WNT10B mutations in human obesity

Diabetologia. 2006 Apr;49(4):678-84. doi: 10.1007/s00125-006-0144-4. Epub 2006 Feb 14.

Abstract

Aims/hypothesis: Recent studies suggest that wingless-type MMTV integration site family, member 10B (WNT10B) may play a role in the negative regulation of adipocyte differentiation in vitro and in vivo. In order to determine whether mutations in WNT10B contribute to human obesity, we screened two independent populations of obese subjects for mutations in this gene.

Subjects and methods: We studied 96 subjects with severe obesity of early onset (less than 10 years of age) from the UK Genetics of Obesity Study and 115 obese Italian subjects of European origin.

Results: One proband with early-onset obesity was found to be heterozygous for a C256Y mutation, which abrogated the ability of WNT10B to activate canonical WNT signalling and block adipogenesis and was not found in 600 control alleles. All relatives of the proband who carried this allele were either overweight or obese. Three other rare missense variants were found in obese probands, but these did not clearly cosegregate with obesity in family studies and one (P301S), which was found in three unrelated subjects with early-onset obesity, had normal functional properties.

Conclusions/interpretation: These mutations represent the first naturally occurring missense variants of WNT10B. While the pedigree analysis in the case of C256Y WNT10B does not provide definitive proof of a causal link of this variant with obesity, the finding of a non-functioning WNT10B allele in a human family affected by obesity should encourage further study of this gene in other obese populations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / cytology
  • Adipocytes / metabolism
  • Adult
  • Amino Acid Sequence
  • Animals
  • Cell Differentiation / genetics
  • Cell Line
  • Conserved Sequence
  • Cysteine / genetics
  • Cysteine / metabolism
  • DNA Mutational Analysis
  • Female
  • Humans
  • Male
  • Mice
  • Molecular Sequence Data
  • Mutation / genetics*
  • Obesity / genetics*
  • Pedigree
  • Proline / genetics
  • Proline / metabolism
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Sequence Alignment
  • Signal Transduction
  • Wnt Proteins / chemistry
  • Wnt Proteins / genetics*
  • Wnt Proteins / metabolism

Substances

  • Proto-Oncogene Proteins
  • WNT10B protein, human
  • Wnt Proteins
  • Proline
  • Cysteine