Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder which is characterized by the loss of both upper and lower motor neurons in the central nervous system. In a significant fraction of ALS cases - irrespective of family history- a genetic background may be identified. The genetic background of ALS shows a high variability from one ethnicity to another. The most frequent genetic cause of ALS is the repeat expansion of the C9orf72 gene. With the emergence of next-generation sequencing techniques and copy number alteration calling tools the focus in ALS genetics has shifted from disease causing genes and mutations towards genetic susceptibility and risk factors.
In this review we aimed to summarize the most widely recognized and studied ALS linked repeat expansions and copy number variations other than the hexanucleotide repeat expansion in the C9orf72 gene. We compare and contrast their involvement and phenotype modifying roles in ALS among different populations.
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Introduction
Amyotrophic lateral sclerosis (ALS) is a progressive, currently incurable neurodegenerative disease which leads to the degeneration of upper- and lower motor neurons [1]. The majority of the cases arise sporadically (sALS), while around 10–15% of the patients have a positive family history for the disease (fALS) [2].
The genetic background of ALS shows a great heterogeneity, around 130 genes with various inheritance patterns and penetrance have been associated with the development of the disease up to date [1]. The first gene to be linked to ALS was the superoxide dismutase 1 (SOD1) in 1993 [3]. The most important breakthrough in ALS genetics came in 2008 when two unrelated research groups identified an intronic hexanucleotide repeat element (GGGGCC) expansion of the Chromosome 9 open reading frame 72 gene (C9orf72) in ALS patients [4, 5].
In the last decade numerous studies aimed to uncover the role of repeat expansions other than C9orf72 in ALS, such as NIPA1, ATXN1 and ATXN2. Repeat expansions of these genes were primarily associated with other neurodegenerative conditions such as spinocerebellar ataxias and hereditary spastic paraplegia [6,7,8]. Furthermore, copy number variations (CNVs) in ALS have been in the focus of research in the recent years as well [9]. Excluding C9orf72 repeat expansions, 17.6% of clinically diagnosed ALS and FTD cases had at least one expanded short tandem repeat (STR) allele reported to be pathogenic or intermediate for another neurodegenerative diseases such as ATXN1 [spinal cerebellar ataxia type 1 (SCA1)], ATXN2 (SCA2), ATXN8 (SCA8), TBP (SCA17), HTT (Huntington’s disease), DMPK [myotonic dystrophy type 1 (DM1)], CNBP (DM2), and FMR1 (fragile-X disorders) [10]. Our review focuses on the most extensively studied and most widely validated repeat expansions and copy number variations (Table 1) associated with ALS.
Within a single neuronal cell several pathogenic mechanisms may coexist, including RNA/protein toxic gain-of-function and/or protein loss-of-function. In case of C9orf72 hexanucleotide repeat expansion the proposed pathogenic mechanisms can be both loss-of-function (LOF) and gain-of-function (GOF) mechanism. The formation of toxic dipeptide repeats and sequestration of RNA are characteristics of the GOF mechanism, while haploinsufficiency due to decreased expression from the altered C9orf72 allele is a loss-of-function mechanism [11]. Out of the repeat expansions described in detail below ATXN1 and ATXN2 intermediate length trinucleotide repeat expansions are thought to be pathogenic by disrupting RNA processing mechanisms and by mislocalizing and sequestering important intracellular proteins [12, 13]. NIPA1 polyalanine repeats are thought to change the secondary protein structure and increasing stability of interprotein bonds. Inclusion bodies similar to ATXN1 and ATXN2 intermediate length repeat expansion associated ALS cases have been observed in NIPA1 repeat expansion carrier patients as well [14, 15]. The pathomechanism behind SMN1 and SMN2 copy number variations in connection to ALS remains elusive, several concepts were proposed. Overexpression of SMN proteins could be toxic to motor neurons, although there is no evidence that points this way. Another idea is that the copy number variation of the neighboring genomic region could be the key to understanding the role of SMN genes in ALS pathomechanism [16].
Genetics of ALS shows a great variability from one ethnicity to another which can only partly be explained by the different geographical locations of the populations [17]. Thus, it is of highest priority to genetically characterize ALS patients of different origins. In this review we aimed to summarize the current knowledge about the relationship of ALS and repeat expansions and CNVs in different genes from various ethnic groups.
C9orf72 repeat expansion
This is the most intensively studied repeat expansion in ALS. At the molecular level, the C9orf72 GGGGCC repeat expansion has been linked to both frontotemporal dementia (FTD) and ALS [4, 5]. The expansion appears in approximately 25% of familial FTD patients and 20–67% of familial ALS patients depending on the population studied, making this the most prevalent genetic mutation in both diseases. The expansion also appears in approximately 6% of sporadic FTD patients and 7% of sporadic ALS patients [18].
