Identification of a Novel Hemizygous SQSTM1 Nonsense Mutation in Atypical Behavioral Variant Frontotemporal Dementia

Sun, Lin; Rong, Zhouyi; Li, Wei; Zheng, Honghua; Xiao, Shifu; Li, Xia

doi:10.3389/fnagi.2018.00026

Cited by 7 publications

(4 citation statements)

References 22 publications

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“…Waddling gait, neck flexion weakness, and positive Beevor's sign were characteristic, while distal strength was preserved; previously reported systemic involvement, such as dyspnea and arrhythmia, was not present. Nonsense mutations in SQSTM1 were also associated with frontotemporal dementia and progressive ataxia movement disorders in previous studies ( 17 , 18 ). Other SQSTM1-linked phenotypes (e.g., PDB, ALS, and FTD) were excluded based on examinations, suggesting that the muscle was selectively involved.…”

Section: Discussionmentioning

confidence: 52%

Frameshift mutation in SQSTM1 causes proximal myopathy with rimmed vacuoles: A case report

Shao²,

Li³

et al. 2023

Front. Neurol.

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p62/Sequestosome-1 (SQSTM1) is a stress-inducible scaffold protein involved in multiple cellular processes, including apoptosis, inflammation, cell survival, and selective autophagy. SQSTM1 mutations are associated with a spectrum of multisystem proteinopathy, including Paget disease of the bone, amyotrophic lateral sclerosis, frontotemporal dementia, and distal myopathy with rimmed vacuoles (MRV). Herein, we report a new phenotype of SQSTM1-associated proteinopathy, a novel frameshift mutation in SQSTM1 causing proximal MRV. A 44-year-old Chinese patient presented with progressive limb–girdle weakness. She had asymmetric proximal limb weakness and myopathic features on electromyography. The magnetic resonance images showed fatty infiltration into muscles, predominantly in the thighs and medial gastrocnemius, sparing the tibialis anterior. Muscle histopathology revealed abnormal protein deposition, p62/SQSTM1-positive inclusions, and rimmed vacuoles. Next-generation sequencing showed a novel pathogenic SQSTM1 frameshift mutation, c.542_549delACAGCCGC (p. H181Lfs*66). We expanded the pathogenic genotype of SQSTM1 to include a new, related phenotype: proximal MRV. We suggest that SQSTM1 variations should be screened in cases of proximal MRV.

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Section: Discussionmentioning

confidence: 52%

Frameshift mutation in SQSTM1 causes proximal myopathy with rimmed vacuoles: A case report

Shao²,

Li³

et al. 2023

Front. Neurol.

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“…In this study, five missense variants were first identified to be related to FTD. Among these variants, two (i.e., SQSTM1 C671A and ERBB4 T2136G) were first reported by our team (Sun et al, 2018(Sun et al, , 2020 and were confirmed function deficits of the target proteins. MAPT G389A was previously reported to affect a 17-year-old girl with the initial symptoms of atypical depression and emotional blunting and a 21-year-old woman with the initial symptom of postpartum depression.…”

Section: Discussionmentioning

confidence: 68%

“…No. 005 with SQSTM1 variant (NM_003900: c.C671A, p.S224X) was identified and reported by our team in 2018 (Sun et al, 2018), which resulted in the premature termination of protein synthesis and a predicted truncated protein. However, we did not detect truncated proteins in this variant overexpressing HEK-293T cells because of the degradability of truncated protein.…”

Section: Phenotypes Of Patients With Frontotemporal Dementia and Associated Variantsmentioning

confidence: 93%

Analysis of Genotype-Phenotype Correlations in Patients With Degenerative Dementia Through the Whole Exome Sequencing

Sun

Zhang

et al. 2021

Front. Aging Neurosci.

