Identification, genomic organization, chromosomal mapping and mutation analysis of the human INV gene, the ortholog of a murine gene implicated in left-right axis development and biliary atresia.
Determination of left-right axis is a precocious embryonic event, and all phenotypic anomalies resulting from disruption of the normal lateralization process are collectively referred to as the lateralization defect. A transgenic mouse with lateralization defect and hepatic, kidney, and pancreatic anomalies has resulted from disruption of the inv gene by insertion of a transgene. The human ortholog is thus a good candidate for lateralization defect in humans, in particular in cases with associated hepatic anomalies. Here, we have identified, mapped, and characterized the INV human gene and screened a series of heterotaxic patients (with or without biliary anomalies) for mutation in this gene. In a German family of Turkish origin, we have found that all available affected and unaffected individuals are heterozygous for a mutation in the splicing donor site of intron 12 in the INV gene resulting in two different aberrant splicing isoforms. This can be explained either by a randomization of lateralization defects or, as suggested earlier, di- or trigenic inheritance, although we have been unable to detect, in this family, a mutation in genes known to be involved in the human lateralization defect ( LEFTY1, LEFTY2, ACVR2B, NODAL, ZIC3, and CFC1). In contrast to the mouse, the affected individuals have no biliary anomalies, and the absence of mutation in a series of seven cases with lateralization defect and biliary anomalies demonstrates that INV is not frequently involved in such a phenotype in humans.
Schön
Patric
P
Laboratoire de Génétique Moléculaire Humaine, EA 3088, Faculté de Médecine Pharmacie, Université C. Bernard Lyon 1, France.
Tsuchiya
Ken
K
Lenoir
Didier
D
Mochizuki
Toshio
T
Guichard
Cécile
C
Takai
Setsuo
S
Maiti
Amit K
AK
Nihei
Hiroshi
H
Weil
Johan
J
Yokoyama
Takahiko
T
Bouvagnet
Patrice
P
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001656:Biliary Atresia / Q000235:genetics*; D001921:Brain / Q000196:embryology; D001923:Brain Chemistry; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D017931:DNA Primers; D005314:Embryonic and Fetal Development; D005260:Female; D005333:Fetus; D007839:Functional Laterality / Q000235:genetics; D015723:Gene Library; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010375:Pedigree; D011506:Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors
D017931:DNA Primers; C114503:INVS protein, human; C491947:Invs protein, mouse; D011506:Proteins; D014157:Transcription Factors