biostudies-literatureCurran JENIDDK NIH HHSNCRR NIH HHSNIMH NIH HHSNHLBI NIH HHS183-90https://www.ebi.ac.uk/biostudies/studies/S-EPMC2829432biostudies-literatureUnknown127(2)Given their involvement in processes necessary for life, mitochondrial damage and subsequent dysfunction can lead to a wide range of human diseases. Previous studies of both animal models and humans have suggested that presenilins-associated rhomboid-like protein (PARL) is a key regulator of mitochondrial integrity and function, and plays a role in cellular apoptosis. As a surrogate measure of mitochondrial integrity, we previously measured mitochondrial content in a Caucasian population consisting of large extended pedigrees, with results highlighting a substantial genetic component to this trait. To assess the influence of variation in the PARL gene on mitochondrial content, we re-sequenced 6.5 kb of the gene, identifying 16 SNPs and genotyped these in 1,086 Caucasian individuals, distributed across 170 families. Statistical genetic analysis revealed that one promoter variant, T-191C, exhibited significant effects (after correction for multiple testing) on mitochondrial content levels. Comparison of the transcription factor binding characteristics of the T-191C promoter SNP by EMSA indicates preferential binding of nuclear factors to the T allele, suggesting functional variation in PARL expression. These results suggest that genetic variation within PARL influences mitochondrial abundance and integrity.Human geneticsGenetic variation in PARL influences mitochondrial content.PMC2829432R01 DK079169DK079169C06 RR013556R37 MH059490R01 DK071895-03R01 DK065598-05R01 DK079169-03C06 RR013556-01DK065598R01 DK071895R01 MH059490P01 HL045522R01 DK065598DK071895MH059490R37 MH059490-12Abraham LJJowett JBElliott KSWalder KRJohnson MPMoses EKBlangero JDyer TDComuzzie AGDiepeveen LAKerr-Bayles LJCollier GRCurran JEKissebah AHfalseGenetic variation in PARL influences mitochondrial content.Given their involvement in processes necessary for life, mitochondrial damage and subsequent dysfunction can lead to a wide range of human diseases. Previous studies of both animal models and humans have suggested that presenilins-associated rhomboid-like protein (PARL) is a key regulator of mitochondrial integrity and function, and plays a role in cellular apoptosis. As a surrogate measure of mitochondrial integrity, we previously measured mitochondrial content in a Caucasian population consisting of large extended pedigrees, with results highlighting a substantial genetic component to this trait. To assess the influence of variation in the PARL gene on mitochondrial content, we re-sequenced 6.5 kb of the gene, identifying 16 SNPs and genotyped these in 1,086 Caucasian individuals, distributed across 170 families. Statistical genetic analysis revealed that one promoter variant, T-191C, exhibited significant effects (after correction for multiple testing) on mitochondrial content levels. Comparison of the transcription factor binding characteristics of the T-191C promoter SNP by EMSA indicates preferential binding of nuclear factors to the T allele, suggesting functional variation in PARL expression. These results suggest that genetic variation within PARL influences mitochondrial abundance and integrity.2010-01-01T00:00:00Z2010 Feb2024-11-19T17:30:56Z2020-11-07T09:51:09ZS-EPMC28294321986255610.1007/s00439-009-0756-0