LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population

被引：79

作者：

Olahova, Monika ^{[1
]}

Hardy, Steven A. ^{[1
]}

Hall, Julie ^{[2
]}

Yarham, John W. ^{[1
]}

Haack, Tobias B. ^{[3
,4
]}

Wilson, William C. ^{[1
]}

Alston, Charlotte L. ^{[1
]}

He, Langping ^{[1
]}

Aznauryan, Erik ^{[1
]}

Brown, Ruth M. ^{[5
]}

Brown, Garry K. ^{[5
]}

Morris, Andrew A. M. ^{[6
]}

Mundy, Helen ^{[7
]}

Broomfield, Alex ^{[6
]}

Barbosa, Ines A. ^{[8
]}

Simpson, Michael A. ^{[8
]}

Deshpande, Charu ^{[9
]}

Moeslinger, Dorothea ^{[10
]}

Koch, Johannes ^{[11
]}

Stettner, Georg M. ^{[12
]}

Bonnen, Penelope E. ^{[13
]}

Prokisch, Holger ^{[3
,4
]}

Lightowlers, Robert N. ^{[1
]}

McFarland, Robert ^{[1
]}

Chrzanowska-Lightowlers, Zofia M. A. ^{[1
]}

Taylor, Robert W. ^{[1
]}

机构：

[1] Newcastle Univ, Wellcome Trust Ctr Mitochondrial Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[2] Royal Victoria Infirm, Dept Neuroradiol, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England

[3] Helmholtz Zentrum Munchen, Inst Human Genet, D-85764 Neuherberg, Germany

[4] Tech Univ Munich, Inst Humangenet, D-80333 Munich, Germany

[5] Univ Oxford, Dept Biochem, Oxford OX1 3QU, England

[6] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Ctr Genom Med, Willink Biochem Genet Unit, Manchester M13 9WL, Lancs, England

[7] Guys & St Thomas NHS Fdn Trust, Evelina Childrens Hosp, Ctr Inherited Metab Dis, London SE1 7EH, England

[8] Kings Coll London, Sch Med, Div Genet & Mol Med, London SE1 9RY, England

[9] Guys & St Thomas NHS Fdn Trust, Dept Genet, London SE1 9RT, England

[10] Univ Childrens Hosp, Dept Paediat, A-1090 Vienna, Austria

[11] Paracelsus Med Univ Salzburg, Dept Paediat, A-5020 Salzburg, Austria

[12] Univ Gottingen, Dept Paediat Neurol, D-37075 Gottingen, Germany

[13] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

来源：

BRAIN | 2015年 / 138卷

基金：

英国惠康基金;

关键词：

LRPPRC; COX deficiency; mitochondrial disease; Leigh syndrome; malformations; CYTOCHROME-C-OXIDASE; COMPLEX IV DEFICIENCY; LEIGH-SYNDROME; POLY(A) POLYMERASE; FOUNDER MUTATION; GENE-EXPRESSION; MESSENGER-RNAS; COX DEFICIENCY; PROTEIN; TRANSLATION;

D O I：

10.1093/brain/awv291

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

100204 [神经病学];

摘要：

Mitochondrial Complex IV [cytochrome 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 Qu,bec 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.

引用

页码：3503 / 3519

页数：17

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[1]

Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency [J].