Dataset Information

Respiratory chain deficiency in nonmitochondrial disease.

ABSTRACT:

Objective

In this study, we report 5 patients with heterogeneous phenotypes and biochemical evidence of respiratory chain (RC) deficiency; however, the molecular diagnosis is not mitochondrial disease.

Methods

The reported patients were identified from a cohort of 60 patients in whom RC enzyme deficiency suggested mitochondrial disease and underwent whole-exome sequencing.

Results

Five patients had disease-causing variants in nonmitochondrial disease genes ORAI1, CAPN3, COLQ, EXOSC8, and ANO10, which would have been missed on targeted next-generation panels or on MitoExome analysis.

Conclusions

Our data demonstrate that RC abnormalities may be secondary to various cellular processes, including calcium metabolism, neuromuscular transmission, and abnormal messenger RNA degradation.

SUBMITTER: Pyle A

PROVIDER: S-EPMC4821083 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Publications

Respiratory chain deficiency in nonmitochondrial disease.

Pyle Angela A Nightingale Helen J HJ Griffin Helen H Abicht Angela A Kirschner Janbernd J Baric Ivo I Cuk Mario M Douroudis Konstantinos K Feder Lea L Kratz Markus M Czermin Birgit B Kleinle Stephanie S Santibanez-Koref Mauro M Karcagi Veronika V Holinski-Feder Elke E Chinnery Patrick F PF Horvath Rita R

Neurology. Genetics 20150427 1

<h4>Objective</h4>In this study, we report 5 patients with heterogeneous phenotypes and biochemical evidence of respiratory chain (RC) deficiency; however, the molecular diagnosis is not mitochondrial disease.<h4>Methods</h4>The reported patients were identified from a cohort of 60 patients in whom RC enzyme deficiency suggested mitochondrial disease and underwent whole-exome sequencing.<h4>Results</h4>Five patients had disease-causing variants in nonmitochondrial disease genes ORAI1, CAPN3, COL ...[more]

PMID: 27066545

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Project description:Primary mitochondrial respiratory chain (RC) diseases are heterogeneous in etiology and manifestations but collectively impair cellular energy metabolism. To identify a common cellular response to RC disease, systems biology level transcriptome investigations were performed in human RC disease skeletal muscle and fibroblasts. Global transcriptional and post-transcriptional dysregulation in a tissue-specific fashion was identified across diverse RC complex and genetic etiologies. RC disease muscle was characterized by decreased transcription of cytosolic ribosomal proteins to reduce energy-intensive anabolic processes, increased transcription of mitochondrial ribosomal proteins, shortened 5'-UTRs to improve translational efficiency, and stabilization of 3'-UTRs containing AU-rich elements. These same modifications in a reversed direction typified RC disease fibroblasts. RC disease also dysregulated transcriptional networks related to basic nutrient-sensing signaling pathways, which collectively mediate many aspects of tissue-specific cellular responses to primary RC disease. These findings support the utility of a systems biology approach to improve mechanistic understanding of mitochondrial RC disease. To identify a common cellular response to primary RC that might improve mechanistic understanding and lead to targeted therapies for human RC disease, we performed collective transcriptome profiling in skeletal muscle biopsy specimens and fibroblast cell lines (FCLs) of a diverse cohort of human mitochondrial disease subjects relative to controls. Systems biology investigations of common cellular responses to primary RC disease revealed a collective pattern of transcriptional, post-transcriptional and translational dysregulation occurring in a highly tissue-specific fashion. Affymetrix Human Exon 1.0ST microarray analysis was performed on 29 skeletal muscle samples and Fibroblast cell lines from mitochondrial disease patients and age- and gender-matched controls.

Dataset Information

Respiratory chain deficiency in nonmitochondrial disease.

Objective

Methods

Results

Conclusions

Publications

Respiratory chain deficiency in nonmitochondrial disease.

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