Identification of a novel loss-of-function C9orf72 splice site mutation in a patient with amyotrophic lateral sclerosis

Liu, Fang; Liu, Qing; Lü, Chao; Cui, Bo; Guo, Xia; Wang, Rong Rong; Liu, Ming-Sheng; Li, Xiao Guang; Cui, Liying; Zhang, Xue

doi:10.1016/j.neurobiolaging.2016.07.027

Cited by 18 publications

(14 citation statements)

References 38 publications

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“…Interestingly, a patient with a heterozygous splice site mutation ( c.601–2A > G) was identified using the method of targeted sequencing of coding regions. Functional analysis indicated that the splice site mutation created a premature stop codon (p. I201fsX235) with a decreased mutant messenger RNA levels, supporting the potential loss-of-function mechanism in the pathogenesis of C9ORF72 mutation (Liu et al, 2016a). …”

Section: Genetic Characteristics Of Chinese Als Patientsmentioning

confidence: 82%

“…Among the patients with expanded G 4 C 2 repeats, four of them were reported to have a phenotype of ALS-FTD or a family history of FTD (Jiao et al, 2014; Soong et al, 2014), another three patients exhibited cognitive impairment (Chen et al, 2016b). An intermediate length of G 4 C 2 repeats might also be pathological in Caucasian ALS patients (Byrne et al, 2014), while the phenomenon was not detected in the studies of Chinese patients (Chen et al, 2016b; Jiao et al, 2014; Liu et al, 2016a). Interestingly, a patient with a heterozygous splice site mutation ( c.601–2A > G) was identified using the method of targeted sequencing of coding regions.…”

Section: Genetic Characteristics Of Chinese Als Patientsmentioning

confidence: 93%

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The epidemiology and genetics of Amyotrophic lateral sclerosis in China

Liu

Gao

et al. 2018

Brain Research

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with loss of motor neurons. Previous knowledge of the disease has been mainly based on studies from Caucasian ALS patients of European descent. Here we review the epidemiological characteristics of ALS among the Chinese population in order to compare the similarities and differences between Chinese ALS cases and those from other countries. We describe a potential lower incidence and prevalence of ALS, a younger age of onset and a lower proportion of familial ALS cases in the Chinese population. Additionally, we highlight potential genetic differences between Chinese and Caucasian ALS patients. Most notably, the frequency of GGGGCC repeat expansions in C9ORF72 in Chinese ALS is significantly lower than in Caucasians. Since some conclusions might not be consistent across all of the studies around China to date, we suggest that it is necessary to carry out a prospective population-based study and large-scale gene sequencing around to better define epidemiological and genetic features of Chinese ALS patients.

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Section: Genetic Characteristics Of Chinese Als Patientsmentioning

confidence: 82%

Section: Genetic Characteristics Of Chinese Als Patientsmentioning

confidence: 93%

The epidemiology and genetics of Amyotrophic lateral sclerosis in China

Liu

Gao

et al. 2018

Brain Research

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“…However, only a single sporadic ALS patient has ever been found to carry a mutation potentially capable of causing a heterozygous loss of function, and it is unclear if this mutation is causative of the disease state [18,19]. Additionally, a patient homozygous for the repeat expansion had a similar clinical phenotype to heterozygote patients, rather than a much more severe phenotype typical of homozygous loss of function mutations [12].…”

Section: Loss Of Functionmentioning

confidence: 99%

Genetic models of C9orf72: what is toxic?

Moens

Partridge

Isaacs³

2017

Current Opinion in Genetics & Development

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A hexanucleotide repeat expansion in the gene C9orf72 is the most common genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Pathogenesis may occur either due to loss of function of the C9orf72 gene, or a toxic gain of function, via the production of repetitive sense and antisense RNA and/or repetitive dipeptide repeat proteins. Recently, mouse knockouts have suggested that a loss of function of C9orf72 alone is insufficient to lead to neurodegeneration, whilst overexpression of hexanucleotide DNA is sufficient in a wide range of model systems. Additionally, models have now been created to attempt to study the effects of repetitive RNA and dipeptide proteins in isolation and thus determine their relevance to disease.

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“…In addition to the toxicity resulting from the expanded repeat (Taylor et al 2016), the reduction in C9orf72 transcript and protein levels in patient cells and brain tissue suggests that loss-of-function mechanisms may contribute to ALS and FTD pathogenesis (DeJesus-Hernandez et al 2011;Gijselinck et al 2012;Belzil et al 2013;Ciura et al 2013;Donnelly et al 2013;Mori et al 2013;Xi et al 2013;Haeusler et al 2014;Liu et al 2014;Waite et al 2014). Additionally, there has been one report of a loss-of-function splice site mutation in C9orf72 causing ALS (Liu et al 2016). Furthermore, higher C9orf72 levels may have beneficial effects against neurodegeneration in humans (van Blitterswijk et al 2015;McGoldrick et al 2018).…”

mentioning

confidence: 99%

A C9orf72–CARM1 axis regulates lipid metabolism under glucose starvation-induced nutrient stress

Liu¹,

Wang²,

Ji³

et al. 2018

Genes Dev.

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Cells undergo metabolic adaptation during environmental changes by using evolutionarily conserved stress response programs. This metabolic homeostasis is exquisitely regulated, and its imbalance could underlie human pathological conditions. We report here that C9orf72, which is linked to the most common forms of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), is a key regulator of lipid metabolism under stress. Loss of C9orf72 leads to an overactivation of starvation-induced lipid metabolism that is mediated by dysregulated autophagic digestion of lipids and increased de novo fatty acid synthesis. C9orf72 acts by promoting the lysosomal degradation of coactivator-associated arginine methyltransferase 1 (CARM1), which in turn regulates autophagy-lysosomal functions and lipid metabolism. In ALS/FTD patient-derived neurons or tissues, a reduction in C9orf72 function is associated with dysregulation in the levels of CARM1, fatty acids, and NADPH oxidase NOX2. These results reveal a C9orf72-CARM1 axis in the control of stress-induced lipid metabolism and implicates epigenetic dysregulation in relevant human diseases.

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Identification of a novel loss-of-function C9orf72 splice site mutation in a patient with amyotrophic lateral sclerosis

Cited by 18 publications

References 38 publications

The epidemiology and genetics of Amyotrophic lateral sclerosis in China

The epidemiology and genetics of Amyotrophic lateral sclerosis in China

Genetic models of C9orf72: what is toxic?

A C9orf72–CARM1 axis regulates lipid metabolism under glucose starvation-induced nutrient stress

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