LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population
| Autor: | Penelope E. Bonnen, Langping He, Monika Oláhová, Garry K. Brown, Ines A. Barbosa, Erik Aznauryan, Charlotte L. Alston, Johannes Koch, John W. Yarham, Michael A. Simpson, Helen Mundy, Alex Broomfield, Ruth M. Brown, Tobias B. Haack, William C. Wilson, Charu Deshpande, Holger Prokisch, Georg M. Stettner, Julie Hall, Dorothea Moeslinger, Zofia M.A. Chrzanowska-Lightowlers, Steven A. Hardy, Robert McFarland, Robert W. Taylor, Andrew A. M. Morris, Robert N. Lightowlers |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Candidate gene Mitochondrial Diseases RNA Mitochondrial Respiratory chain Cytochrome-c Oxidase Deficiency Mitochondrion Leucine-Rich Repeat Proteins 0302 clinical medicine Cells Cultured Genetics 0303 health sciences education.field_of_study 3. Good health Neoplasm Proteins Pedigree LRPPRC mitochondrial disease Child Preschool malformations Female medicine.medical_specialty Mitochondrial DNA Canada Mitochondrial disease Population Biology Electron Transport Complex IV Mitochondrial Proteins 03 medical and health sciences Internal medicine medicine Cytochrome c oxidase Humans RNA Messenger Leigh disease education Muscle Skeletal 030304 developmental biology Cox Deficiency Lrpprc Leigh Syndrome Malformations Mitochondrial Disease Infant Newborn Infant Proteins Original Articles Fibroblasts medicine.disease Leigh syndrome Endocrinology Mutation biology.protein COX deficiency Neurology (clinical) 030217 neurology & neurosurgery |
| Zdroj: | Brain Brain 138, 3503-3519 (2015) Oláhová, M, Hardy, S A, Hall, J, Yarham, J W, Haack, T B, Wilson, W C, Alston, C L, He, L, Aznauryan, E, Brown, R M, Brown, G K, Morris, A A M, Mundy, H, Broomfield, A, Barbosa, I A, Simpson, M A, Deshpande, C, Moeslinger, D, Koch, J, Stettner, G M, Bonnen, P E, Prokisch, H, Lightowlers, R N, McFarland, R, Chrzanowska-Lightowlers, Z M A & Taylor, R W 2015, ' LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population ', Brain : a journal of neurology, vol. 138, no. 12, pp. 3503-3519 . https://doi.org/10.1093/brain/awv291 |
| ISSN: | 1460-2156 0006-8950 |
| DOI: | 10.1093/brain/awv291 |
| Popis: | The French-Canadian variant of COX-deficient Leigh syndrome (LSFC) is unique to Québec and caused by a founder mutation in the LRPPRC gene. Using whole exome sequencing, Oláhová et al. identify mutations in this gene associated with multisystem mitochondrial disease and early-onset neurodevelopmental problems in ten patients from different ethnic backgrounds. Mitochondrial Complex IV [cytochrome c oxidase (COX)] deficiency is one of the most common respiratory chain defects in humans. The clinical phenotypes associated with COX deficiency include liver disease, cardiomyopathy and Leigh syndrome, a neurodegenerative disorder characterized by bilateral high signal lesions in the brainstem and basal ganglia. COX deficiency can result from mutations affecting many different mitochondrial proteins. The French-Canadian variant of COX-deficient Leigh syndrome is unique to the Saguenay-Lac-Saint-Jean region of Québec and is caused by a founder mutation in the LRPPRC gene. This encodes the leucine-rich pentatricopeptide repeat domain protein (LRPPRC), which is involved in post-transcriptional regulation of mitochondrial gene expression. Here, we present the clinical and molecular characterization of novel, recessive LRPPRC gene mutations, identified using whole exome and candidate gene sequencing. The 10 patients come from seven unrelated families of UK-Caucasian, UK-Pakistani, UK-Indian, Turkish and Iraqi origin. They resemble the French-Canadian Leigh syndrome patients in having intermittent severe lactic acidosis and early-onset neurodevelopmental problems with episodes of deterioration. In addition, many of our patients have had neonatal cardiomyopathy or congenital malformations, most commonly affecting the heart and the brain. All patients who were tested had isolated COX deficiency in skeletal muscle. Functional characterization of patients’ fibroblasts and skeletal muscle homogenates showed decreased levels of mutant LRPPRC protein and impaired Complex IV enzyme activity, associated with abnormal COX assembly and reduced steady-state levels of numerous oxidative phosphorylation subunits. We also identified a Complex I assembly defect in skeletal muscle, indicating different roles for LRPPRC in post-transcriptional regulation of mitochondrial mRNAs between tissues. Patient fibroblasts showed decreased steady-state levels of mitochondrial mRNAs, although the length of poly(A) tails of mitochondrial transcripts were unaffected. Our study identifies LRPPRC as an important disease-causing gene in an early-onset, multisystem and neurological mitochondrial disease, which should be considered as a cause of COX deficiency even in patients originating outside of the French-Canadian population. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|