ESPE Abstracts (2018) 89 P-P2-309

MKRN3 Gene Mutations in a Cohort of Patients with Central Precocious Puberty

Magdalena Avbelj Stefanijaa, Jernej Kovača, Galia Yablonskib,c,d, Alma Toromanoviće, Gordana Stipančičf, Tatjana Milenkovićg, Aleksandra Jančevskah, Vera Zdravkovići, Maja Jesići, Rade Vukovićg, Sandra Stankovićj, Sladana Todorovićg, Tinka Hovnika, Moshe Phillipc,d, Tadej Battelinoa,k & Liat de Vriesc,d

aUniversity Children’s Hospital Ljubljana, Ljubljana, Slovenia; bFelsentein Medical Research Center, Petah Tikva, Israel; cThe Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel; dSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; eUniversity Clinical Centre Tuzla, Tuzla, Bosnia and Herzegovina; fUniversity Hospital Centre Sestre Milosrdnice, Zagreb, Croatia; gInstitute for Health Protection of Mother and Child of Serbia, Beograd, Serbia; hUniversity Children’s Hospital Skopje, Skopje, Republic of Macedonia, The Former Yugoslav; iUniversity Children‘s Hospital Tiršova, Beograd, Serbia; jClinic for Childrens Internal Disease, Clinical Center Niš, Niš, Serbia; kFaculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

Background: MKRN3 gene, encoding Makorin RING-finger protein 3, is a maternally imprinted gene located at a Prader-Willi syndrome region on chromosome 15q11.13. Deleterious mutations of MKRN3 gene are a common cause of paternally inherited central precocious puberty (CPP), being identified in 33-46% of familial cases and in about 5% and 40% of apparently sporadic female and male cases, respectively.

Objectives: To evaluate the presence of mutations, deletions and methylation abnormalities in MKRN3 gene in a cohort of patients with CPP.

Population and methods: Patients with familial CPP demonstrating paternal (n=12) or recessive (n=10) inheritance from 11 pedigrees, their unaffected relatives (n=8), and 22 patients (three males) with sporadic idiopathic CPP were included. CPP was diagnosed by clinical signs of central puberty, increased basal and/or peak luteinizing hormone, growth spurt and/or advanced bone age. Coding regions of the MKRN3 gene and exon-intron boundaries were analyzed using Sanger sequencing in all probands. In the 6 probands with familial CPP without identified mutations in the reading frame and in sporadic males, MKRN3 deletion and methylation analysis by commercially available methylation- specific MLPA (SALSA MS”MLPA - A probemix ME028-C1 Prader-Willi/Angelman) was performed.

Results: A previously reported heterozygous MKRN3 mutation (c.482dupC) was identified and segregated with disease in 10 patients from 5 pedigrees with familial CPP, two pedigrees were distantly related. No mutations in the MKRN3 gene were identified in sporadic patients nor in 12 patients from other 6 pedigrees with familial CPP. No abnormal methylation pattern or gene deletion was identified in any of the tested patients by methylation-specific MLPA. Estimated average age at the beginning of puberty in 8 female carriers of an MKRN3 mutation was 6.3 years (range 5.3–8 years), two girls untreated with GnRH analog had menarche at 7 and 9 years. Two male carriers reported growth spurt at 9 years. Estimated average age at the beginning of puberty in patients without identified MKRN3 mutation was 6.5 years in 6 boys (range 4.5–8.5 years) and 5.8 years in 23 girls (range 1–8 years), two girls untreated with GnRH analog had menarche at 7.9 and 8.5 years.

Conclusions: We demonstrated a high frequency (45%) of MKRN3 mutations in patients with familial CPP, but not in sporadic cases. Although MKRN3 is one of the gatekeepers of the postnatal activation of the gonadotropic axis, other inhibiting factors, are yet to be discovered.