Format

Send to

Choose Destination
Arch Neurol. 2011 Nov;68(11):1440-6. doi: 10.1001/archneurol.2011.250.

SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis.

Author information

1
Division of Neuromuscular Medicine, Ken and Ruth Davee Department of Neurology and Clinical Neurological Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

Abstract

BACKGROUND:

The SQSTM1 gene encodes p62, a major pathologic protein involved in neurodegeneration.

OBJECTIVE:

To examine whether SQSTM1 mutations contribute to familial and sporadic amyotrophic lateral sclerosis (ALS).

DESIGN:

Case-control study.

SETTING:

Academic research. Patients  A cohort of 546 patients with familial (n = 340) or sporadic (n = 206) ALS seen at a major academic referral center were screened for SQSTM1 mutations.

MAIN OUTCOME MEASURES:

We evaluated the distribution of missense, deletion, silent, and intronic variants in SQSTM1 among our cohort of patients with ALS. In silico analysis of variants was performed to predict alterations in p62 structure and function.

RESULTS:

We identified 10 novel SQSTM1 mutations (9 heterozygous missense and 1 deletion) in 15 patients (6 with familial ALS and 9 with sporadic ALS). Predictive in silico analysis classified 8 of 9 missense variants as pathogenic.

CONCLUSIONS:

Using candidate gene identification based on prior biological knowledge and the functional prediction of rare variants, we identified several novel SQSTM1 mutations in patients with ALS. Our findings provide evidence of a direct genetic role for p62 in ALS pathogenesis and suggest that regulation of protein degradation pathways may represent an important therapeutic target in motor neuron degeneration.

PMID:
22084127
DOI:
10.1001/archneurol.2011.250
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center