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

Abstract

Bardet–Biedl syndrome (BBS, MIM 209900) is a heterogeneous autosomal recessive disorder characterized by obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation, and hypogenitalism1,2,3,4. The disorder is also associated with diabetes mellitus, hypertension, and congenital heart disease4,5,6. Six distinct BBS loci map to 11q13 (BBS1), 16q21 (BBS2), 3p13–p12 (BBS3), 15q22.3–q23 (BBS4), 2q31 (BBS5), and 20p12 (BBS6)7,8,9,10,11,12,13. Although BBS is rare in the general population (<1/100,000), there is considerable 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 (hydrometrocolpos, post-axial polydactyly, and congenital heart defects)14,15. MKKS has sequence homology to the alpha subunit of a prokaryotic chaperonin in the thermosome Thermoplasma acidophilum15. We recently identified a novel gene that causes BBS216. The BBS2 protein has no significant similarity to other chaperonins or known proteins. Here we report the positional cloning and identification of mutations in BBS patients in a novel gene designated BBS4.

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Figure 1: Schematic of BBS4 structure.
Figure 2: Sequence from affected patients and controls.
Figure 3: Segregation of the exon 3 and 4 deletion in members of a consanguineous Italian family and Israeli Arab family.
Figure 4: Expression of BBS4.

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Acknowledgements

We are grateful to the patients and their families for their participation in this study. We thank K. Bugge and C. Hartzler for technical assistance, and D. Aguiar Crouch for administrative assistance. We also wish to thank L. Biesecker, E. Heon, D. Nishimura, and R. Swiderski for advice and many helpful suggestions. This work was supported by the following grants and organizations: NIH grant R01-EY-11298 (E.M.S. and V.C.S.), Foundation Fighting Blindness (S.G.J., E.M.S., and V.C.S.), Carver Endowment for Molecular Ophthalmology (E.M.S. and V.C.S.), Research to Prevent Blindness, New York, NY (Department of Ophthalmology, University of Iowa; Department of Ophthalmology, University of Tennessee, Memphis; and Senior Scientific Investigator Award to SGJ) and the British Retinitis Pigmentosa Society (AFW). V.C.S. is an associate investigator of the Howard Hughes Medical Institute.

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Correspondence to Val C. Sheffield.

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Mykytyn, K., Braun, T., Carmi, R. et al. Identification of the gene that, when mutated, causes the human obesity syndrome BBS4. Nat Genet 28, 188–191 (2001). https://doi.org/10.1038/88925

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