title: A new pathway in the control of the initiation of puberty: the MKRN3 gene.
abstract: Pubertal timing is influenced by complex interactions among genetic, nutritional, environmental, and socioeconomic factors. The role of MKRN3, an imprinted gene located in the Prader-Willi syndrome critical region (chromosome 15q11-13), in pubertal initiation was first described in 2013 after the identification of deleterious MKRN3 mutations in five families with central precocious puberty (CPP) using whole-exome sequencing analysis. Since then, additional loss-of-function mutations of MKRN3 have been associated with the inherited premature sexual development phenotype in girls and boys from different ethnic groups. In all of these families, segregation analysis clearly demonstrated autosomal dominant inheritance with complete penetrance, but with exclusive paternal transmission, consistent with the monoallelic expression of MKRN3 (a maternally imprinted gene). Interestingly, the hypothalamic Mkrn3 mRNA expression pattern in mice correlated with a putative inhibitory input on puberty initiation. Indeed, the initiation of puberty depends on a decrease in factors that inhibit the release of GnRH combined with an increase in stimulatory factors. These recent human and animal findings suggest that MKRN3 plays an inhibitory role in the reproductive axis to represent a new pathway in pubertal regulation.
authors.affiliation: Division of EndocrinologyDiabetes and Hypertension, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USAUnidade de Endocrinologia do DesenvolvimentoDisciplina de Endocrinologia e Metabologia, Laboratório de Hormônios e Genética Molecular, LIM 42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Avenida Dr Enéas de Carvalho Aguiar, 255, 7° andar, sala 7037, CEP: 05403-900, São Paulo, Brazil.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Abreu
authors.affiliation: Division of EndocrinologyDiabetes and Hypertension, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USAUnidade de Endocrinologia do DesenvolvimentoDisciplina de Endocrinologia e Metabologia, Laboratório de Hormônios e Genética Molecular, LIM 42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Avenida Dr Enéas de Carvalho Aguiar, 255, 7° andar, sala 7037, CEP: 05403-900, São Paulo, Brazil.
authors.forename: Delanie B
authors.initials: DB
authors.lastname: Macedo
authors.affiliation: Division of EndocrinologyDiabetes and Hypertension, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USAUnidade de Endocrinologia do DesenvolvimentoDisciplina de Endocrinologia e Metabologia, Laboratório de Hormônios e Genética Molecular, LIM 42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Avenida Dr Enéas de Carvalho Aguiar, 255, 7° andar, sala 7037, CEP: 05403-900, São Paulo, Brazil.
authors.forename: Vinicius N
authors.initials: VN
authors.lastname: Brito
authors.affiliation: Division of EndocrinologyDiabetes and Hypertension, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USAUnidade de Endocrinologia do DesenvolvimentoDisciplina de Endocrinologia e Metabologia, Laboratório de Hormônios e Genética Molecular, LIM 42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Avenida Dr Enéas de Carvalho Aguiar, 255, 7° andar, sala 7037, CEP: 05403-900, São Paulo, Brazil.
authors.forename: Ursula B
authors.initials: UB
authors.lastname: Kaiser
authors.affiliation: Division of EndocrinologyDiabetes and Hypertension, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USAUnidade de Endocrinologia do DesenvolvimentoDisciplina de Endocrinologia e Metabologia, Laboratório de Hormônios e Genética Molecular, LIM 42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Avenida Dr Enéas de Carvalho Aguiar, 255, 7° andar, sala 7037, CEP: 05403-900, São Paulo, Brazil anacl@usp.br.
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Latronico
mesh_terms: D017668:Age of Onset; D000595:Amino Acid Sequence; D000818:Animals; D015870:Gene Expression; D056726:Genetic Association Studies; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D008969:Molecular Sequence Data; D010641:Phenotype; D011218:Prader-Willi Syndrome / Q000235:genetics / Q000378:metabolism; D011627:Puberty / Q000235:genetics*; D011629:Puberty, Precocious / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases
chemical_list: D012261:Ribonucleoproteins; C119425:MKRN3 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: gonadotropins; hypothalamus and neuroendocrinology; mutations; secretion