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Loss of the SKI proto-oncogene in individuals affected with 1p36 deletion syndrome is predicted by strain-dependent defects in Ski−/− mice

Nature Genetics volume 30, pages 106109 (2002) | Download Citation

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Abstract

Experiments involving overexpression of Ski have suggested that this gene is involved in neural tube development and muscle differentiation1,2,3,4. In agreement with these findings, Ski−/− mice display a cranial neural tube defect that results in exencephaly and a marked reduction in skeletal muscle mass5. Here we show that the penetrance and expressivity of the phenotype changes when the null mutation is backcrossed into the C57BL6/J background, with the principal change involving a switch from a neural tube defect to midline facial clefting. Other defects, including depressed nasal bridge, eye abnormalities, skeletal muscle defects and digit abnormalities, show increased penetrance in the C57BL6/J background. These phenotypes are interesting because they resemble some of the features observed in individuals diagnosed with 1p36 deletion syndrome, a disorder caused by monosomy of the short arm of human chromosome 1p (refs. 6,​7,​8,​9). These similarities prompted us to re-examine the chromosomal location of human SKI and to determine whether SKI is included in the deletions of 1p36. We found that human SKI is located at distal 1p36.3 and is deleted in all of the individuals tested so far who have this syndrome. Thus, SKI may contribute to some of the phenotypes common in 1p36 deletion syndrome, and particularly to facial clefting.

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Acknowledgements

This work was funded by grants from the NIH (to C.C., H.H., S.S., J.M. and E.S.). We thank P. Klepcyk, N. Lerner, B. Ludwig and W. Matheny for technical assistance and A. Lidral and J. Nadeau for insightful suggestions.

Author information

Affiliations

  1. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.

    • Clemencia Colmenares
    •  & Michael Berk
  2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.

    • Heidi A. Heilstedt
    •  & Lisa G. Shaffer
  3. Department of Human Genetics, University Hospital Research Institute and Case Western Reserve University, Cleveland, Ohio 44106, USA.

    • Stuart Schwartz
  4. Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, USA.

    • Jeffrey C. Murray
  5. Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA.

    • Ed Stavnezer

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Correspondence to Clemencia Colmenares.

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DOI

https://doi.org/10.1038/ng770

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