•Analysis 51 ALS causative genes in a large ALS cohort from central-south of China.•Site of onset of ALS was influenced by rare damage variants and sex.•SOD1 gene was the most common mutated gene in ...China, followed by ATXN2 and NEK1.•Mutation spectrum of AD-ALS patients differed from that of sporadic ALS patients.
To analyze the mutational spectrum of known ALS causative genes in China ALS patients. We comprehensively analyzed 51 ALS causative genes by combining different sequencing technologies in 753 unrelated ALS patients from Central South China. The mean age at onset (AAO) was 53.7±11.4 years. The AAO was earlier in the autosomal dominant (AD) ALS patients than in the sporadic ALS (sALS) patients. Bulbar onset was more frequent in females than in males. SOD1 was the most frequently mutated gene in the AD-ALS and the sALS patients, followed by the ATXN2 and FUS genes in the AD-ALS patients and the NEK1 and CACNA1H genes in the sALS patients. Patients with RDVs in the SOD1 or FUS genes had an earlier AAO than the mean AAO of all the patients, while the patients with RDVs in the NEK1 gene showed later onset. SOD1 gene was the most commonly mutated gene in ALS patients in China, followed by ATXN2 and NEK1. The phenotype might be determined synergistically by sex and genetic variants.
Background
Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder. Mitochondrial dysfunction is involved in the complex pathophysiology of ALS; however, the role of ...mitochondrial DNA (mtDNA) variants in ALS is poorly understood. We aimed to elucidate the role of mtDNA variants in the pathogenesis of ALS.
Methods
The mitochondrial haplogroups of 585 ALS patients and 371 healthy controls were determined; 38 ALS patients and 42 controls underwent long-range polymerase chain reaction combined with next-generation sequencing technology to analyze whole mitochondrial genome variants.
Results
A higher percentage of variants accumulated in ALS patients than in controls. Analysis of coding region variations that were further stratified by mtDNA genes revealed that nonsynonymous variants were more vulnerable in ALS patients than in controls, particularly in the
ND4L
,
ND5
, and
ATP8
genes. Moreover, pathogenic nonsynonymous variants tended to over-represent in ALS patients. Unsurprisingly, nonsynonymous variants were not related to the phenotype. Haplogroup analysis did not found evidence of association between haplogroups with the risk of ALS, however, patients belonging to haplogroup Y and M7c were prone to develop later onset of ALS.
Conclusions
This is the first study to profile mtDNA variants in ALS patients from mainland China. Our results suggest that an increase in the number of nonsynonymous variants is linked to the pathogenesis of ALS. Moreover, haplogroup Y and M7c may modulate the clinical expression of ALS. Our findings provide independent, albeit limited, evidence for the role of mtDNA in the pathogenesis of ALS.
was recently identified as a novel causative gene for amyotrophic lateral sclerosis (ALS). We aimed to determine the contribution of variations in
in the Chinese ALS population and to further explore ...the genotype-phenotype correlations.
We screened rare, putative pathogenic
mutations in a large Chinese ALS cohort and performed association analysis of both rare and common
variations between cases and controls.
Of the 985 ALS patients studied, six rare, heterozygous putative pathogenic variants in
were identified among six unrelated sALS patients. Exon 14 of
might be a mutant hotspot in our cohort. Patients with ALS with only rare, putative pathogenic
mutations exhibited a characteristic clinical profile. Patients harboring multiple mutations in
and other ALS-related genes displayed a significantly earlier onset of ALS. Association analysis revealed that rare
variants in the untranslated regions (UTRs) were enriched among ALS patients; meanwhile, two common variants in the exon-intron boundary were discovered to be associated with ALS.
We demonstrate that
variations also have contributed to ALS in the Asian population and broaden the genotypic and phenotypic spectrum of
variants in the ALS-frontotemporal dementia (FTD) spectrum. Furthermore, our findings first suggest that
is not only a causative gene, but also exerts a disease-modifying effect. These results may contribute to a better understanding of the molecular mechanism of ALS.
Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects neurons in the central nervous system and the spinal cord. As in many other neurodegenerative ...disorders, the genetic risk factors and pathogenesis of ALS involve dysregulation of cytoskeleton and neuronal transport. Notably, sensory and motor neuron diseases such as hereditary sensory and autonomic neuropathy type 2 (HSAN2) and spastic paraplegia 30 (SPG30) share several causative genes with ALS, as well as having common clinical phenotypes. KIF1A encodes a kinesin 3 motor that transports presynaptic vesicle precursors (SVPs) and dense core vesicles and has been reported as a causative gene for HSAN2 and SPG30.
