ReviewGenetic causes of amyotrophic lateral sclerosis: New genetic analysis methodologies entailing new opportunities and challenges
Introduction
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons leading to rapidly progressive paralysis and eventually death from respiratory failure. Although this core definition is remarkably straightforward, it is becoming increasingly apparent that ALS is not a monolithic entity, but rather represents a heterogeneous group of diseases that share clinical features.
Examples of the heterogeneity associated with ALS are easy to find: the majority of cases die within three to four years of disease onset, but up to 10% of ALS patients survive for more than 10 years (Chiò et al., 2009a); there is wide variability in disease from population to population and across geographical region (Cronin et al., 2007); age at onset ranges from early twenties to the ninth decade of life; the clinical manifestation of disease differs from patient to patient in terms of clinical onset (bulbar-onset versus spinal-onset disease, proximal versus distal weakness, upper limb versus lower limb predominant), course (upper motor neuron versus lower motor neuron predominant), and frontotemporal lobe involvement (normal cognition versus mild cognitive impairment and/or dementia), to name but a few. Variability in neuropathology has also been observed with TDP-43 positive inclusions dominating most cases, but other cases lacking these inclusions.
Genetics offers a means to dissect out this heterogeneity and understand the cellular mechanisms leading to motor neuron degeneration. Paradoxically, however, it is this very heterogeneity associated with ALS that is the biggest obstacle to unraveling the genetics (Singleton et al., 2010).
For decades after its initial description in the half of 19th century (Aran, 1848, Cruveilhier, 1852, Charcot and Joffroy, 1869), ALS was thought to be a non-hereditary disease. It was not until Kurland and Mulder (1955) reported on familial aggregation in the 1950s that heritable factors were considered important in ALS etiology. Today, a family history of disease is recognized in 10% of cases, whereas the remaining 90% of cases are labeled as sporadic as they appear to occur randomly in the community. Even here, however, the sands are shifting, with an increasing portion of cases recognized as having a family history of related neurodegenerative diseases such as frontotemporal dementia. Autosomal dominant inheritance is by far the most common, but incomplete penetrance appears to be the rule.
To date, the genetic etiology of approximately two thirds of familial ALS and about 10% of sporadic disease has been identified (Renton et al., 2014). Genetic mutations are clearly responsible for the remaining one third of familial disease, but it is not known how much of the remaining sporadic disease is genetic and how much is due to other factors such as environmental exposures, aging or lifestyle choices. Genome-wide data suggest that genetic factors contribute to at least 23% of sporadic ALS (Keller et al., 2014). Even this high value, however, is likely to be an underestimate as the calculation was based on common variants in the human genome and would not capture the portion of disease arising from rare variants.
To date, more than 25 genes linked to ALS have been identified (Table 1, Fig. 1). We present these genes in two categories, namely (a) genes identified using linkage analysis and positional cloning, and (b) genes identified through the application of advanced genome-wide technologies. Though not every gene fits neatly into this framework, describing the genetic discoveries in ALS in this way provides a historical context and highlights how advances in genomic technologies are revolutionizing the way we think about this fatal neurodegenerative disease.
Section snippets
SOD1
In 1993, an international consortium identified SOD1 as a gene responsible for autosomal dominant FALS cases, by means of linkage analysis in 18 ALS pedigrees (Rosen et al., 1993). Through this method is possible to map the location of disease-causing loci by testing the co-segregation of genetic markers with the phenotype of interest. Multiple markers across the whole genome are usually screened in large families and a statistical test is performed to determine which markers are inherited by
Genome-wide association studies of ALS
Association studies involve comparison of the frequencies of genetic variants between groups of unrelated affected individuals and control subjects. Initial association studies were based on a candidate gene approach, but, with advances in genomic assay technology, several million markers across the genome can now be interrogated in a single experiment. This is known as genome-wide association study (GWAS).
Several GWAS have been published in ALS (Schymick et al., 2007, van Es et al., 2007, van
Epigenetics
Epigenetic modifications influence the expression pattern of the genome, Alteration of epigenetic processes, including DNA methylation, have been long known as causes of human diseases (e.g. imprinting syndromes, conditions caused by mutation in genes regulating epigenetic modifications, and cancer). Epigenetic mechanisms also appear to be involved in motor neuron cell death (Chestnut et al. 2011). Furthermore, epigenetics changes are the consequence of a dynamic process influenced by the
Unraveling the genetics of ALS: The way forward
Recent years have seen a boom in the identification of new ALS genes. The discovery of the C9orf72 repeat expansion had the biggest impact, explaining a significant proportion of both FALS and SALS cases and of the observed overlap between ALS and FTD. It has been argued that are unlikely to be other genetic discoveries with as high a frequency as the C9orf72 mutation and that, given the high cost of genetic studies, the ALS research community should focus their efforts elsewhere. Perhaps not
References (198)
- et al.
