Sporadic ALS with compound heterozygous mutations in the SQSTM1 gene

Shimizu, Hiroshi; Toyoshima, Yasuko; Shiga, Atsushi; Yokoseki, Akio; Arakawa, Keiko; Sekine, Yumi; Shimohata, Takayoshi; Ikeuchi, Takeshi; Nishizawa, Masatoyo; Kakita, Akiyoshi; Onodera, Osamu; Takahashi, Hitoshi

doi:10.1007/s00401-013-1150-5

Cited by 35 publications

(37 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…UBQLN2 is a component of inclusion bodies in the brains and spinal cords of patients harboring UBQLN2 mutations that impair normal proteasome-mediated protein degradation. Polymorphisms in sequestosome-1 (SQSTM1, p62) are also associated with fALS and sALS (79)(80)(81)(82). This ubiquitin-binding scaffold protein decorates the surface of inclusion bodies in many neurodegenerative diseases.…”

Section: Protein Toxicity: Protein Aggregation and Prion Domainsmentioning

confidence: 99%

Emerging mechanisms of molecular pathology in ALS

Peters¹,

Ghasemi²,

Brown³

2015

J. Clin. Invest.

242

142

View full text Add to dashboard Cite

Section: Protein Toxicity: Protein Aggregation and Prion Domainsmentioning

confidence: 99%

Emerging mechanisms of molecular pathology in ALS

Peters¹,

Ghasemi²,

Brown³

2015

J. Clin. Invest.

242

142

View full text Add to dashboard Cite

“…Mutations not previously associated with FTLD, ALS, or PDB are in red and bold . In the green panel , SQSTM1 mutations reported in previous studies are given [7, 11, 17, 28, 29, 33]. Mutations absent from tested and published controls are in green .…”

Section: Methodsmentioning

confidence: 99%

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration

et al. 2014

View full text Add to dashboard Cite

Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24–3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-014-1298-7) contains supplementary material, which is available to authorized users.

show abstract

“…To maintain intracellular homeostasis, p62 participates in the degradation of protein aggregates and cytoplasmic bodies via selective autophagy through its PB1, LIR, and UBA domains (30). SQSTM1 has been screened as a candidate gene in eight studies of ALS patients (31)(32)(33)(34)(35)(36)(37)(38).…”

Section: Introductionmentioning

confidence: 99%

Six SQSTM1 mutations in a Chinese amyotrophic lateral sclerosis cohort

Yang¹,

Tang²,

Zhang³

et al. 2015

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

View full text Add to dashboard Cite

The purpose of this study was to identify SQSTM1 gene mutations, estimate survival based on the progression rate of the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) score (ΔFS), and characterize the relationships between SQSTM1 mutations and clinical phenotypes in Chinese ALS patients. We sequenced the SQSTM1 gene in 35 familial ALS patients, 436 sporadic ALS patients, and 384 healthy controls. SQSTM1 gene mutations were screened with PCR and direct sequencing; the correlations between genotype and phenotype and the progressive ALSFRS-R ratio were analyzed. Results revealed six heterozygous missense mutations in 471 ALS patients: c.241 G> A (p.E81K), c.717 C> A (p.N239K), c.889 G> A (p.G297S), c.1116 G> C (p.E372D), c.1162 C> T (p.P388S) and c.1175 C> T (p.P392 L). The gender ratio was 1:1, and the limb was the site of disease onset in mutation-positive patients. Notably, the ΔFS analysis revealed that the risk of death or tracheostomy was significantly increased in SQSTM1 mutation carriers (p < 0.05). In conclusion, E81K, N239K, G297S, E372D, P388S and P392 L were detected in the PB1, TRAF6, PEST and UBA domains, which are important to p62 function and prone to ALS. The incidence of ALS caused by the SQSTM1 mutation has increased from 30 to 35 worldwide.

show abstract

Sporadic ALS with compound heterozygous mutations in the SQSTM1 gene

Cited by 35 publications

References 21 publications

Emerging mechanisms of molecular pathology in ALS

Emerging mechanisms of molecular pathology in ALS

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration

Six SQSTM1 mutations in a Chinese amyotrophic lateral sclerosis cohort

Contact Info

Product

Resources

About