Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome (original) (raw)

Nature Genetics volume 26, pages 67–70 (2000)Cite this article

Abstract

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder predominantly characterized by obesity, retinal dystrophy, polydactyly, learning difficulties, hypogenitalism and renal malformations, with secondary features that include diabetes mellitus, endocrinological dysfunction and behavioural abnormalities1,2. Despite an initial expectation of genetic homogeneity due to relative clinical uniformity, five BBS loci have been reported, with evidence for additional loci in the human genome3,4,5,6,7; however, no genes for BBS have yet been identified. We performed a genome screen with BBS families from Newfoundland that were excluded from BBS1_–_5 and identified linkage with D20S189. Fine-mapping reduced the critical interval to 1.9 cM between D20S851 and D20S189, encompassing a chaperonin-like gene. Mutations in this gene were recently reported to be associated with McKusick-Kaufman syndrome (MKKS; ref. 8). Given both the mapping position and clinical similarities of these two syndromes, we screened MKKS and identified mutations in five Newfoundland and two European-American BBS pedigrees. Most are frameshift alleles that are likely to result in a non-functional protein. Our data suggest that a complete loss of function of the MKKS product, and thus an inability to fold a range of target proteins, is responsible for the clinical manifestations of BBS.

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Acknowledgements

We thank the families described for cooperation and the Kleberg Genotyping Center for expertise and fluorescent microsatellites. This study was supported in part by a National Eye Institute, NIH, grant EY12666 (N.K.), the Foundation Fighting Blindness (R.A.L., J.R.L.), the Wellcome Trust (P.L.B.), the Kidney Foundation of Canada, the Canadian Medical Research Council and the Janeway Foundation (J.S.G., P.S.P., W.S.D.).

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Author notes

  1. Nicholas Katsanis, Philip L. Beales and Michael O. Woods: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
    Nicholas Katsanis, Philip L. Beales, Richard A. Lewis, Stephen J. Ansley & James R. Lupski
  2. Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
    Richard A. Lewis & James R. Lupski
  3. Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
    Richard A. Lewis
  4. Department of Ophthalmology, Baylor College of Medicine, Houston, Texas, USA
    Richard A. Lewis
  5. The Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
    Richard A. Lewis & James R. Lupski
  6. Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
    Michael O. Woods, Jane S. Green, Patrick S. Parfrey & William S. Davidson
  7. Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada
    Michael O. Woods & William S. Davidson
  8. Molecular Medicine Unit, Institute of Child Health, University College London, London, UK
    Philip L. Beales

Authors

  1. Nicholas Katsanis
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  2. Philip L. Beales
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  3. Michael O. Woods
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  4. Richard A. Lewis
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  5. Jane S. Green
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  6. Patrick S. Parfrey
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  7. Stephen J. Ansley
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  8. William S. Davidson
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  9. James R. Lupski
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Corresponding author

Correspondence toJames R. Lupski.

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Katsanis, N., Beales, P., Woods, M. et al. Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome.Nat Genet 26, 67–70 (2000). https://doi.org/10.1038/79201

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