ESPE Abstracts (2015) 84 P-2-463

aCentro de Investigaciones Endocrinológicas ‘Dr. César Bergadá’ (CEDIE) CONICET – FEI – División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina; bServicio de Huellas Digitales Genéticas, Facultad de Farmacia y Bioquímica, UBA – CONICET, Buenos Aires, Argentina; cDivision of Pediatric Endocrinology, Federeal University of Sao Paulo, UNIFESP/EPM, Sao Paulo, Brazil

Background: Some IGFALS variants have been reported in more than one ALS-deficient 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 five 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 and hypotheses: To test the hypothesis of a founder effect vs. hot spot by studying polymorphic variants surrounding IGFALS gene and uniparental lineage markers in families harboring the c.103dupG and c.(1225C>T;1424C>T) variants.

Method: We sequenced the whole IGFALS gene and characterized two STRs flanking IGFALS gene locus in 30 individuals from six unrelated families, two harboring the c.(1225C>T;1424C>T) variants and four carriers of c.103dupG. Nine informative SNPs and two 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: Four families carrying the c.103dupG variant presented the same STRs and SNPs microhaplotype (CA)12/gtcggtgcc/(CA)21 while all the c.(1225C>T;1424C>T) carriers of the other two families presented a different microhaplotype (CA)15/acgaaccgt/(CA)22 or (CA)23. 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 this 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 ancestor alleles.

Funding: This work was supported by grants from the Agencia Nacional de Promoción Científica y Tecnológica (PICT-2010 Nro.1916), and SANDOZ International GmbH, Business Unit Biopharmaceuticals.

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