Copy-number variation in sporadic amyotrophic lateral sclerosis: a genome-wide screen
Lancet Neurol.
(2008) - et al.
The genomically mosaic brain: aneuploidy and more in neural diversity and disease
Semin. Cell Dev. Biol.
(2013) - et al.
Yunis–Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase
Am. J. Hum. Genet.
(2013) - et al.
DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4)
Am. J. Hum. Genet.
(2004) - et al.
Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis
J. Biol. Chem.
(2010) - et al.
Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS
Am. J. Hum. Genet.
(2009) - et al.
P525L FUS mutation is consistently associated with a severe form of juvenile amyotrophic lateral sclerosis
Neuromuscul. Disord
(2012) - et al.
Mitochondria and ALS: implications from novel genes and pathways
Mol. Cell. Neurosci.
(2013) - et al.
Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
Neuron
(2011) - et al.
Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene
Am. J. Hum. Genet.
(2002)
A seeding reaction recapitulates intracellular formation of Sarkosyl-insoluble transactivation response element (TAR) DNA-binding protein-43 inclusions
J. Biol. Chem.
A frameshift deletion in peripherin gene associated with amyotrophic lateral sclerosis
J. Biol. Chem.
A novel locus for familial amyotrophic lateral sclerosis, on chromosome 18q
Am. J. Hum. Genet.
Exome sequencing reveals VCP mutations as a cause of familial ALS
Neuron
Valosin-containing protein (VCP) mutations in sporadic amyotrophic lateral sclerosis
Neurobiol. Aging
Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy
Neurogenetics
Genetic analysis and SOD1 mutation screening in Iranian amyotrophic lateral sclerosis patients
Neurobiol. Aging
Repeat expansion in C9ORF72 is not a major cause of amyotrophic lateral sclerosis among Iranian patients
Neurobiol. Aging
Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome
Nat. Genet.
Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis
Hum. Mol. Genet.
“True” sporadic ALS associated with a novel SOD-1 mutation
Ann. Neurol.
A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis
Ann. Neurol.
Loss of ERLIN2 function leads to juvenile primary lateral sclerosis
Ann. Neurol.
Age of onset of amyotrophic lateral sclerosis is modulated by a locus on 1p34.1
Somatic mosaicism in a case of apparently sporadic Creutzfeldt–Jakob disease carrying a de novo D178N mutation in the PRNP gene
Am. J. Med. Genet. B: Neuropsychiatr. Genet
Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene
Curr. Neurol. Neurosci. Rep.
Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation. A clinical and genealogical study of 36 patients
Brain
Research on an as yet undescribed disease of the muscular system (progressive muscular atrophy)
Arch. Gen. Med
Somatic retrotransposition alters the genetic landscape of the human brain
Nature
A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement
Brain
Somatic and germline mosaicism in sporadic early-onset Alzheimer’s disease
Hum. Mol. Genet.
Motor neuron involvement in multisystem proteinopathy: implications for ALS
Neurology
A rare motor neuron deleterious missense mutation in the DPYSL3 (CRMP4) gene is associated with ALS
Hum. Mutat.
A large genome scan for rare CNVs in amyotrophic lateral sclerosis
Hum. Mol. Genet.
SMN1 gene duplications are associated with sporadic ALS
Neurology
Mutation within TARDBP leads to frontotemporal dementia without motor neuron disease
Hum. Mutat.
SOD1, ANG, TARDBP and FUS mutations in amyotrophic lateral sclerosis: a United States clinical testing lab experience
Amyotroph. Lateral Scler.
TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis
JAMA Neurol.
A de novo nonsense mutation of the FUS gene in an apparently familial amyotrophic lateral sclerosis case
Neurobiol. Aging
Deux cas d’atrophie musculaire progressive avec lesions de la substance grise et des faisceaux antero-lateraux de la moelle epiniere [French]
Arch. Physiol. Neurol. Pathol.
Screening of CHCHD10 in a French cohort confirms the involvement of this gene in frontotemporal dementia with amyotrophic lateral sclerosis patients
Neurobiol. Aging
SQSTM1 mutations in Han Chinese populations with sporadic amyotrophic lateral sclerosis
Neurobiol. Aging
Exome sequencing to identify de novo mutations in sporadic ALS trios
Nat. Neurosci.
Epigenetic regulation of motor neuron cell death through DNA methylation
J. Neurosci.
Prevalence of SOD1 mutations in the Italian ALS population
Neurology
Prognostic factors in ALS: a critical review
Amyotroph. Lateral Scler.
A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis
Hum. Mol. Genet.
Amyotrophic lateral sclerosis-frontotemporal lobar dementia in 3 families with p.Ala382Thr TARDBP mutations
Arch. Neurol.
Large proportion of amyotrophic lateral sclerosis cases in Sardinia due to a single founder mutation of the TARDBP gene
Arch. Neurol.
A de novo missense mutation of the FUS gene in a “true” sporadic ALS case
Neurobiol. Aging
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