Dataset Information

Mutations in FUS cause FALS and SALS in French and French Canadian populations.

ABSTRACT:

Background

The identification of mutations in the TARDBP and more recently the identification of mutations in the FUS gene as the cause of amyotrophic lateral sclerosis (ALS) is providing the field with new insight about the mechanisms involved in this severe neurodegenerative disease.

Methods

To extend these recent genetic reports, we screened the entire gene in a cohort of 200 patients with ALS. An additional 285 patients with sporadic ALS were screened for variants in exon 15 for which mutations were previously reported.

Results

In total, 3 different mutations were identified in 4 different patients, including 1 3-bp deletion in exon 3 of a patient with sporadic ALS and 2 missense mutations in exon 15 of 1 patient with familial ALS and 2 patients with sporadic ALS.

Conclusions

Our study identified sporadic patients with mutations in the FUS gene. The accumulation and description of different genes and mutations helps to develop a more comprehensive picture of the genetic events underlying amyotrophic lateral sclerosis.

SUBMITTER: Belzil VV

PROVIDER: S-EPMC3462471 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Publications

Mutations in FUS cause FALS and SALS in French and French Canadian populations.

Belzil V V VV Valdmanis P N PN Dion P A PA Daoud H H Kabashi E E Noreau A A Gauthier J J Hince P P Desjarlais A A Bouchard J-P JP Lacomblez L L Salachas F F Pradat P-F PF Camu W W Meininger V V Dupré N N Rouleau G A GA

Neurology 20090909 15

<h4>Background</h4>The identification of mutations in the TARDBP and more recently the identification of mutations in the FUS gene as the cause of amyotrophic lateral sclerosis (ALS) is providing the field with new insight about the mechanisms involved in this severe neurodegenerative disease.<h4>Methods</h4>To extend these recent genetic reports, we screened the entire gene in a cohort of 200 patients with ALS. An additional 285 patients with sporadic ALS were screened for variants in exon 15 f ...[more]

PMID: 19741216

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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.

Dataset Information

Mutations in FUS cause FALS and SALS in French and French Canadian populations.

Background

Methods

Results

Conclusions

Publications

Mutations in FUS cause FALS and SALS in French and French Canadian populations.

Similar Datasets

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