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Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome

Nature Genetics volume 31, pages 435–438 (2002)Cite this article

Abstract

Bardet-Biedl syndrome (BBS, OMIM 209900) is a genetic disorder with the primary features of obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation and hypogenitalism1,2,3,4. Individuals with BBS are also at increased risk for diabetes mellitus, hypertension and congenital heart disease4,5,6. What was once thought to be a homogeneous autosomal recessive disorder is now known to map to at least six loci: 11q13 (BBS1), 16q21 (BBS2), 3p13–p12 (BBS3), 15q22.3–q23 (BBS4), 2q31 (BBS5) and 20p12 (BBS6)7,8,9,10,11,12,13. There has been considerable interest in identifying the genes that underlie BBS, because some components of the phenotype are common. Cases of BBS mapping ro BBS6 are caused by mutations in MKKS12,13; mutations in this gene also cause McKusick-Kaufman syndrome (hydrometrocolpos, post-axial polydactyly and congenital heart defects)14,15. In addition, we recently used positional cloning to identify the genes underlying BBS2 (ref. 16) and BBS4 (ref. 17). The BBS6 protein has similarity to a Thermoplasma acidophilum chaperonin15, whereas BBS2 and BBS4 have no significant similarity to chaperonins. It has recently been suggested that three mutated alleles (two at one locus, and a third at a second locus) may be required for manifestation of BBS (triallelic inheritance)18. Here we report the identification of the gene BBS1 and show that a missense mutation of this gene is a frequent cause of BBS. In addition, we provide data showing that this common mutation is not involved in triallelic inheritance.

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Figure 1: Fine mapping of the BBS1 interval using extended families (PR1–PR5).
Figure 2: Diagram of BBS1 structure and mutations.
Figure 3: Sequence from affected individuals and controls.
Figure 4: Expression of BBS1 in human tissue.

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Acknowledgements

We are grateful to the patients and their families for their participation in this study. We thank G. Beck, K. Bugge, R. Englehardt, J. Andorf and A. Nalley for technical assistance, and D. Aguiar-Crouch for administrative assistance. We thank M. Berg for important contributions to the genetic mapping of the BBS1 locus. We also wish to thank L.G. Biesecker for advice and many helpful suggestions. This work was supported by grants from the following organizations: National Institutes of Health (to V.C.S. and E.M.S.), Foundation Fighting Blindness (to S.G.J., E.M.S. and V.C.S.), Carver Endowment for Molecular Ophthalmology (to E.M.S. and V.C.S.) and Research to Prevent Blindness (to Dept. of Ophthalmology, Univ. of Iowa). V.C.S. is an associate investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Pediatrics, Division of Medical Genetics and the Howard Hughes Medical Institute, University of Iowa, Iowa City, 52242, Iowa, USA

    Kirk Mykytyn, Darryl Y. Nishimura, Charles C. Searby, Mythreyi Shastri, Hsan-jan Yen, John S. Beck & Val C. Sheffield

  2. Department of Electrical Engineering, University of Iowa, Iowa City, 52242, Iowa, USA

    Terry Braun

  3. Department of Ophthalmology, University of Iowa, Iowa City, 52242, Iowa, USA

    Luan M. Streb & Edwin M. Stone

  4. Department of Biochemistry, Ponce School of Medicine, Ponce, Puerto Rico

    Alberto S. Cornier

  5. Division of Genetics, Children's Hospital, Boston, Massachusetts, USA

    Gerald F. Cox

  6. Department of Ophthalmology, Children's Hospital, Boston, Massachusetts, USA

    Anne B. Fulton

  7. Genetics Institute, Soroka Medical Center, Ben Gurion University of the Negev, Beer-Sheva, Israel

    Rivka Carmi

  8. Department of Medical Biology-Genetics, Arkdeniz University, Turkey

    Güven Lüleci

  9. National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA

    Settara C. Chandrasekharappa & Francis S. Collins

  10. Scheie Eye Institute, Philadelphia, Pennsylvania, USA

    Samuel G. Jacobson

  11. Jules Stein Eye Institute, Harbor-UCLA Medical Center, Torrance, California, USA

    John R. Heckenlively

  12. Casey Eye Institute, Oregon Health Sciences University, Portland, Oregon, USA

    Richard G. Weleber

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Correspondence to Val C. Sheffield.

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Mykytyn, K., Nishimura, D., Searby, C. et al. Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome. Nat Genet 31, 435–438 (2002). https://doi.org/10.1038/ng935

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