The following is a summary of “Novel MKRN3 Missense Mutations Associated With Central Precocious Puberty Reveal Distinct Effects on Ubiquitination,” published in the July 2023 issue of Endocrinology & Metabolism by Magnotto, et al.

Loss-of-function mutations in the imprinted genes MKRN3 and DLK1 have been associated with central precocious puberty (CPP), with MKRN3 mutations being the most common known genetic cause of CPP. For a study, researchers sought to screen patients with CPP for mutations in MKRN3 and DLK1 genes and investigate the effects of identified mutations on protein function in vitro.

A total of 84 unrelated children with CPP (79 girls, 5 boys) and their first-degree relatives, when available, were included in the study. Five academic medical institutions participated in the research. Sanger sequencing was conducted on DNA extracted from peripheral blood leukocytes to analyze the 5′ upstream flanking and coding regions of MKRN3 and DLK1 genes. Western blot analysis was performed to assess protein ubiquitination profiles.

The study identified eight heterozygous MKRN3 mutations in nine unrelated girls with CPP. Among the mutations, five were novel missense mutations, two were previously identified in patients with CPP, and one was a frameshift variant not previously associated with CPP. No pathogenic variants were found in DLK1. Girls with MKRN3 mutations showed an earlier age of initial pubertal signs and higher basal serum luteinizing hormone and follicle-stimulating hormone levels compared to girls with CPP without MKRN3 mutations. Western blot analysis revealed that mutations within the RING finger domain of MKRN3 reduced ubiquitination, while mutations outside this domain increased ubiquitination compared to wild-type MKRN3.

MKRN3 mutations were present in 10.7% of the CPP cohort, consistent with previous studies. The newly identified mutations in different domains of MKRN3 displayed different ubiquitination patterns, indicating distinct molecular mechanisms by which the loss of MKRN3 leads to early-onset puberty.

Source: academic.oup.com/jcem/article/108/7/1646/7077020