Transmission distortion of human genome involves mutant allele in a family with erythropoietic protoporphyria in Argentina

COLOMBO, F; MARCUCCI, V; MARTINEZ, J; MELITO, VA; BATLLE, A; ROSSETTI, MV; PARERA, VE

Cardiff

Congreso; International Porphyrins and Porphyrias Meeting; 2011

The British Association of Dermatologists

biosynthesis produced by a decreased activity of ferrochelatase (FECH). The human FECH gene contains a total of 11 exons and spans about 45kb of genomic DNA on chromosome 18 in the q21.3 region. Its inheritance is complex and can be either autosomal dominant with low clinical penetrance, or autosomal recessive. In the autosomal dominant inheritance form, the clinical phenotype of EPP results from co-inheritance of a mutated allele and a wild-type low-expressed allele of the FECH gene. We analyzed the mutation segregation of the FECH gene, and parental transmission in three generations of the same family (EPP patients, asymptomatic carriers and healthy non consanguineous relatives). All exons and flanking sequences of intragenic polymorphisms of the FECH gene were PCR amplified and sequenced or digested with specific restriction enzymes respectively. We detected a new variant c.1099A>T (p.R367X) of the FECH gene responsible of EPP.  The c.1099T variant was found in all individuals (eight) of the three generations. Our results clearly evidence the positive selection of the mutated allele responsible of EPP leading to a transmission distortion. Considering the relatively small number of individuals, this trait is still compatible with Mendelian inheritance. However, our observation shows that in this case it would exist additional factors associated with the mutated allele that favors the transmission of the mutation. Transmission distortion observed in this family could be due to positive selection of the mutated allele during gametogenesis or during post-fertilization processes but due to preliminary results, this still can not determine. The most important finding of our study was the meiotic drive, evidenced by cosegregation with a mutated FECH gene nearby to the site positively selected in meiosis. This would be the reason why the gene variant is overrepresented in this family.