@article {709,
	title = {Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic  Variants.},
	journal = {J Clin Med},
	volume = {8},
	year = {2019},
	month = {2019 Nov 19},
	abstract = {<p> (PNPase-polynucleotide phosphorylase) is involved in multiple RNA processing functions in the mitochondria. Bi-allelic pathogenic  variants cause heterogeneous clinical phenotypes affecting multiple organs without any established genotype-phenotype correlations. Defects in PNPase can cause variable combined respiratory chain complex defects. Recently, it has been suggested that PNPase can lead to activation of an innate immune response. To better understand the clinical and molecular spectrum of patients with bi-allelic  variants, we captured detailed clinical and molecular phenotypes of all 17 patients reported in the literature, plus seven new patients, including a 78-year-old male with the longest reported survival. A functional follow-up of genomic sequencing by cDNA studies confirmed a splicing defect in a novel, apparently synonymous, variant. Patient fibroblasts showed an accumulation of mitochondrial unprocessed  transcripts, while blood showed an increased interferon response. Our findings suggest that functional analyses of the RNA processing function of PNPase are more sensitive than testing downstream defects in oxidative phosphorylation (OXPHPOS) enzyme activities. This research extends our knowledge of the clinical and functional consequences of bi-allelic pathogenic  variants that may guide management and further efforts into understanding the pathophysiological mechanisms for therapeutic development.</p>},
	issn = {2077-0383},
	doi = {10.3390/jcm8112020},
	author = {Rius, Rocio and Van Bergen, Nicole J and Compton, Alison G and Riley, Lisa G and Kava, Maina P and Balasubramaniam, Shanti and Amor, David J and Fanjul-Fernandez, Miriam and Cowley, Mark J and Fahey, Michael C and Koenig, Mary K and Enns, Gregory M and Sadedin, Simon and Wilson, Meredith J and Tan, Tiong Y and Thorburn, David R and Christodoulou, John}
}
@article {342,
	title = {MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder.},
	journal = {Am J Hum Genet},
	volume = {99},
	year = {2016},
	month = {2016 Dec 01},
	pages = {1229-1244},
	abstract = {<p>Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes. We report here a unique neurometabolic human disorder caused by defective mtFAS. Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. All affected individuals were found to harbor recessive mutations in MECR encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS. All six mutations are extremely rare in the general population, segregate with the disease in the families, and are predicted to be deleterious. The nonsense c.855T>G (p.Tyr285), c.247_250del (p.Asn83Hisfs4), and splice site c.830+2_830+3insT mutations lead to C-terminal truncation variants of MECR. The missense c.695G>A (p.Gly232Glu), c.854A>G (p.Tyr285Cys), and c.772C>T (p.Arg258Trp) mutations involve conserved amino acid residues, are located within the cofactor binding domain, and are predicted by structural analysis to have a destabilizing effect. Yeast modeling and complementation studies validated the pathogenicity of the MECR mutations. Fibroblast cell lines from affected individuals displayed reduced levels of both MECR and lipoylated proteins as well as defective respiration. These results suggest that mutations in MECR cause a distinct human disorder of the mtFAS pathway. The observation of decreased lipoylation raises the possibility of a potential therapeutic strategy.</p>},
	keywords = {Basal Ganglia, Cells, Cultured, Child, Child, Preschool, Dystonic Disorders, Fatty Acids, Female, Fibroblasts, Genetic Complementation Test, Humans, Infant, Male, Mitochondria, Mitochondrial Diseases, Models, Molecular, Mutation, Mutation, Missense, Optic Atrophy, Oxidoreductases Acting on CH-CH Group Donors, Pedigree, RNA Splice Sites, Saccharomyces cerevisiae},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2016.09.021},
	author = {Heimer, Gali and Ker{\"a}t{\"a}r, Juha M and Riley, Lisa G and Balasubramaniam, Shanti and Eyal, Eran and Pietik{\"a}inen, Laura P and Hiltunen, J Kalervo and Marek-Yagel, Dina and Hamada, Jeffrey and Gregory, Allison and Rogers, Caleb and Hogarth, Penelope and Nance, Martha A and Shalva, Nechama and Veber, Alvit and Tzadok, Michal and Nissenkorn, Andreea and Tonduti, Davide and Renaldo, Florence and Kraoua, Ichraf and Panteghini, Celeste and Valletta, Lorella and Garavaglia, Barbara and Cowley, Mark J and Gayevskiy, Velimir and Roscioli, Tony and Silberstein, Jonathon M and Hoffmann, Chen and Raas-Rothschild, Annick and Tiranti, Valeria and Anikster, Yair and Christodoulou, John and Kastaniotis, Alexander J and Ben-Zeev, Bruria and Hayflick, Susan J}
}
