MKRN3 and KISS1R mutations in precocious and early puberty

Abstract

Background: Pubertal timing is known to be influenced by interactions among various genetic, nutritional, environmental and socioeconomic 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. Methods: We 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. Results: Direct 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. Conclusion: In 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.

LKB1 alleviates high glucose‑ and high fat‑induced inflammation and the expression of GnRH and sexual precocity‑related genes, in mouse hypothalamic cells by activating the AMPK/FOXO1 signaling pathway

“…All patients were female (age, 5-8 years) recruited between April 2020 and August 2020. The diagnostic criteria used were consistent with the previous study ( 12 ). The inclusion criteria were as follows: Patients diagnosed with ICPP who had been treated with GnRHa with a follow-up >3 months and complete clinical data.…”

Incidental pineal gland cyst in girls with early onset of puberty

“…One of the most stimulating developments in this field has been the identification of genetic mutations underlying sporadic and familial cases of CPP [ 6 , 7 ]. We recently reported the presence of mutations and polymorphisms of KISS1R and MKRN3 genes, not only in CPP patients but also in subjects with anticipated puberty [ 12 ]. The hypothalamic hamartoma represents the most common organic cause in both sexes, usually manifesting before 4 years of age [ 13 ].…”

The Role of Genetics in Central Precocious Puberty: Confirmed and Potential Neuroendocrine Genetic and Epigenetic Contributors and Their Interactions with Endocrine Disrupting Chemicals (EDCs)

“…Interestingly, in a 2019 review of the contribution of these genes to both HH and CPP, Ke et al extensively reviewed previously reported cases and demonstrated the biochemical relevance of the location of the mutations on the functionality of the protein, and noted that some mutations of KISS1/KISS1R can be associated in both HH and CPP [47]. Since then, there have been a handful of studies from various countries that show polymorphisms of KISS1/KISSR1 in their cohorts [60][61][62][63][64].…”