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.
Curran
Joanne E
JE
Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX 78227, USA. jcurran@sfbrgenetics.org
Jowett
Jeremy B M
JB
Abraham
Lawrence J
LJ
Diepeveen
Luke A
LA
Elliott
Katherine S
KS
Dyer
Thomas D
TD
Kerr-Bayles
Lyndal J
LJ
Johnson
Matthew P
MP
Comuzzie
Anthony G
AG
Moses
Eric K
EK
Walder
Ken R
KR
Collier
Gregory R
GR
Blangero
John
J
Kissebah
Ahmed H
AH
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