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Genetic variation in PARL influences mitochondrial content

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Abstract

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.

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Acknowledgments

This work was supported by grants DK065598 and DK071895 from the National Institutes of Health to the Medical College of Wisconsin; and the Clinical and Translational Services Institute at the Medical College of Wisconsin. TOPS Club, Inc. provided funds for establishment of the family database and clinical phenotyping. Funds for resequencing, genotyping, functional and statistical analyses were provided in part by ChemGenex Pharmaceuticals Ltd., Australia. This work was also supported in part by grants MH059490, and DK079169 from the National Institutes of Health. Parts of this investigation were conducted in facilities constructed with support from the Research Facilities Improvement Program Grant Number C06 RR013556 from the National Center for Research Resources, National Institutes of Health. The AT&T Genomics Computing Center supercomputing facilities used for this work were supported in part by a gift from the AT&T Foundation.

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Authors and Affiliations

  1. Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX, 78227, USA

    Joanne E. Curran, Thomas D. Dyer, Matthew P. Johnson, Anthony G. Comuzzie, Eric K. Moses & John Blangero

  2. Genomics and Systems Biology, Baker IDI Heart and Diabetes Institute, Caulfield, VIC, 3162, Australia

    Jeremy B. M. Jowett

  3. Biochemistry and Molecular Biology, School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, Crawley, WA, 6009, Australia

    Lawrence J. Abraham & Luke A. Diepeveen

  4. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    Katherine S. Elliott

  5. Metabolic Research Unit, Deakin University, Waurn Ponds, VIC, 3217, Australia

    Lyndal J. Kerr-Bayles & Ken R. Walder

  6. ChemGenex Pharmaceuticals, Geelong, VIC, 3216, Australia

    Gregory R. Collier

  7. TOPS Center for Obesity and Metabolic Research, Medical College of Wisconsin, Madison, WI, 53226, USA

    Ahmed H. Kissebah

  8. Department of Genetics, Southwest Foundation for Biomedical Research, P.O. Box 760549, San Antonio, TX, 78245-0549, USA

    Joanne E. Curran

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  1. Joanne E. Curran
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  14. Ahmed H. Kissebah
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Corresponding author

Correspondence to Joanne E. Curran.

Additional information

J. Blangero and A. H. Kissebah contributed equally to this work.

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Curran, J.E., Jowett, J.B.M., Abraham, L.J. et al. Genetic variation in PARL influences mitochondrial content. Hum Genet 127, 183–190 (2010). https://doi.org/10.1007/s00439-009-0756-0

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