of sexual development, controlled at hypothalamic level by activation of pulsatile gonadotropin-releasing hormone (GnRH) secretion, which stimulates hormonal cascade and gonadal activation [1].Pubertal timing is known to be influenced by interactions among various genetic, nutritional, environmentalCentral precocious puberty (CPP) is clinically identified by the development of secondary sexual characteristics such as breast development before 8 years of age in females (B2 according to Tanner classification) and the increase of testicular volume before 9 years of age in boys. Pubertal timing is known to be influenced by interactions among various genetic, nutritional, environmental. Gain-of-function mutations in the KISS1 and KISSR1 Kisspeptin, the peptide product of the KISS1 gene, and its receptor, the G-protein 54 (GPR54) signaling complex, are essential gatekeepers of pubertal activation of GnRH neurons [2, 7,8,9,10,11]. Gain-offunction mutations in KISS1 or KISSR1 genes may induce precocious activation of puberty. Pubertal timing is known to be influenced by interactions among various genetic, nutritional, environmental and socio-economic factors, the ultimate mechanisms underlying the increase in pulsatile GnRH secretion at puberty have yet to be fully elucidated. The aim of our research was to verify the role of KISSR1 (previously named GPR54) and MKRN3 genes on pubertal timing

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