Genetic 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.
Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX 78227, USA. jcurran@sfbrgenetics.org
Joanne E
JE
Curran
Jeremy B M
JB
Jowett
Lawrence J
LJ
Abraham
Luke A
LA
Diepeveen
Katherine S
KS
Elliott
Thomas D
TD
Dyer
Lyndal J
LJ
Kerr-Bayles
Matthew P
MP
Johnson
Anthony G
AG
Comuzzie
Eric K
EK
Moses
Ken R
KR
Walder
Gregory R
GR
Collier
John
J
Blangero
Ahmed H
AH
Kissebah
D004272:DNA, Mitochondrial / Q000737:chemistry / Q000235:genetics*; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D045726:Metalloproteases / Q000235:genetics*; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics
D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D045726:Metalloproteases; C485223:PARL protein, human