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Background: Sporadic dementias generally occur in older age and are highly polygenic, which indicates some patients transmitted in a poly-genes hereditary fashion.Objective: Our study aimed to analyze the correlations of genetic features with clinical symptoms in patients with degenerative dementia.Methods: We recruited a group of 84 dementia patients and conducted the whole exome sequencing (WES). The data were analyzed focusing on 153 dementia-related causing and susceptible genes.Results: According to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines, we identified four reported pathogenic variants, namely, PSEN1 c.A344G, APP c.G2149A, MAPT c.G1165A, and MAPT c.G742A, one reported likely pathogenic variant, namely, PSEN2 c.G100A, one novel pathogenic variants, SQSTM1 c.C671A, and three novel likely pathogenic variants, namely, ABCA7 c.C4690T, ATP13A2 c.3135delC, and NOS3 c.2897-2A > G. 21 variants with uncertain significance in PSEN2, C9orf72, NOTCH3, ABCA7, ERBB4, GRN, MPO, SETX, SORL1, NEFH, ADCM10, and SORL1, etc., were also detected in patients with Alzheimer’s disease (AD) and frontotemporal dementia (FTD).Conclusion: The new variants in dementia-related genes indicated heterogeneity in pathogenesis and phenotype of degenerative dementia. WES could serve as an efficient diagnostic tool for detecting intractable dementia.

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“…Several studies have shown that reduced SQSTM1 gene expression and lack of cytoplasmic p62 provoke the aggregation of pathological tau and neurofibrillary tangles [ 46 , 47 ], implying an important role of p62 in the pathogenesis of AD. Although no risk or causal SQSTM1 variants have been identified in AD patients so far [ 48 ], the wide clinical spectrum of SQSTM1 variants is exemplified by case reports of familial hippocampal amnestic syndrome closely resembling AD [ 49 ] and atypical FTD with prominent memory decline [ 50 ]. Replication of SQSTM1 variants in larger AD cohorts is needed before it can be included in genetic risk prediction.…”

Section: Discussionmentioning

confidence: 99%

Mapping the genetic landscape of early-onset Alzheimer’s disease in a cohort of 36 families

et al. 2022

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Background Many families with clinical early-onset Alzheimer’s disease (EOAD) remain genetically unexplained. A combination of genetic factors is not standardly investigated. In addition to monogenic causes, we evaluated the possible polygenic architecture in a large series of families, to assess if genetic testing of familial EOAD could be expanded. Methods Thirty-six pedigrees (77 patients) were ascertained from a larger cohort of patients, with relationships determined by genetic data (exome sequencing data and/or SNP arrays). All families included at least one AD patient with symptom onset <70 years. We evaluated segregating rare variants in known dementia-related genes, and other genes or variants if shared by multiple families. APOE was genotyped and duplications in APP were assessed by targeted test or using SNP array data. We computed polygenic risk scores (PRS) compared with a reference population-based dataset, by imputing SNP arrays or exome sequencing data. Results In eight families, we identified a pathogenic variant, including the genes APP, PSEN1, SORL1, and an unexpected GRN frameshift variant. APOE-ε4 homozygosity was present in eighteen families, showing full segregation with disease in seven families. Eight families harbored a variant of uncertain significance (VUS), of which six included APOE-ε4 homozygous carriers. PRS was not higher in the families combined compared with the population mean (beta 0.05, P = 0.21), with a maximum increase of 0.61 (OR = 1.84) in the GRN family. Subgroup analyses indicated lower PRS in six APP/PSEN1 families compared with the rest (beta −0.22 vs. 0.10; P = 0.009) and lower APOE burden in all eight families with monogenic cause (beta 0.29 vs. 1.15, P = 0.010). Nine families remained without a genetic cause or risk factor identified. Conclusion Besides monogenic causes, we suspect a polygenic disease architecture in multiple families based on APOE and rare VUS. The risk conveyed by PRS is modest across the studied families. Families without any identified risk factor render suitable candidates for further in-depth genetic evaluation.

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Identification of a Novel Hemizygous SQSTM1 Nonsense Mutation in Atypical Behavioral Variant Frontotemporal Dementia

Cited by 7 publications

References 22 publications

Frameshift mutation in SQSTM1 causes proximal myopathy with rimmed vacuoles: A case report

Frameshift mutation in SQSTM1 causes proximal myopathy with rimmed vacuoles: A case report

Analysis of Genotype-Phenotype Correlations in Patients With Degenerative Dementia Through the Whole Exome Sequencing

Mapping the genetic landscape of early-onset Alzheimer’s disease in a cohort of 36 families

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