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Arch Neurol. 2010 Apr;67(4):455-61. doi: 10.1001/archneurol.2010.52.

Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis.

Author information

1
Academic Unit of Neurology, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, England.

Abstract

OBJECTIVE:

To determine the frequency of and clinicopathologic phenotypes associated with FUS/TLS mutations in a large cohort of amyotrophic lateral sclerosis (ALS) cases from the north of England.

DESIGN:

Genetic screening project with neuropathologic examination of postmortem tissue in selected cases. The clinical details of selected cases are also presented.

SETTING:

Neurology departments of 2 university teaching hospitals in the north of England.

PARTICIPANTS:

The 15 exons of FUS/TLS were sequenced in an initial cohort of 42 familial ALS (FALS) and 117 sporadic ALS (SALS) cases. Exons 14 and 15 were subsequently screened in a larger cohort of 431 SALS cases. Regions mutated in ALS cases were also screened in 293 controls.

MAIN OUTCOME MEASURE:

Evaluation of gene-sequencing chromatographs and detailed histopathologic analysis of the central nervous system.

RESULTS:

Four heterozygous mutations, 1 of which is novel, were identified in 6 patients with ALS (4 with FALS and 2 with SALS). Two of the substitutions were not found to be present in controls, and neuropathology in these cases revealed neuronal and/or glial cytoplasmic inclusions positive for the FUS/TLS protein. One of these cases is also the first reported SALS case with an FUS/TLS mutation. The other 2 substitutions identified were also identified in control cases. Neuropathology in these cases revealed typical SALS pathology, suggesting that they are likely to represent benign polymorphisms.

CONCLUSIONS:

FUS/TLS mutations represented approximately 5% of FALS cases screened. A FUS/TLS mutation was also identified in a single SALS case. Subsequent screening of this region in a larger cohort of SALS cases, however, did not reveal any additional mutations.

PMID:
20385912
DOI:
10.1001/archneurol.2010.52
[Indexed for MEDLINE]
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