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Abstract

Vertebrates position unpaired organs of the chest and abdomen asymmetrically along the left–right (LR) body axis. Each structure comes to lie non-randomly with respect to the midline in an overall position designated situs solitus, exemplified in humans by placement of the heart, stomach and spleen consistently to the left. Aberrant LR axis development can lead to randomization of individual organ position (situs ambiguus) or to mirror-image reversal of all lateralized structures (situs in versus)1. Previously we mapped a locus for situs abnormalities in humans, HTX1, to Xq26.2 by linkage analysis in a single family (LR1) and by detection of a deletion in an unrelated situs ambiguus male (Family LR2; refs 2,3). From this chromosomal region we have positionally cloned ZIC3, a gene encoding a putative zinc-finger transcription factor. One frameshift, two missense and two nonsense mutations have been identified in familial and sporadic situs ambiguus. The frameshift allele is also associated with situs inversus among some heterozygous females, suggesting that ZIC3 functions in the earliest stages of LR-axis formation. ZIC3, which has not been previously implicated in vertebrate LR-axis development, is the first gene unequivocally associated with human situs abnormalities.

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Author information

Affiliations

  1. Departments of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030-3498, USA.

    • Marinella Gebbia
    • , Giovanni B. Ferrero
    • , Maria T. Bassi
    •  & Brett Casey
  2. Department of Molecular Microbiology, Washington University, St. Louis, Missouri 63130, USA.

    • Giuseppe Pilia
    •  & David Schlessinger
  3. Department of Pediatrics and the Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

    • Arthur S. Aylsworth
  4. Department of Human Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4AA, UK.

    • Miranda Penman-Splitt
    •  & John Burn
  5. Children's Hospital and Health Center, San Diego, California 92123, USA.

    • Lynne M. Bird
  6. Department of Medical Genetics, University of Alberta Hospitals, Edmonton, Alberta T6G 2B7, Canada.

    • John S. Bamforth
  7. Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030-3498, USA.

    • David L. Nelson

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Correspondence to Brett Casey.

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https://doi.org/10.1038/ng1197-305

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