LACK OF EVIDENCE FOR CONNEXIN-43 GENE-MUTATIONS IN HUMAN AUTOSOMAL RECESSIVE LATERALIZATION DEFECTS

Heterotaxy is the failure of the developing embryo to establish normal left-right asymmetry, which is often associated with multiple malform ations. Previous studies have identified different mutations in the cy toplasmic tail of the connexin 43 (ex 43) gene in six patients from a series of six sporadic cases with defects of laterality and severe hea rt malformations, These cases showed that of the genes involved in lat eralization defects with autosomal recessive transmission, ex 43 was t he most important. This result was challenged by two different teams, which, on sequencing only the carboxyl terminal end of the ex 43 gene in 30 patients, found no mutations. To assess the responsibility of th e ex 43 gene in human autosomal recessive lateralization defects, we t ested its involvement in a selected group of 25 patients (19 familial cases) with a wide variety of lateralization defects and cardiovascula r malformations. The whole coding sequence and direct nanking sequence s were screened for mutations, both by single strand conformation anal ysis and direct fluorescent sequencing. We could only detect a single base pair insertion in the 3' untranslated region of one patient. To t est the possibility of mutations in other parts of the ex 43 gene, the gene was located onto the physical map of chromosome 6, and flanking polymorphic markers were genotyped. Haplotype analysis excluded the ex 43 gene locus in nearly all of the familial cases of lateralization d efects. Thus, our results do not support the suggestion that this gene is implicated in human autosomal recessive lateralization defects. (C ) 1997 Academic Press Limited.