X-LINKED SITUS ABNORMALITIES RESULT FROM MUTATIONS IN ZIC3

Vertebrates position unpaired organs of the chest and abdomen asymmetr ically along the left-right (LR) body axis. Each structure comes to li e non-randomly with respect to the midline in an overall position desi gnated sites solitus, exemplified in humans by placement of the heart, stomach and spleen consistently to the left. Aberrant LR axis develop ment can lead to randomization of individual organ position (sites amb iguus) or to mirror-image reversal of all lateralized structures (site s inversus)(1). Previously we mapped a locus for sites abnormalities i n humans, HTX1, to Xq26.2 by linkage analysis in a single family (LR1) and by detection of a deletion in an unrelated sites ambiguus male (F amily LR2; refs 2,3). From this chromosomal region we have positionall y cloned ZIC3, a gene encoding a putative zinc-finger transcription fa ctor. One frameshift, two missense and two nonsense mutations have bee n identified in familial and sporadic sites ambiguus. The frameshift a llele is also associated with sites inverses among some heterozygous f emales, suggesting that ZIC3 functions in the earliest stages of LR-ax is formation. ZIC3, which has not been previously implicated in verteb rate LR-axis development, is the first gene unequivocally associated w ith human sites abnormalities.