UNC13A variant rs12608932 is associated with increased risk of amyotrophic lateral sclerosis and reduced patient survival: a meta-analysis

Yang, Baiyuan; Jiang, Haixia; Wang, Fang; Li, Shimei; Wu, Chongmin; Bao, Jianjian; Zhu, Yongyun; Xu, Zhenhe; Liu, Bin; Ren, Hui; Yang, Xinglong

doi:10.1007/s10072-019-03951-y

Cited by 29 publications

(32 citation statements)

References 27 publications

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“…These studies contributed to identify some genes relevant for ALS, such as C9orf72 [ 14 , 18 ], KIF5A [ 19 ], and C21orf2 [ 20 ]. On the other hand, in remaining susceptibility loci, pathogenic variants have not been reported yet [ 21 ]. Nonetheless, the genotyping of the tagging SNPs identified (which are quite common in the general population) might play an important role in the near future in clinical trials and prognostic counseling [ 22 ]; Another category of genes and loci efficiently detected by association studies are those acting as ALS phenotype modifiers, showing in a few cases an overlap with Mendelian genes and susceptibility genetic factors [ 23 ].…”

Section: Als Genes: What Are They?mentioning

confidence: 99%

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

Lattante

Marangi

Doronzio

et al. 2020

Genes

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The development of high-throughput sequencing technologies and screening of big patient cohorts with familial and sporadic amyotrophic lateral sclerosis (ALS) led to the identification of a significant number of genetic variants, which are sometimes difficult to interpret. The American College of Medical Genetics and Genomics (ACMG) provided guidelines to help molecular geneticists and pathologists to interpret variants found in laboratory testing. We assessed the application of the ACMG criteria to ALS-related variants, combining data from literature with our experience. We analyzed a cohort of 498 ALS patients using massive parallel sequencing of ALS-associated genes and identified 280 variants with a minor allele frequency < 1%. Examining all variants using the ACMG criteria, thus considering the type of variant, inheritance, familial segregation, and possible functional studies, we classified 20 variants as “pathogenic”. In conclusion, ALS’s genetic complexity, such as oligogenic inheritance, presence of genes acting as risk factors, and reduced penetrance, needs to be considered when interpreting variants. The goal of this work is to provide helpful suggestions to geneticists and clinicians dealing with ALS.

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Section: Als Genes: What Are They?mentioning

confidence: 99%

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

Lattante

Marangi

Doronzio

et al. 2020

Genes

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“…SNPs in UNC13A are associated with increased risk of sporadic ALS 23 and sporadic FTLD-TDP pathology, especially Type B, the subtype associated with FTD-ALS 22 . In addition to increasing susceptibility to ALS, SNPs in UNC13A are associated with shorter survival in ALS patients [28][29][30][31] . But the mechanism by which genetic variation in UNC13A increases risk for ALS and FTD is unknown.…”

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confidence: 99%

TDP-43 represses cryptic exon inclusion in FTD/ALS geneUNC13A

Prudencio

Koike

et al. 2021

Preprint

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A hallmark pathological feature of neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing. Single nucleotide polymorphisms (SNPs) in UNC13A are among the strongest genome-wide association study (GWAS) hits associated with FTD/ALS in humans, but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines, and iPSC-derived motor neurons resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. Remarkably, the top variants associated with FTD/ALS risk in humans are located in the cryptic exon harboring intron itself and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD/ALS (UNC13A genetic variants) and loss of TDP-43 function.

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“…Strikingly, we found that both risk alleles for these SNPs independently and additively promoted cryptic splicing in vitro. Intriguingly, when the two variants are not co-inherited, as seen in East Asian individuals with ALS, an attenuated effect is observed 20 . A similar phenomenon wherein SNP pairs both contribute to risk has been widely studied at the APOE locus in Alzheimer's disease 27 .…”

Section: Discussionmentioning

confidence: 99%

“…1C-F). Notably, UNC13A polymorphisms modify both disease risk and progression in ALS and FTLD-TDP 4,[14][15][16][17][18][19][20][21] pointing towards a potential functional relationship between TDP-43, UNC13A, and disease risk.…”

Section: Tdp-43 Knockdown Leads To Inclusion Of a Cryptic Exon In Unc13amentioning

confidence: 99%

Common ALS/FTD risk variants in UNC13A exacerbate its cryptic splicing and loss upon TDP-43 mislocalization

Brown

Wilkins

Keuss

et al. 2021

Preprint

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Variants within the UNC13A gene have long been known to increase risk of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43. Here, we show that TDP-43 depletion induces robust inclusion of a cryptic exon (CE) within UNC13A, a critical synaptic gene, resulting in nonsense-mediated decay and protein loss. Strikingly, two common polymorphisms strongly associated with ALS/FTD risk directly alter TDP-43 binding within the CE or downstream intron, increasing CE inclusion in cultured cells and in patient brains. Our findings, which are the first to demonstrate a genetic link specifically between loss of TDP-43 nuclear function and disease, reveal both the mechanism by which UNC13A variants exacerbate the effects of decreased nuclear TDP-43 function, and provide a promising therapeutic target for TDP-43 proteinopathies.

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UNC13A variant rs12608932 is associated with increased risk of amyotrophic lateral sclerosis and reduced patient survival: a meta-analysis

Cited by 29 publications

References 27 publications

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

TDP-43 represses cryptic exon inclusion in FTD/ALS geneUNC13A

Common ALS/FTD risk variants in UNC13A exacerbate its cryptic splicing and loss upon TDP-43 mislocalization

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