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Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.

ABSTRACT: Whole-exome sequencing and autozygosity mapping studies, independently performed in subjects with defective combined mitochondrial OXPHOS-enzyme deficiencies, identified a total of nine disease-segregating FBXL4 mutations in seven unrelated mitochondrial disease families, composed of six singletons and three siblings. All subjects manifested early-onset lactic acidemia, hypotonia, and developmental delay caused by severe encephalomyopathy consistently associated with progressive cerebral atrophy and variable involvement of the white matter, deep gray nuclei, and brainstem structures. A wide range of other multisystem features were variably seen, including dysmorphism, skeletal abnormalities, poor growth, gastrointestinal dysmotility, renal tubular acidosis, seizures, and episodic metabolic failure. Mitochondrial respiratory chain deficiency was present in muscle or fibroblasts of all tested individuals, together with markedly reduced oxygen consumption rate and hyperfragmentation of the mitochondrial network in cultured cells. In muscle and fibroblasts from several subjects, substantially decreased mtDNA content was observed. FBXL4 is a member of the F-box family of proteins, some of which are involved in phosphorylation-dependent ubiquitination and/or G protein receptor coupling. We also demonstrate that FBXL4 is targeted to mitochondria and localizes in the intermembrane space, where it participates in an approximately 400 kDa protein complex. These data strongly support a role for FBXL4 in controlling bioenergetic homeostasis and mtDNA maintenance. FBXL4 mutations are a recurrent cause of mitochondrial encephalomyopathy onset in early infancy.

SUBMITTER: Gai X

PROVIDER: S-EPMC3769923 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.

Gai Xiaowu X Ghezzi Daniele D Johnson Mark A MA Biagosch Caroline A CA Shamseldin Hanan E HE Haack Tobias B TB Reyes Aurelio A Tsukikawa Mai M Sheldon Claire A CA Srinivasan Satish S Gorza Matteo M Kremer Laura S LS Wieland Thomas T Strom Tim M TM Polyak Erzsebet E Place Emily E Consugar Mark M Ostrovsky Julian J Vidoni Sara S Robinson Alan J AJ Wong Lee-Jun LJ Sondheimer Neal N Salih Mustafa A MA Al-Jishi Emtethal E Raab Christopher P CP Bean Charles C Furlan Francesca F Parini Rossella R Lamperti Costanza C Mayr Johannes A JA Konstantopoulou Vassiliki V Huemer Martina M Pierce Eric A EA Meitinger Thomas T Freisinger Peter P Sperl Wolfgang W Prokisch Holger H Alkuraya Fowzan S FS Falk Marni J MJ Zeviani Massimo M

American journal of human genetics 20130829 3

Whole-exome sequencing and autozygosity mapping studies, independently performed in subjects with defective combined mitochondrial OXPHOS-enzyme deficiencies, identified a total of nine disease-segregating FBXL4 mutations in seven unrelated mitochondrial disease families, composed of six singletons and three siblings. All subjects manifested early-onset lactic acidemia, hypotonia, and developmental delay caused by severe encephalomyopathy consistently associated with progressive cerebral atrophy ...[more]

PMID: 23993194

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Project description: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.

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Dataset Information

Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.

Publications

Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.

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