Here, we analyzed whole-exome sequencing data from 941 patients with ALS to investigate the genetic association of KIF1A with ALS.
We identified rare damage variants (RDVs) in the KIF1A gene associated with ALS and delineated the clinical characteristics of ALS patients with KIF1A RDVs. Clinically, these patients tended to exhibit sensory disturbance. Interestingly, the majority of these variants are located at the C-terminal cargo-binding region of the KIF1A protein. Functional examination revealed that the ALS-associated KIF1A variants located in the C-terminal region preferentially enhanced the binding of SVPs containing RAB3A, VAMP2, and synaptophysin. Expression of several disease-related KIF1A mutants in cultured mouse cortical neurons led to enhanced colocalization of RAB3A or VAMP2 with the KIF1A motor.
Our study highlighted the importance of KIF1A motor-mediated transport in the pathogenesis of ALS, indicating KIF1A as an important player in the oligogenic scenario of ALS.
Background
Repeat expansions, including those in
C9orf72
and
ATXN2
, have been implicated in amyotrophic lateral sclerosis (ALS). However, there have been few studies on the association of
AR
and
...NOP56
repeat expansion with ALS, especially in China. Accordingly, we aimed to evaluate the frequency of
C9orf72
and
ATXN2
repeat mutations and investigate whether
NOP56
and
AR
repeat expansion are risk factors for ALS.
Methods
In this study, 736 ALS patients and several hundred healthy controls were recruited. Polymerase chain reaction (PCR) and repeat-primed PCR (RP-PCR) were performed to determine the repeat lengths in
C9orf72, ATXN2, AR
, and
NOP56
.
Results
GGGGCC repeats in
C9orf72
were observed in six ALS patients (0.8%, 6/736) but not in any of the controls (0/365). The patients with pathogenic GGGGCC repeats showed shorter median survival times than those with a normal genotype (
p
= 0.006). Regarding
ATXN2
CAG repeats, we identified that intermediate repeat lengths (29–34 copies) were associated with ALS (
p
= 0.033), and there was no difference in clinical characteristics between the groups with and without intermediate repeats (
p
> 0.05). Meanwhile, we observed that there was no association between the repeat size in
AR
and
NOP56
and ALS (
p
> 0.05).
Conclusions
Our results demonstrated that pathogenetic repeats in
C9orf72
are rare in China, while intermediate CAG repeats in
ATXN2
are more frequent but have no effect on disease phenotypes; the repeat size in
AR
and
NOP56
may not be a risk factor for ALS.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons, and it demonstrates high clinical heterogeneity and complex ...genetic architecture. A variation within
TRMT2B
(c.1356G>T; p.K452N) was identified to be associated with ALS in a family comprising two patients with juvenile ALS (JALS). Two missense variations and one splicing variation were identified in 10 patients with ALS in a cohort with 910 patients with ALS, and three more variants were identified in a public ALS database including 3317 patients with ALS. A decreased number of mitochondria, swollen mitochondria, lower expression of ND1, decreased mitochondrial complex I activities, lower mitochondrial aerobic respiration, and a high level of ROS were observed functionally in patient-originated lymphoblastoid cell lines and
TRMT2B
interfering HEK293 cells. Further,
TRMT2B
variations overexpression cells also displayed decreased ND1. In conclusion, a novel JALS-associated gene called
TRMT2B
was identified, thus broadening the clinical and genetic spectrum of ALS.
