Variation of the McKusick-Kaufman gene and studies of relationships with common forms of obesity

Obesity is a prominent feature of the Bardet-Biedl syndrome (BBS), one subset of which, BBS6, is due to mutations in the chaperonin-like gene termed the McKusick-Kaufman syndrome (MKKS) gene. We tested whether variation in MKKS contributes to common and probably polygenic forms of obesity by performing mutation analysis of the coding region in 60 Danish white men with juvenile-onset obesity. Five variants were identified, including two synonymous mutations (Pro³⁹Pro and Ile¹⁷⁸Ile) and three nonsynonymous variants (Ala²⁴²Ser, Arg⁵¹⁷Cys, and Gly ⁵³²Val). Furthermore, the rare Ala²⁴²Ser was identified in two families and showed partial cosegregation with obesity. The Pro ³⁹Pro, Ile¹⁷⁸Ile, and Arg⁵¹⁷Cys variants are in complete linkage disequilibrium and defined a prevalent haplotype. In a case-control study, the Arg⁵¹⁷Cys polymorphism allele prevalence was 11.4% [95% confidence interval (CI), 9.7-13.0] among 744 men with juvenile-onset obesity and 9.3% (CI, 7.9-10.7) among 867 control subjects (P = 0.048). However, among middle-aged men the allelic prevalence was 9.7% (CI, 7.9-11.4) among 523 obese men and 12.2% (CI, 10.8-13.6) among 1051 lean men (P = 0.037). In conclusion, it is unlikely that MKKS variants play a major role in the pathogenesis of nonsyndromic obesity, although in rare cases the A242S allele may contribute to obesity.