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Original Contributions |

SQSTM1 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis

Faisal Fecto, MD; Jianhua Yan, MD, PhD; S. Pavan Vemula; Erdong Liu, MD; Yi Yang, MS; Wenjie Chen, MD; Jian Guo Zheng, MD; Yong Shi, MD, PhD; Nailah Siddique, RN, MSN; Hasan Arrat, MD; Sandra Donkervoort, MS; Senda Ajroud-Driss, MD; Robert L. Sufit, MD; Scott L. Heller, MD; Han-Xiang Deng, MD, PhD; Teepu Siddique, MD
Arch Neurol. 2011;68(11):1440-1446. doi:10.1001/archneurol.2011.250.
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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.

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Figure.SQSTM1 mutations in amyotrophic lateral sclerosis. A, Structure of SQSTM1 indicating coding regions (thick bars) and introns (thin lines). The white boxes indicate the untranslated regions. The location of each mutation identified in amyotrophic lateral sclerosis is shown by diamonds above the exons. B, Primary structure of p62 indicating all the major domains. SH2 indicates Src homology 2–binding domain; AID, acidic interaction domain; ZZ, zinc finger domain; TRAF6, tumor necrosis factor receptor–associated factor 6–binding domain; PEST, proline, glutamic acid, serine, and threonine–rich region; and UBA, ubiquitin-associated domain. The arrowheads indicate the position of each amino acid change identified in our cohort. C, Alignment of p62 sequences from different species. Sequence cluster alignment was performed with a system (HomoloGene; National Center for Biotechnology Information, Bethesda, Maryland) that uses BlastP to compare related sequences. Mutated residues are boxed. Sequences used include NP_003891.1 (Homo sapiens), XP_518154.2 (Pan troglodytes), NP_788814.1 (Bos taurus), NP_035148.1 (Mus musculus), NP_787037.2 (Rattus norvegicus), XP_001233249.1 (Gallus gallus), and NP_998338.1 (Danio rerio).




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