Artículo
APOA5 Q97X Mutation Identified through homozygosity mapping causes severe hypertriglyceridemia in a Chilean consanguineous family
Fecha
2012Registro en:
BMC Medical Genetics. 2012 Nov 15;13(1):106
10.1186/1471-2350-13-106
Autor
Dussaillant, Catalina
Serrano Larrea, Valentina
Maiz Gurruchaga, Manuel Alberto
Eyheramendy Duerr, Susana
Cataldo Bascuñan, Luis Rodrigo
Smalley Meylan, Susan Valerie
Rigotti Rivera, Attilio
Rubio, Lorena.
Lagos Arévalo, Carlos Fernando
Santos Martín, José Luis
Institución
Resumen
Abstract
Background
Severe hypertriglyceridemia (HTG) has been linked to defects in LPL, APOC2, APOA5, LMF1 and GBIHBP1 genes. However, a number of severe HTG cases are probably caused by as yet unidentified mutations. Very high triglyceride plasma levels (>112 mmol/L at diagnosis) were found in two sisters of a Chilean consanguineous family, which is strongly suggestive of a recessive highly penetrant mutation. The aim of this study was to determine the genetic locus responsible for the severe HTG in this family.
Methods
We carried out a genome-wide linkage study with nearly 300,000 biallelic markers (Illumina Human CytoSNP-12 panel). Using the homozygosity mapping strategy, we searched for chromosome regions with excess of homozygous genotypes in the affected cases compared to non-affected relatives.
Results
A large homozygous segment was found in the long arm of chromosome 11, with more than 2,500 consecutive homozygous SNP shared by the proband with her affected sister, and containing the APOA5/A4/C3/A1 cluster. Direct sequencing of the APOA5 gene revealed a known homozygous nonsense Q97X mutation (p.Gln97Ter) found in both affected sisters but not in non-affected relatives nor in a sample of unrelated controls.
Conclusion
The Q97X mutation of the APOA5 gene in homozygous status is responsible for the severe hypertriglyceridemia in this family. We have shown that homozygosity mapping correctly pinpointed the genomic region containing the gene responsible for severe hypertriglyceridemia in this consanguineous Chilean family.