A Model for Human Situs Determination

Abstract

Alterations of human laterality range from situs reversal or consensus isometry to isolated anomalies of the cardiac, respiratory, gastrointestinal, skeletal, and central nervous systems. A mechanism for human situs determination has been derived from the general model of Brown and Wolpert (1990), with steps involving A-P axis, D-V axis, midline, global situs, and local situs specification. Comparison with Drosophila segmentation is supported by maternal transmission of certain human situs defects and mutation of appropriate Drosophila gene homologues in the human Waardenburg and Greig syndromes. Anteroposterior gradients in expression of vertebrate homeotic genes may relate to a proposed hierarchy of regional laterality decisions. Early alterations in A-P or D-V axis polarity would produce situs reversal in 100 of individuals, as observed in pure situs inversus, homozygous inv mice or manipulated Xenopus embryos. Later alterations would permit random right-left decisions and account for heterotaxy in 50 of affected individuals, as observed in poly asplenia or homozygous iv mice. Randomisation of brain asymmetry could explain why situs but not brain laterality may be reversed in humans, with forebrain situs reversal or isometry leading to brain anomalies. Homologues of Drosophila genes regulating axis polarity, heart and gut development are attractive candidates in human laterality disorders, but none is uniquely localised to the 6q14-q21 or9q32-q34, 7q22, 10q21-22, 11q13 or 11q25, 12q13, 13qter, or Xq24-q27.1 chromosome regions highlighted by heterotaxic patients or mutant mice.