MOLECULAR GENETICS OF HUMAN LEFT-RIGHT AXIS MALFORMATIONS

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1) In the inv/inv mouse strain, integration of the tyrosinase minigene causes complete mirror image reversal of internal organs. Analysis of the transgenic integration site revealed that loss of function mutation of a novel gene, Inversin, is responsible for the disruption of normal left-right polarity. Based on these results, we hypothesized that mutations in the Inversin gene are associated with some cases of left-right axis malformations in humans. We cloned of the human INVERSIN cDNA, characterized its genomic structure, and screened for mutations among 112 sporadic and 14 familial cases of left-right axis malformations. We demonstrated that human INVERSIN, localizes to chromosome 9q3l, and encodes a protein with 9O% homology to the mouse homologue. Mutation analysis revealed 2 unique nucleotide substitutions, S371G and A650P which result in missense mutations. We conclude from the current study that INVERSIN mutations are rarely associated with human left-right axis malformations.2) Bioinformatic analyses of the human/mouse genome sequences of the flanking the lefty gene region revealed that mouse Lefty 1 is the ortholog of human LEFTY2 (also known as LEFTYB). Right sided silencer element of the mouse Lefty 1 is conserved in humans as well. Mutation analysis of more than one hundred patients with situs abnormalities, however, did not reveal any patients with LEFTY2 coding mutations.3) Left-right axis malformations is commonly observed in the F1 offspring of NOD (non-obese diabetic) mouse dams and sires from ICR strains. The ICR strain had 1) a 0.2 kb insertion in the putative promoter region of the isoform E of Hnf3beta together with a G to A change that could create a potential splice acceptor in the exon 3 of Hnf3beta (gene frequency 0.36), 2) five single base substitutions within the 5' controlling element and a proline to serine substitution (P2S) of Lefty1 (0.77). These substitutions may contribute to increased susceptibility to maternal diabetes.