The genetics of amyotrophic lateral sclerosis: current insights

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that results in loss of the upper and lower motor neurons from motor cortex, brainstem, and spinal cord. While the majority of cases are sporadic, approximately 10% show familial inheritance. ALS is usually inherited in an autosomal dominant manner, although autosomal recessive and X-linked inheritance do occur. To date, 24 of the genes at 26 loci have been identified; these include loci linked to ALS and to frontotemporal dementia-ALS, where family pedigrees contain individuals with frontotemporal dementia with/without ALS. The most commonly established genetic causes of familial ALS (FALS) to date are the presence of a hexanucleotide repeat expansion in the C9ORF72 gene (39.3% FALS) and mutation of SOD1, TARDBP, and FUS, with frequencies of 12%–23.5%, 5%, and 4.1%, respectively. However, with the increasing use of next-generation sequencing of small family pedigrees, this has led to an increasing number of genes being associated with ALS. This review provides a comprehensive review on the genetics of ALS and an update of the pathogenic mechanisms associated with these genes. Commonly implicated pathways have been established, including RNA processing, the protein degradation pathways of autophagy and ubiquitin–proteasome system, as well as protein trafficking and cytoskeletal function. Elucidating the role genetics plays in both FALS and sporadic ALS is essential for understanding the subsequent cellular dysregulation that leads to motor neuron loss, in order to develop future effective therapeutic strategies.

Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia

“…Many of the additional ALS genes can also be categorized into these pathways ( Table 1 and Figure 2 ), such as SETX, ANG, ATXN2, hnRNPA1 , and MATR3 , which are all involved in RNA processing and SPG11, KIF5A , and PFN1 that are associated with the cytoskeleton and mutations in which cause axonal defects ( Alsultan et al, 2016 ). Many of the genes also encode proteins involved in trafficking components within the cell, such as endosomes ( ALS2, FIG4 , and NEK1 ) or in the unfolded protein response ( VAPB and SIGMAR1 ).…”

New Insights on the Role of N6-Methyladenosine RNA Methylation in the Physiology and Pathology of the Nervous System

“…About 90% of all cases of ALS are sporadic (sALS), while the remaining ∼10% is familial (fALS). Familial cases are inherited through an autosomal dominant pattern due to mutations in several genes ( Alsultan et al, 2016 ; Grad et al, 2017 ). Usually, ALS is a disease of mid and late life with only 10% beginning before the age of 40 ( Rowland et al, 2010 ).…”

Answer ALS: A Large-Scale Resource for Sporadic and Familial ALS Combining Clinical Data with Multi-Omics Data from Induced Pluripotent Cell Lines

“…There are 33 genes in which mutations have been associated with ALS 50,51 , speci cally: ALS2 52,53 , ANG 54-56 , ANXA11, ATXN2, C21orf2, C9orf72, CAMTA1, CCNF, CHCHD10, DAO, DCTN1, FIG4, FUS, HNRNPA1, HNRNPA2B, KIF5, MATR3, MOBP, NEK1, OPTN, PFN1, SCFD1, SETX, SOD1, SQSTM1, TAF15, TARDBP [57][58][59] , TBK1, TUBA4A, UBQLN2, UNC13A, VAPB and VCP 60 . We refer to these as the "33-ALS" genes.…”

“…We also investigated IS-D variants in the 33-ALS genes. 98 individuals harbored at least 1 IS-D variant in the 33-ALS genes, and 9 individuals harbored 2 IS-D variants in the 33 genes associated with ALS as described above 50,51 (Extended Table 4 and 8). In general, Intervar called a variant as pathogenic or likely pathogenic much less than Clinvar and hence appears to be more stringent in its pathogenic determination.…”