Mutation analysis of NR0B2 among 1545 Danish men identifies a novel c.278G>A (p.G93D) variant with reduced functional activity

Research output: Contribution to journalJournal articleResearchpeer-review

Søren Morgenthaler Echwald, Kirstine L Andersen, Thorkild I A Sørensen, Lesli H Larsen, Teis Andersen, Naoko Tonooka, Hideaki Tomura, Jun Takeda, Oluf Pedersen

Variations of the small heterodimer partner (SHP, NR0B2) gene, an atypical nuclear receptor that inhibits transactivation by hepatocyte nuclear factor (HNF)-4alpha, are associated with obesity among Japanese. The purpose of the study was to evaluate the prevalence of SHP variants among obese Danish men. Using combined SSCP and heteroduplex analysis, we analyzed the entire coding region of SHP for variants in a cohort of 750 Danish men with early-onset obesity and genotyped a cohort of 795 nonobese control subjects using PCR-RFLP. Functional analyses of the identified coding region variants were performed in both MIN6-m9 and HepG2 cell lines. A total of five novel variants, including three missense variants (c.100C>G [p.R34G], c.278G>A [p.G93D], and c.415C>A [p.P139H]) and two silent variants (c.65C>T [p.Y22Y] and c.339G>A [p.P113P]) were identified. Moreover, the previously reported c.512G>C [p.G171A] polymorphism was identified. The 171A allele was not associated with obesity (p = 0.07). The 34G, 93D, and 139H-alleles were rare variants, which were found only among obese subjects. Among the four coding region variants, the 93D-allele showed a reduced in vitro inhibition of the HNF-4alpha transactivation of the HNF-1alpha promoter expression when expressed in MIN6-m9 and HepG2 cell lines (p
Original languageEnglish
JournalHuman Mutation
Issue number5
Pages (from-to)381-387
Number of pages7
Publication statusPublished - 2004

    Research areas

  • Adolescent, Adult, Age of Onset, Alleles, Amino Acid Sequence, Case-Control Studies, Cell Line, Tumor, DNA Mutational Analysis, Genetic Variation, Humans, Male, Middle Aged, Molecular Sequence Data, Mutation, Missense, Netherlands, Obesity, Phenotype, Polymerase Chain Reaction, Polymorphism, Restriction Fragment Length, Polymorphism, Single-Stranded Conformational, Receptors, Cytoplasmic and Nuclear

ID: 96477