CEDIE   05498
CENTRO DE INVESTIGACIONES ENDOCRINOLOGICAS "DR. CESAR BERGADA"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Gene founder effect: The underlying mechanism of recurrent IGFALS mutations
Autor/es:
SCAGLIA, P.; BERGADÁ, I; BRASLAVSKY, D; KESELMAN, A; ESPÍNOLA CASTRO, A.; DOMENÉ, S.; JASPER, H.; DOMENÉ, H.
Lugar:
Puerto Varas
Reunión:
Congreso; XXV Reunión anual de la Sociedad Latinoamericana de Endocrinología; 2015
Resumen:
Background: In ALS-deficient patients, some IGFALS variants have been reported in more than one family, raising the question whether they originated from a single common ancestor allele (founder effect) or alternatively, as independent mutational events (hot spot). Since c.103dupG (p.E35Gfs*17) is located in a stretch of 5 consecutive guanine residues, where both G-duplication and deletion have been described in several families, we speculate that this region could be a hot spot. In contrast, c.[1225C>T;1424C>T] (p.[L409F;A475V]) variants, both present in the same allele in two unrelated families, could result from a founder effect. Objective: To test the hypothesis of hot spot vs. founder effect by studying polymorphic variants surrounding IGFALS gene and uniparental lineage markers in families harboring the c.103dupG and c.[1225C>T;1424C>T] variants. Methods: We sequenced the IGFALS gene (2 exons and intron 1 plus 900 and 40 bp flanking exon 1 and 2, respectively) and characterized 2 flanking STRs in 30 individuals from 6 families, 4 of them carrying the c.103dupG (9 heterozygous individuals) and 2 families harboring the c.[1225C>T;1424C>T] variants (3 homozygous and 8 heterozygous individuals). Nine informative SNPs and the 2 STRs were used to define the specific haplotype associated to the mutation (D16S3435/9 SNPs/D16S3024). In addition, patri- and matrilineal lineages were analyzed by means of 23 Y-STRs typing and mtDNA-D-Loop sequencing. Results: The four families carrying the c.103dupG variant presented the same STRs and SNPs microhaplotype (CA)12/gtcggtgcc/(CA)21. On the other hand, the c.[1225C>T;1424C>T] carriers of the two remaining families shared a common microhaplotype (CA)15/acgaaccgt/(CA)22 or (CA)23, differing only in one repeat in D16S3024 between the two families. Phylogenetic analysis revealed that all male lineages can be attributed to European or Eurasian haplogroups (50% E1b1b; 33% R1b and 17% Q) while mtDNA lineage belonged to Native American (56%), African (22%) and European (22%) haplogroups. Conclusion: Based on the number of families studied, the finding of two particular microhaplotypes support the hypothesis of a founder effect for both variants, c.103dupG (p.E35Gfs*17) and c.[1225C>T;1424C>T] (p.[L409F;A475V]); each originating from two independent mutagenic events occurring in two different ancestor alleles.