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Mutation of a gene encoding a putative chaperonin causes McKusick-Kaufman syndrome

Nature Geneticsvolume 25pages7982 (2000) | Download Citation



McKusick-Kaufman syndrome (MKKS, MIM 236700) is a human developmental anomaly syndrome comprising hydrometrocolpos (HMC), postaxial polydactyly (PAP) and congenital heart disease1,2 (CHD). MKKS has been mapped in the Old Order Amish population to 20p12, between D20S162 and D20S894 (ref. 3). Here we describe the identification of a gene mutated in MKKS. We analysed the approximately 450-kb candidate region by sample sequencing, which revealed the presence of several known genes and EST clusters. We evaluated candidate transcripts by northern-blot analysis of adult and fetal tissues. We selected one transcript with widespread expression, MKKS, for analysis in a patient from the Amish pedigree and a sporadic, non-Amish case. The Old Order Amish patient was found to be homozygous for an allele that had two missense substitutions and the non-Amish patient was a compound heterozygote for a frameshift mutation predicting premature protein truncation and a distinct missense mutation. The MKKS predicted protein shows amino acid similarity to the chaperonin family of proteins, suggesting a role for protein processing in limb, cardiac and reproductive system development. We believe that this is the first description of a human disorder caused by mutations affecting a putative chaperonin molecule.

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We thank T. Ben-Yosef, L. Brody, S. Chandrasekharappa, P. Clouser, J. Davis, C. Francomano, E. Green, J. Johnston, D. Leja, R. Nussbaum, T. Oda, W. Pavan, M. Rosenberg, A. Schäffer, J. Touchman and the staff of NISC for production sequencing, critical review, helpful discussions, patient ascertainment, graphics and laboratory support.

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Author notes

  1. Deborah L. Stone and Anne Slavotinek: These authors contributed equally to this study.


  1. Genetic Diseases Research Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA

    • Deborah L. Stone
    • , Anne Slavotinek
    •  & Leslie G. Biesecker
  2. NIH Intramural Sequencing Center, Gaithersburg, Maryland, USA

    • Gerard G. Bouffard
  3. Genome Technology Branch, NHGRI, NIH

    • Sharmila Banerjee-Basu
    •  & Andreas D. Baxevanis
  4. Departments of Pediatrics and Obstetrics, University of Michigan Medical Center, Ann Arbor, USA, Michigan

    • Mason Barr


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Correspondence to Leslie G. Biesecker.

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