Unaffected individuals have < 20 hexanucleotide repeats, while affected individuals have > 30 repeats and often even > 1000 repeats [4, 5]. The range of 20–30 repeats is considered to be an intermediate field with no clinical evidence of manifestation of either motor neuron disease or dementia. However, intermediate repeat lengths (20–30 repeats) have been reported to be a significant risk factor for developing Parkinson’s disease (PD) [19].
ATXN1 intermediate length repeat expansions
The presence of more than 44 CAG repeats in the ATXN1 gene were identified as causative behind spinocerebellar ataxia 1 (SCA1) in 1993 [7]. ATXN1 encodes ataxin-1, an RNA binding protein which has an important role in RNA metabolism [20]. According to experimental data the overexpression of ataxin-1 leads to the formation of both nuclear and cytoplasmic inclusion bodies. These inclusion bodies contribute to the mislocalization of TDP-43 (TAR DNA-binding protein 43) which is a core feature of ALS pathology [12].
The first paper exploring ATXN1 repeat expansions in ALS was published in 2011, intermediate length alleles of the ATXN2 gene were identified only a year after as a risk factor of ALS [13, 21]. However, in the 2011 study Lee et al., did not find a relationship between the two by testing more than 500 patients and the same number of controls [21].
The first report of ATXN1 and ALS being connected came in 2012 when Conforti et al have found an association between ALS and ATXN1 intermediate repeat lengths. The authors defined intermediate length alleles as more than 27 repeats but less than 44 CAG units. CAT triplet interruptions in the CAG repeat tract were also present in ALS patients just like in SCA1 patients. No clinical variables seemed to be linked to ATXN1 intermediate repeat length alleles [22].
Subsequently Lattante et al., confirmed the link between ALS and intermediate length alleles of ATXN1 (> 32). In their study, 9.16% of ALS patients and 5.48% of control individuals were positive for the intermediate repeat expansion. Interestingly, in more than one fifth of the C9orf72 positive subgroup a concurrent ATXN1 intermediate repeat expansion was detected as well. This finding highlights the oligogenic background of ALS and suggests a strong association of these two genes. A common pathology behind C9orf72 and ATXN1 genes cannot be excluded [23].
The link between ATXN1 and the C9orf72 repeat expansions was further explored in a paper published in 2020. 15.15% of sporadic ALS patients and almost twice this many familial ALS patients positive for the C9orf72 expansion also carried ATXN1 intermediate repeat expansions. The authors proposed that ATXN1 is a disease modifier in C9orf72 repeat expansion carriers and shifts the patients to develop ALS [24].
Among 182 investigated Hungarian ALS patients 8.79% carried the ATXN1 intermediate allele compared to 1.12% of control individuals [25]. In the case of a female patient, who had a relatively late onset and fast progressing disease, co-harboring ATXN1 and C9orf72 repeat expansion was also described [25]. It could be proposed that the faster progression was due to the interplay between these two repeat expansions.
In a Maltese cohort describing 52 ALS patients, 17% of patients were identified to carry the intermediate repeat expansion (vs. 4.5% of healthy control individuals) [26]. This is the highest rate of ATXN1 intermediate repeat expansion carriers reported, which may be due to the fact that the population of Malta is a relatively secluded island nation.
ATXN1 intermediate alleles are also associated with ALS among Brazilian patients. 5.84% of ALS patients and 2.75% of control individuals carried an intermediate length allele longer than 33 CAG repeats. Frontotemporal dementia was also observed in 12.5% of ATXN1 intermediate allele carrier ALS patients. However, the link between C9orf72 and ATXN1 could not be proved in this study [27].
Similarly to Brazil, the link between ALS and ATXN1 intermediate repeat expansion could not be confirmed in African ALS patients and even the distribution of allele length significantly varied from European cohorts [28].
Reports on the co-occurrence of SCA1 and ALS have also been published. In a large SCA1 pedigree a male patient was described having a rapidly progressing motor neuron disease at the age of 47. ATXN1 genotyping showed two intermediate length alleles without CAT triplet interruption. His brother, who developed ataxic symptoms at the age of 45, had a fully expanded ATXN1 locus. At later stages of his diseases he showed ALS-like features as well (anarthria, dysphagia, fasciculations in the tongue) [29]. An another extended SCA1-ALS family was identified by targeted sequencing of ALS associated genes and CNV analysis. Furthermore, in this case a functional pathway analysis of the affected genes was also carried out. This revealed that dysregulation of synaptic transmission and lysosomal vesicular trafficking are important adversely altered processes in ALS patients and SCA1 patients with motor neuron signs [30].
The most comprehensive analysis on ALS and ATXN1 up to date was published by Tazelaar et al [12]. More than 2600 ALS patients of different European countries were investigated. 12.2% (328/2672) of ALS patients and 10.1% (244/2416) of healthy individuals carried an intermediate allele in the ATXN1 gene. The authors also performed a meta-analysis which concluded that ALS and ATXN1 intermediate alleles are in fact linked to each other, however, ATXN1 intermediate alleles do not influence either the survival or the age at onset [12]. Findings of a study on a model organism are also reported in that paper. Co-expression of ATXN1 and C9orf72 repeats resulted a more severe eye phenotype in Drosophila melanogaster compared to the expression of either of the C9orf72 repeat expansion or the ATXN1 repeat expansion [12]. This is a further evidence that the two repeat expansions aggravate the effect of each other in animal model, even though this phenotype modifying effect is yet to be confirmed in humans.