To date, conflicting results about the role of vitamins in amyotrophic lateral sclerosis (ALS) have been reported along with a lack of systematic studies on all types of serum vitamins in patients ...with ALS. Moreover, extensive studies have been conducted on vitamins in other neurodegenerative diseases; however, whether serum vitamin alterations in ALS are similar to those in other neurodegenerative diseases remains unclear. Therefore, we performed a study involving a large Chinese cohort of patients with ALS to address this gap. In this study, 202 patients with ALS, 214 with a neurodegenerative disease that mimicked ALS (mimics), and 208 healthy controls were enrolled. Serum vitamins of all subjects were examined under fasting state in Clinical Laboratory. As a result, we found that higher vitamin A and E levels and lower vitamin B2, B9, and C levels were in patients with ALS compared to healthy controls, and that high vitamin A and E levels, and low vitamin B2, B9, and C levels were associated with an increased risk for ALS. In addition, serum vitamin C was lower in early-onset ALS patients compared to those in late-onset ALS patients; however, there was no significant correlation between serum vitamins and age at onset, sites at onset, disease duration, or disease severity of ALS. We also found that patients with ALS showed similar vitamin alterations to mimics, with the exception of vitamin E. In summary, our study adds information to the literature on the role of vitamins in ALS and provides support for clinical guidance regarding dietary changes and vitamin supplements in patients with ALS.To date, conflicting results about the role of vitamins in amyotrophic lateral sclerosis (ALS) have been reported along with a lack of systematic studies on all types of serum vitamins in patients with ALS. Moreover, extensive studies have been conducted on vitamins in other neurodegenerative diseases; however, whether serum vitamin alterations in ALS are similar to those in other neurodegenerative diseases remains unclear. Therefore, we performed a study involving a large Chinese cohort of patients with ALS to address this gap. In this study, 202 patients with ALS, 214 with a neurodegenerative disease that mimicked ALS (mimics), and 208 healthy controls were enrolled. Serum vitamins of all subjects were examined under fasting state in Clinical Laboratory. As a result, we found that higher vitamin A and E levels and lower vitamin B2, B9, and C levels were in patients with ALS compared to healthy controls, and that high vitamin A and E levels, and low vitamin B2, B9, and C levels were associated with an increased risk for ALS. In addition, serum vitamin C was lower in early-onset ALS patients compared to those in late-onset ALS patients; however, there was no significant correlation between serum vitamins and age at onset, sites at onset, disease duration, or disease severity of ALS. We also found that patients with ALS showed similar vitamin alterations to mimics, with the exception of vitamin E. In summary, our study adds information to the literature on the role of vitamins in ALS and provides support for clinical guidance regarding dietary changes and vitamin supplements in patients with ALS.
Variants in the
DNAJC7
gene have been shown to be novel causes of amyotrophic lateral sclerosis (ALS). However, the contributions of
DNAJC7
mutations in Asian ALS patients remain unclear. In this ...study, we screened rare pathogenic variants in the
DNAJC7
gene in a cohort of 578 ALS patients from Mainland China. A novel, rare, putative pathogenic variant c.712A>G (p.R238G) was identified in one sporadic ALS patient. The carrier with this variant exhibited symptom onset at a relatively younger age and experienced rapid disease progression. Our results expand the pathogenic variant spectrum of
DNAJC7
and indicate that variants in the
DNAJC7
gene may also contribute to ALS in the Chinese population.
Accumulating evidence has revealed that immunity plays an important role in amyotrophic lateral sclerosis (ALS) progression. However, the results regarding the serum levels of immunoglobulin and ...complement are inconsistent in patients with ALS. Although immune dysfunctions have also been reported in patients with other neurodegenerative diseases, few studies have explored whether immune dysfunction in ALS is similar to that in other neurodegenerative diseases. Therefore, we performed this study to address these gaps. In the present study, serum levels of immunoglobulin and complement were measured in 245 patients with ALS, 65 patients with multiple system atrophy (MSA), 60 patients with Parkinson's disease (PD), and 82 healthy controls (HCs). Multiple comparisons revealed that no significant differences existed between patients with ALS and other neurodegenerative diseases in immunoglobulin and complement levels. Meta-analysis based on data from our cohort and eight published articles was performed to evaluate the serum immunoglobulin and complement between patients with ALS and HCs. The pooled results showed that patients with ALS had higher C4 levels than HCs. In addition, we found that the IgG levels were lower in early-onset ALS patients than in late-onset ALS patients and HCs, and the correlations between age at onset of ALS and IgG or IgA levels were significant positive. In conclusion, our data supplement existing literature on understanding the role of peripheral immunity in ALS.
Short tandem repeats (STRs) are highly variable elements that play a pivotal role in multiple genetic diseases and the regulation of gene expression. Long-read sequencing (LRS) offers a potential ...solution to genome-wide STR analysis. However, characterizing STRs in human genomes using LRS on a large population scale has not been reported.
We conducted the large LRS-based STR analysis in 193 unrelated samples of the Chinese population and performed genome-wide profiling of STR variation in the human genome. The repeat dynamic index (RDI) was introduced to evaluate the variability of STR. We sourced the expression data from the Genotype-Tissue Expression to explore the tissue specificity of highly variable STRs related genes across tissues. Enrichment analyses were also conducted to identify potential functional roles of the high variable STRs.
This study reports the large-scale analysis of human STR variation by LRS and offers a reference STR database based on the LRS dataset. We found that the disease-associated STRs (dSTRs) and STRs associated with the expression of nearby genes (eSTRs) were highly variable in the general population. Moreover, tissue-specific expression analysis showed that those highly variable STRs related genes presented the highest expression level in brain tissues, and enrichment pathways analysis found those STRs are involved in synaptic function-related pathways.
Our study profiled the genome-wide landscape of STR using LRS and highlighted the highly variable STRs in the human genome, which provide a valuable resource for studying the role of STRs in human disease and complex traits.
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