WNT10B mutations in human obesity.
OBJECTIVE
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.


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
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.
Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Box 232, Cambridge, CB2 2QQ, UK.
C
C
Christodoulides
A
A
Scarda
M
M
Granzotto
G
G
Milan
E
E
Dalla Nora
J
J
Keogh
G
G
De Pergola
H
H
Stirling
N
N
Pannacciulli
J K
JK
Sethi
G
G
Federspil
A
A
Vidal-Puig
I S
IS
Farooqi
S
S
O'Rahilly
R
R
Vettor
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D017124:Conserved Sequence; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009765:Obesity / Q000235:genetics*; D010375:Pedigree; D011392:Proline / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D051153:Wnt Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D011518:Proto-Oncogene Proteins; C491119:WNT10B protein, human; D051153:Wnt Proteins; D011392:Proline; D003545:Cysteine