Sequestosome-1 (SQSTM1) sequence variants in ALS cases in the UK: prevalence and coexistence of SQSTM1 mutations in ALS kindred with PDB

Kwok, Chun Tak; Morris, Adam P.; Belleroche, Jacqueline de

doi:10.1038/ejhg.2013.184

Cited by 48 publications

(38 citation statements)

References 28 publications

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“…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

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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.

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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

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“…A recent study reported a splice donor variant in SQSTM1 in a family with an autosomal dominant distal myopathy and also in an unrelated patient with sporadic distal myopathy (Bucelli et al., 2015). In addition, mutations in SQSTM1 are well known to be associated with familial and/or sporadic Paget disease of bone, ALS, and frontotemporal dementia (FTD) (Fecto et al., 2011, Kwok et al., 2014, Laurin et al., 2002, Le Ber et al., 2013, Miller et al., 2015, Rubino et al., 2012). Mutations in valosin-containing protein ( VCP ) gene are known to cause an inherited form of IBM with Paget disease and frontotemporal dementia (IBMPFD) (Gidaro et al., 2008, Watts et al., 2004) and have also been reported in cases with ALS and FTD (Johnson et al., 2010, Koppers et al., 2012).…”

Section: Introductionmentioning

confidence: 99%

Rare variants in SQSTM1 and VCP genes and risk of sporadic inclusion body myositis

Gang¹,

Bettencourt²,

Machado³

et al. 2016

Neurobiology of Aging

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Genetic factors have been suggested to be involved in the pathogenesis of sporadic inclusion body myositis (sIBM). Sequestosome 1 (SQSTM1) and valosin-containing protein (VCP) are 2 key genes associated with several neurodegenerative disorders but have yet to be thoroughly investigated in sIBM. A candidate gene analysis was conducted using whole-exome sequencing data from 181 sIBM patients, and whole-transcriptome expression analysis was performed in patients with genetic variants of interest. We identified 6 rare missense variants in the SQSTM1 and VCP in 7 sIBM patients (4.0%). Two variants, the SQSTM1 p.G194R and the VCP p.R159C, were significantly overrepresented in this sIBM cohort compared with controls. Five of these variants had been previously reported in patients with degenerative diseases. The messenger RNA levels of major histocompatibility complex genes were upregulated, this elevation being more pronounced in SQSTM1 patient group. We report for the first time potentially pathogenic SQSTM1 variants and expand the spectrum of VCP variants in sIBM. These data suggest that defects in neurodegenerative pathways may confer genetic susceptibility to sIBM and reinforce the mechanistic overlap in these neurodegenerative disorders.

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“…However, several studies failed to confirm the association of VCP [51][52][53][54][55][56] and UBQLN2 [57][58][59][60][61][62][63][64][65][66] with ALS/FTD, suggesting that mutations in these genes are not a common cause of ALS/FTD globally. Conversely, the presence of sequestosome (SQSTM1) mutations in 1-3.5% of ALS/FTD patients has been confirmed [67][68][69][70][71][72][73][74][75]. In 2014, whole-exome sequencing led to the identification of one mutation in the gene coiled-coil-helix-coiledcoil-helix domain-containing protein 10 (CHCHD10) in two families presenting with ALS/FTD [76].…”

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confidence: 99%