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In silico analysis of a novel MKRN 3 missense mutation in familial central precocious puberty
Author(s) -
Neocleous Vassos,
Shammas Christos,
Phelan Marie M.,
Nicolaou Stella,
Phylactou Leonidas A.,
Skordis Nicos
Publication year - 2016
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/cen.12854
Subject(s) - missense mutation , genetics , in silico , exon , gene , biology , sanger sequencing , mutation , loss function , phenotype
Summary Background The onset of puberty is influenced by the interplay of stimulating and restraining factors, many of which have a genetic origin. Premature activation of the Gn RH secretion in central precocious puberty ( CPP ) may arise either from gain‐of‐function mutations of the KISS 1 and KISS 1R genes or from loss‐of‐function manner mutations of the MKRN 3 gene leading to MKRN 3 deficiency. Objective To explore the genetic causes responsible for CPP and the potential role of the RING finger protein 3 ( MKRN 3 ) gene. Design and patients We investigated potential sequence variations in the intronless MKRN 3 gene by Sanger sequencing of the entire 507 amino acid coding region of exon 1 in a family with two affected girls presented with CPP at the age of 6 and 5·7 years, respectively. Results A novel heterozygous g.Gly312Asp missense mutation in the MKRN 3 gene was identified in these siblings. The imprinted MKRN 3 missense mutation was also identified as expected in the unaffected father and followed as expected an imprinted mode of inheritance. In silico analysis of the altered missense variant using the computational algorithms Polyphen2, SIFT and Mutation Taster predicted a damage and pathogenic alteration causing CPP . The pathogenicity of the alteration at the protein level via an i n silico structural model is also explored. Conclusion A novel mutation in the MKRN 3 gene in two sisters with CPP was identified, supporting the fundamental role of this gene in the suppression of the hypothalamic Gn RH neurons.