Christodoulides C, Scarda A, Granzotto M, Milan G, Dalla Nora E, Keogh J, De Pergola G, Stirling H, Pannacciulli N, Sethi J K, Federspil G, Vidal-Puig A, Farooqi I S, O'Rahilly S, Vettor R
Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Box 232, Cambridge, CB2 2QQ, UK.
Diabetologia. 2006 Apr;49(4):678-84. doi: 10.1007/s00125-006-0144-4. Epub 2006 Feb 14.
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.
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.
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.
目的/假设：近期研究表明，无翅型MMTV整合位点家族成员10B（WNT10B）可能在体外和体内对脂肪细胞分化的负调控中发挥作用。为了确定WNT10B中的突变是否导致人类肥胖，我们在两个独立的肥胖受试者群体中筛查了该基因的突变。
我们研究了来自英国肥胖遗传学研究的96名早发性严重肥胖（小于10岁）受试者以及115名欧洲裔意大利肥胖受试者。
发现一名早发性肥胖先证者为C256Y突变的杂合子，该突变消除了WNT10B激活经典WNT信号传导并阻断脂肪生成的能力，且在600个对照等位基因中未发现。携带该等位基因的先证者的所有亲属均超重或肥胖。在肥胖先证者中还发现了其他三个罕见的错义变体，但在家族研究中这些变体与肥胖并未明显共分离，其中一个（P301S）在三名早发性肥胖的无关受试者中被发现，其具有正常的功能特性。
结论/解读：这些突变代表了WNT10B首次自然发生的错义变体。虽然C256Y WNT10B的系谱分析并未提供该变体与肥胖因果关系的确切证据，但在一个受肥胖影响的人类家族中发现无功能的WNT10B等位基因应促使在其他肥胖人群中对该基因进行进一步研究。
