Genetic and clinical features of Chinese sporadic amyotrophic lateral sclerosis patients with <i>TARDBP</i> mutations

Feng, Feng; Wang, Hongfen; Liu, Jiajin; Wang, Zhanjun; Xu, Baixuan; Zhao, Kun; Tao, Xiaoyong; He, Zhengqing; Yang, Fei; Huang, Xusheng

doi:10.1002/brb3.2312

Cited by 6 publications

(3 citation statements)

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“…Fewer TARDBP mutations, including P112H [ 51 ] and G295S [ 52 ], have been linked to FTLD. A reported mutant, I383V, has been implicated in both ALS and FTLD [ 52 – 55 ]. In general, most of the disease-associated mutations in the TARDBP gene are associated with an increase in TDP-43 aggregation and toxicity [ 48 ].…”

Section: Introductionmentioning

confidence: 99%

TDP-43 Pathology in Alzheimer’s Disease

Meneses

Koga

O’Leary

et al. 2021

Mol Neurodegeneration

145

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Transactive response DNA binding protein of 43 kDa (TDP-43) is an intranuclear protein encoded by the TARDBP gene that is involved in RNA splicing, trafficking, stabilization, and thus, the regulation of gene expression. Cytoplasmic inclusion bodies containing phosphorylated and truncated forms of TDP-43 are hallmarks of amyotrophic lateral sclerosis (ALS) and a subset of frontotemporal lobar degeneration (FTLD). Additionally, TDP-43 inclusions have been found in up to 57% of Alzheimer’s disease (AD) cases, most often in a limbic distribution, with or without hippocampal sclerosis. In some cases, TDP-43 deposits are also found in neurons with neurofibrillary tangles. AD patients with TDP-43 pathology have increased severity of cognitive impairment compared to those without TDP-43 pathology. Furthermore, the most common genetic risk factor for AD, apolipoprotein E4 (APOE4), is associated with increased frequency of TDP-43 pathology. These findings provide strong evidence that TDP-43 pathology is an integral part of multiple neurodegenerative conditions, including AD. Here, we review the biology and pathobiology of TDP-43 with a focus on its role in AD. We emphasize the need for studies on the mechanisms that lead to TDP-43 pathology, especially in the setting of age-related disorders such as AD.

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Section: Introductionmentioning

confidence: 99%

TDP-43 Pathology in Alzheimer’s Disease

Meneses

Koga

O’Leary

et al. 2021

Mol Neurodegeneration

145

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“…A variant at the same position but with a different amino acid substitution (c.1035C > A) is a well-known pathogenic variant in adult-onset ALS, included in most genetic databases and used in various molecular models of the disorder [ 21 , 22 ]. TARDBP -associated ALS cases develop a classic ALS phenotype with a mean age of onset of 53 years but with wide variability in both onset and duration [ 23 , 24 ]. The most distinctive phenotypic feature is a more frequent onset in the upper extremities, but with a similar evolution to the sporadic ALS, including the extension to other regions and bulbar involvement.…”

Section: Discussionmentioning

confidence: 99%

An Atypical Presentation of Upper Motor Neuron Predominant Juvenile Amyotrophic Lateral Sclerosis Associated with TARDBP Gene: A Case Report and Review of the Literature

Sánchez-Tejerina¹,

Restrepo-Vera²,

Rovira-Moreno

et al. 2022

Genes

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that can rarely affect young individuals. Juvenile ALS (JALS) is defined for individuals with an onset of the disease before the age of 25. The contribution of genetics to ALS pathology is a field of growing interest. One of the differences between adult-onset ALS and JALS is their genetic background, with a higher contribution of genetic causes in JALS. We report a patient with JALS and a pathogenic variant in the TARDBP gene (c.1035C > G; p.Asn345Lys), previously reported only in adult-onset ALS, and with an atypical phenotype of marked upper motor neuron predominance. In addition, the proband presented an additional variant in the NEK1 gene, c.2961C > G (p.Phe987Leu), which is classified as a variant of unknown significance. Segregation studies showed a paternal origin of the TARDBP variant, while the variant in NEK1 was inherited from the mother. We hypothesize that the NEK1 variant acts as a disease modifier and suggests the possibility of a functional interaction between both genes in our case. This hypothesis could explain the peculiarities of the phenotype, penetrance, and the age of onset. This report highlights the heterogeneity of the phenotypic presentation of ALS associated with diverse pathogenic genetic variants

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“…Approximately 5–10% of total ALS cases are familial (fALS), of which 20% are linked to a point mutation of Cu/Zn superoxide dismutase (SOD1) ( 1 ). SOD1 variants are reported in 15% of people with familial ALS in European populations, in 30% of people with familial ALS in Asian populations, and in 1–2% of people with apparently sporadic ALS in both populations ( 2 ).…”

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confidence: 99%