MKRN3 circulating levels in girls with central precocious puberty caused by MKRN3 gene mutations

• Published in: Journal of endocrinological investigation Vol. 47; no. 6; pp. 1477 - 1485
• Main Authors: Aiello, F., Palumbo, S., Cirillo, G., Tornese, G., Fava, D., Wasniewska, M., Faienza, M. F., Bozzola, M., Luongo, C., Festa, A., Miraglia del Giudice, E., Grandone, A.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.06.2024
• Subjects: Biomarkers - blood; Case-Control Studies; Child; Child, Preschool; DNA Mutational Analysis; Endocrinology; Female; Humans; Internal Medicine; Medicine; Medicine & Public Health; Metabolic Diseases; Mutation; Original Article; Puberty, Precocious - blood; Puberty, Precocious - diagnosis; Puberty, Precocious - genetics; Ribonucleoproteins - blood; Ribonucleoproteins - genetics; Ubiquitin-Protein Ligases - genetics; Molecular screening; MKRN3; Children; Serum MKRN3; Mutation screening; Central precocious puberty
• ISSN: 1720-8386; 1720-8386
• DOI: 10.1007/s40618-023-02255-5

Purpose MKNR3 is a paternally expressed gene whose mutations are the main cause of central precocious puberty (CPP). Protein circulating levels can be easily measured, as demonstrated in idiopathic CPP and healthy controls. No data are available for patients harboring an MKRN3 mutation. Our aim was to perform MKRN3 mutation screening and to investigate if circulating protein levels could be a screening tool to identify MKRN3 mutation in CPP patients. Methods We enrolled 140 CPP girls and performed MKRN3 mutation analysis. Patients were stratified into two groups: idiopathic CPP (iCPP) and MKRN3 mutation-related CPP (MKRN3-CPP). Clinical characteristics were collected. Serum MKRN3 values were measured by a commercially available ELISA assay kit in MKRN3-CPP and a subgroup of 15 iCPP patients. Results We identified 5 patients with MKRN3 mutations: one was a novel mutation (p.Gln352Arg) while the others were previously reported (p.Arg328Cys, p.Arg345Cys, p.Pro160Cysfs*14, p.Cys410Ter). There was a significant difference in circulating MKRN3 values in MKRN3-CPP compared to iCPP ( p  < 0.001). In MKRN3-CPP, the subject harboring Pro160Cysfs*14 presented undetectable levels. Subjects carrying the missense mutations p.Arg328Cys and p.Gln352Arg showed divergent circulating protein levels, respectively 40.56 pg/mL and undetectable. The patient with the non-sense mutation reported low but measurable MKRN3 levels (12.72 pg/mL). Conclusions MKRN3 defect in patients with CPP cannot be predicted by MKRN3 circulating levels, although those patients presented lower protein levels than iCPP. Due to the great inter-individual variability of the assay and the lack of reference values, no precise cut-off can be identified to suspect MKRN3 defect.