Heterozygous Deletions in MKRN3 Cause Central Precocious Puberty Without Prader-Willi Syndrome

Abstract

Context Loss-of-function mutations in the imprinted genes MKRN3 and DLK1 cause central precocious puberty (CPP) but whole gene deletions have not been reported. Larger deletions of the chromosome 15q11-13 imprinted locus, including MKRN3, cause Prader-Willi syndrome (PWS). CPP has been reported in PWS but is not common, and the role of MKRN3 in PWS has not been fully elucidated. Objective To identify copy number variants in puberty-related, imprinted genes to determine their role in CPP. Methods Probands with idiopathic CPP had chromosomal microarray (CMA) and targeted deletion/duplication testing for MKRN3 and DLK1. Results Sixteen female probands without MKRN3 or DLK1 variants identified by Sanger sequencing were studied. Whole gene deletions of MKRN3 were identified in 2 subjects (13%): a complete deletion of MKRN3 in Patient A (pubertal onset at 7 years) and a larger deletion involving MAGEL2, MKRN3, and NDN in Patient B (pubertal onset 5.5 years). Both were paternally inherited. Patient B had no typical features of PWS, other than obesity, which was also present in her unaffected family. Conclusions We identified 2 cases of whole gene deletions of MKRN3 causing isolated CPP without PWS. This is the first report of complete deletions of MKRN3 in patients with CPP, emphasizing the importance of including copy number variant analysis for MKRN3 mutation testing when a genetic diagnosis is suspected. We speculate that there is a critical region of the PWS locus beyond MKRN3, MAGEL2, and NDN that is responsible for the PWS phenotype.

Gonadotropin dependent precocious puberty in a boy with Prader Willi Syndrome

“…MKRN3 and DLK1 genes found on chromosome 15 are considered important in the causation of gonadotrophin-dependent precocious puberty (3). Loss-of-function mutations of the above-imprinted genes result in central precocious puberty in a normal individual (3). It is postulated that larger deletions of the chromosome 15q11-13, including MKRN3, could result in gonadotropin-dependent precocious puberty in Prader-Willi syndrome (3).…”

“…Characteristic features of Prader Willi Syndrome include short stature with severe obesity, hypoplastic external genitalia, cryptorchidism, delayed puberty, suggesting a dysfunction of the hypothalamic-pituitarygonadal axis (1,2,5). Some children with Prader Willi Syndrome have experienced premature adrenarche which is not linked to obesity (3). Gonadotropin-dependent precocious puberty is extremely rare among boys with this syndrome.…”

Atypical 15q11.2-q13 Deletions and the Prader-Willi Phenotype

“…Papers describing cases with balanced translocations were also excluded. In total, 20 papers and 29 cases were included in our literature overview [ 5 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ].…”

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

“…Although classically loss-of-function mutations of MKRN3 are associated with CPP, other mutation variants including missense and complete deletions of MKRN3 have also been described [71,72]. When mutations affect the RING finger domain, the inherent ubiquinase activity of MKRN3 is altered, thus affecting the repression of KISS1 and TAC3 promoter activity and transcription.…”

“…Melanoma antigen L2 (MAGEL2) is one of the genes in the same PWS imprinted area of chromosome 15 as MKRN3. It encodes a protein in the MAGE/necdin family of ubiquitin ligase receptors [71,116,117]. It is highly expressed in hypothalamic tissue, although the neuroendocrine effects are not fully understood.…”