Identification of the gene that, when mutated, causes the human obesity syndrome BBS4

Bardet-Biedl syndrome (BBS. MIM 209900) is a heterogeneous autosomal recess ive disorder characterized by obesity, pigmentary retinopathy. polydactyly, renal malformations, mental retardation, and hypogenitalism(1-4). The diso rder is also associated with diabetes mellitus, hypertension, and congenita l heart disease(4-6). Six distinct BBS loci map to 11q13 (BBS1), 16q21 (BBS 2). 3p13-p12 (BBS3). 15q22,3-q23 (BBS4), 2q31 (BBS5). and 20p12 (BBS6)(7-13 ). Although BBS is rare in the general population (<1/100,000). there is co nsiderable interest in identifying the genes causing BBS because components of the phenotype. such as obesity and diabetes, are common. We and others have demonstrated that BBS6 is caused by mutations in the gene MKKS (refs. 12,13). mutation of which also causes McKusick-Kaufman syndrome (hydrometro colpos. post-axial polydactyly, and congenital heart defects)(14,15). MKKS has sequence homology to the alpha subunit of a prokaryotic chaperonin in t he thermosome Thermoplasma acidophilum(15). We recently identified a novel gene that causes BBS2(16). The BBS2 protein has no significant similarity t o other chaperonins or known proteins. Here we report the positional clonin g and identification of mutations in BBS patients in a novel gene designate d BBS4.