Mutations in MKKS cause Bardet-Biedl syndrome (original) (raw)

Nature Genetics volume 26, pages 15–16 (2000)Cite this article

A Correction to this article was published on 01 June 2001

Abstract

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder with locus heterogeneity5,6,7,8,9. None of the ‘responsible’ genes have previously been identified. Some BBS cases (approximately 10%) remain unassigned to the five previously mapped loci10. McKusick-Kaufma syndrome (MKS) includes hydrometrocolpos, postaxial polydactyly and congenital heart disease, and is also inherited in an autosomal recessive manner11,12. We ascertained 34 unrelated probands with classic features of BBS including retinitis pigmentosa (RP), obesity and polydactyly. The probands were from families unsuitable for linkage because of family size. We found MKKS mutations in four typical BBS probands (Table 1). The first is a 13-year-old Hispanic girl with severe RP, PAP, mental retardation and obesity (BMI >40). She was a compound heterozygote for a missense (1042G→A, G52D) and a nonsense (1679T→A, Y264stop) mutation in exon 3. Cloning and sequencing of the separate alleles confirmed that the mutations were present in trans. A second BBS proband (from Newfoundland), born to consanguineous parents, was homozygous for two deletions (1316delC and 1324-1326delGTA) in exon 3, predicting a frameshift. An affected brother was also homozygous for the deletions, whereas an unaffected sibling had two normal copies of MKKS. Both the proband and her affected brother had RP, PAP, mild mental retardation, morbid obesity (BMI >50 and 37, respectively), lobulated kidneys with prominent calyces and diabetes mellitus (diagnosed at ages 33 and 30, respectively). A deceased sister (DNA unavailable) had similar phenotypic features (RP with blindness by age 13, BMI >45, abnormal glucose tolerance test and IQ=64, vaginal atresia and syndactyly of both feet). Both parents and the maternal grandfather were heterozygous for the deletions. Genotyping with markers from the MKKS region12 confirmed homozygosity at 20p12 in both affected individuals.

Table 1 Diagnosis of BBS and MKS

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Figure 1: Human multiple tissue northern blots analysed with a probe from exons 3-6 of the full-length MKKS cDNA showing a 2.4-kb transcript in tissues affected by BBS.

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Acknowledgements

We thank A. McClain, S. Naylor, T. Young and D. Hefferton for patient ascertainment and collection of DNA samples; C. Searby and H. Naik for technical assistance; and R. Swiderski for collection of RNA and assistance with northern-blot analysis. This work was supported in part by NIH grant EY11298 and the Foundation Fighting Blindness (V.C.S. and E.M.S.). V.C.S. is an associate investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Genetic Diseases Research Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA
    Anne M. Slavotinek & Leslie G. Biesecker
  2. Department of Ophthalmology, University of Iowa, Iowa City, Iowa, USA
    Edwin M. Stone
  3. Howard Hughes Medical Institute and Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA
    Kirk Mykytyn & Val C. Sheffield
  4. Department of Ophthalmology, Harbor-UCLA Medical Center, Torrance, California, USA
    John R. Heckenlively
  5. Faculty of Medicine, Memorial University, St. Johns , Newfoundland, Canada
    Jane S. Green & Patrick S. Parfrey
  6. Department of Ophthalmology and Vision Science Research Program, University of Toronto, Toronto, Canada
    Elise Heon
  7. Long Island College Hospital, Brooklyn, New York, USA
    Maria A. Musarella

Authors

  1. Anne M. Slavotinek
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  2. Edwin M. Stone
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  3. Kirk Mykytyn
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  4. John R. Heckenlively
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  5. Jane S. Green
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  6. Elise Heon
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  7. Maria A. Musarella
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  8. Patrick S. Parfrey
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  9. Val C. Sheffield
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  10. Leslie G. Biesecker
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Correspondence toVal C. Sheffield.

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Slavotinek, A., Stone, E., Mykytyn, K. et al. Mutations in MKKS cause Bardet-Biedl syndrome.Nat Genet 26, 15–16 (2000). https://doi.org/10.1038/79116

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