title: Novel variants in the MC4R and LEPR genes among severely obese children from the Iberian population.
abstract: We screened for mutations in the MC4R and LEPR genes and investigated the genotype-phenotype correlation in obese individuals belonging to families with evident hereditary patterns of severe and early-onset obesity among the Iberian population. A total of 202 unrelated and severely obese patients since childhood, were enrolled in the study. Bidirectional sequencing of the MC4R gene was carried out in all patients; the LEPR gene was sequenced in 15 individuals based on additional clinical signals. Segregation analysis and/or genotype-phenotype description was performed for subjects with the new mutations and with presumably functional variants. Ten MC4R gene mutations were identified in the heterozygous state in 10 patients. Mutations p.R147G and p.G323E are new and mutations p.R7H, p.G32E, p.H76R, p.V103I, p.S127L, p.T150I, p.I251L and p.G252S were previously described. A new dinucleotide insertion -77_-76insTA in the promoter region of the LEPR gene was found in the heterozygous state in one patient. The new p.R147G and the previously published p.R7H, p.S127L, p.T150I and p.G252S MC4R mutations, cosegregate with obesity in our patients and were predicted to be deleterious. For the novel MC4R p.G323E and LEPR -77_-76insTA gene mutations, the genotype-phenotype correlation and bioinformatic analysis did not clarify whether these mutations are indeed implicated in obesity.
authors.affiliation: Research Centre for Anthropology and Health (CIAS), Department of Life Sciences, University of Coimbra, Portugal.
authors.forename: David
authors.initials: D
authors.lastname: Albuquerque
authors.forename: Manuela Núñez
authors.initials: MN
authors.lastname: Estévez
authors.forename: Pilar Beato
authors.initials: PB
authors.lastname: Víbora
authors.forename: Plácida Sánchez
authors.initials: PS
authors.lastname: Giralt
authors.forename: Aránzazu Margallo
authors.initials: AM
authors.lastname: Balsera
authors.forename: Pedro Gil
authors.initials: PG
authors.lastname: Cortés
authors.forename: Mercedes Jiménez
authors.initials: MJ
authors.lastname: López
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Luego
authors.forename: Guillermo
authors.initials: G
authors.lastname: Gervasini
authors.forename: Sergio Barroso
authors.initials: SB
authors.lastname: Hernández
authors.forename: Javier
authors.initials: J
authors.lastname: Arroyo-Díez
authors.forename: Manuel Arrobas
authors.initials: MA
authors.lastname: Vacas
authors.forename: Clévio
authors.initials: C
authors.lastname: Nóbrega
authors.forename: Licínio
authors.initials: L
authors.lastname: Manco
authors.forename: Raquel
authors.initials: R
authors.lastname: Rodríguez-López
mesh_terms: D000886:Anthropometry; D001483:Base Sequence; D019295:Computational Biology; D005820:Genetic Testing; D005838:Genotype; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009767:Obesity, Morbid / Q000208:ethnology* / Q000235:genetics*; D010641:Phenotype; D011174:Portugal; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*; D054411:Receptors, Leptin / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013030:Spain
chemical_list: C515448:LEPR protein, human; C470072:MC4R protein, human; D044105:Receptor, Melanocortin, Type 4; D054411:Receptors, Leptin
keywords: LEPR gene; MC4R gene; obesity; population; segregation analysis