title: In silico analysis of a novel MKRN3 missense mutation in familial central precocious puberty.
abstract: 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 GnRH secretion in central precocious puberty (CPP) may arise either from gain-of-function mutations of the KISS1 and KISS1R genes or from loss-of-function manner mutations of the MKRN3 gene leading to MKRN3 deficiency.
  
  
  OBJECTIVE
  To explore the genetic causes responsible for CPP and the potential role of the RING finger protein 3 (MKRN3) gene.
  
  
  METHODS
  We investigated potential sequence variations in the intronless MKRN3 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 MKRN3 gene was identified in these siblings. The imprinted MKRN3 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 in silico structural model is also explored.
  
  
  CONCLUSIONS
  A novel mutation in the MKRN3 gene in two sisters with CPP was identified, supporting the fundamental role of this gene in the suppression of the hypothalamic GnRH neurons.
authors.affiliation: Department of Molecular Genetics, Function & Therapy, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
authors.forename: Vassos
authors.initials: V
authors.lastname: Neocleous
authors.affiliation: Department of Molecular Genetics, Function & Therapy, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
authors.forename: Christos
authors.initials: C
authors.lastname: Shammas
authors.affiliation: NMR Centre for Structural Biology, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
authors.forename: Marie M
authors.initials: MM
authors.lastname: Phelan
authors.affiliation: Division of Pediatric Endocrinology, Makarios III Hospital, Nicosia, Cyprus.
authors.forename: Stella
authors.initials: S
authors.lastname: Nicolaou
authors.affiliation: Department of Molecular Genetics, Function & Therapy, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
authors.forename: Leonidas A
authors.initials: LA
authors.lastname: Phylactou
authors.affiliation: Department of Molecular Genetics, Function & Therapy, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.|Division of Pediatric Endocrinology, Paedi Center for specialized Pediatrics, Nicosia, Cyprus.|St George's University of London Medical School at the University of Nicosia, Nicosia, Cyprus.
authors.forename: Nicos
authors.initials: N
authors.lastname: Skordis
mesh_terms: D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D011487:Protein Conformation; D011629:Puberty, Precocious / Q000235:genetics*; D012261:Ribonucleoproteins / Q000737:chemistry / Q000235:genetics*; D035781:Siblings; D044767:Ubiquitin-Protein Ligases
chemical_list: D012261:Ribonucleoproteins; C119425:MKRN3 protein, human; D044767:Ubiquitin-Protein Ligases