ATXN2 intermediate length repeat expansions
The ATXN2 gene is responsible for coding the ataxin-2 protein which is involved in receptor trafficking and in modulation of endocytotic processes [31]. Upregulation of the fly-specific ataxin-2 protein in Drosophila melanogaster led to increased TDP-43 aggregation and toxicity which was seen in the eye of the fruit fly [13]. Data also suggests that the connection of ataxin-2 and TDP-43 is limited not only to yeast and Drosophila, but they also interact in human cells through the RNA recognition motif of the TAR DNA-binding protein 43 protein [13]. As the localization of the Ataxin-2, in healthy controls a dispersed pattern, also involving the nucleus, may be observed, while in ALS patients ataxin-2 is confined to intracytoplasmic accumulations in neurons [13]. Intermediate repeat expansion of the ATXN2 gene increases the creation of reactive oxygen species by adversely influencing the function of NADPH oxidase [32]. A proposed pathomechanism behind ATXN2 intermediate repeat expansion toxicity is the disruption of RNA metabolism and thus important RNA binding proteins may become sequestered [32]. Intermediate repeats are defined as more than 26 but less than 34 repeats. Alleles longer than 34 CAG triplets cause spinocerebellar ataxia 2 (SCA2) in an autosomal dominant manner [6].
The minimal cut-off number for intermediate length alleles was reviewed by multiple international research groups to increase the specificity and sensitivity. In 2010 Elden et al. first identified more than 26 CAG units in 4.7% of ALS patients and in 1.4% healthy individuals [13]. Sproviero et al., and Daoud and colleagues independently defined intermediate repeats as more than 28 CAG units [33, 34]. An Italian study recommeneded > 30 trinucleotide units as a cut off value [35].
In the expanded ATXN2 CAG tract CAA interruptions were identified in ALS patients [36, 37]. According to Yu et al., harboring at least 3 interruptions compared to less than three CAA triplets negatively influences the age at onset of the disease [37].
Families and patients co-exhibiting ALS and SCA2 symptoms have been abundantly reported [38,39,40]. A report from the UK described the case of a female patient who developed symptoms resembling SCA at the age of 67. Half a year later muscle wasting started which was accompanied by bulbar and upper motor neuron signs. Her ATXN2 genotype was 33 repeats and a normal allele with 22 repeats and major ALS genes were screened without a relevant finding [41]. Two patients having the same ATXN2 genotype (33/22 repeats) were described to initially present as either SCA2 or lower motor neuron sign dominant ALS. The patient presenting SCA2 later developed symptoms of ALS, his disease progressed rapidly and exited due to respiratory failure [38]. Heterozygous fully expanded alleles (39 repeats for the ALS patient and 40 repeats for the patient with SCA2) were also detected in SCA2 and ALS occurring in the same family in an uncle (ALS, 62 year old at onset, died 23 months after the onset of symptoms) and in his niece (SCA2, with 36 year old at onset) [40].
An Australian ALS patient was identified with the full length hexanucleotide expansion in the C9orf72 gene, the intermediate repeat expansion in the ATXN2 gene and the NEK1 p.R261H variant [42]. His case also supports the polygenic nature of ALS. Two siblings of Guyanese ancestry who developed ataxia, parkinsonian symptoms and dementia were identified carrying both an expanded allele of C9orf72 and ATXN2 (37/22 repeats) [43]. Authors supposed that ATXN2 intermediate expansions could contribute to both ataxic features and to the cognitive impairment and the interplay between these genes could lead to the emergence of the complex phenotype [43]. An animal study further supported this theory: Co-expressing ATXN2 intermediate repeat expansion (30 repeats) and C9orf72 hexanucleotide repeat expansion in zebra fish showed a synergic effect. Higher levels of ATXN2 aggregation was observed and the fish exhibited aberrant swimming patterns and faulty axonal morphology [44].
Data of Russian ALS patients found a European-like percentage of ATXN2 intermediate repeats (5% = 10/199 patients). However, these patients were exclusively recruited from the European region of Russia, so the results were up to the expectations [45]. In a study form Malta only one patient (4.17%) was found with a homozygous 28/28 intermediate length ATXN2 allele, but this may be a consequence of the small sample size (1/24) [46]. Interestingly, patients from India also showed similar data to Europeans, as 4.6% (6/131 patients) of the investigated ALS patients carried an intermediate length allele (between 27 and 32 repeats) of the ATXN2 gene [47]. The highest percentage of ALS patients carrying the intermediate repeat expansion has been reported from Brazil, where 6.3% (29/459 patients) of ALS patients were tested positive for ATXN2 intermediate alleles [48]. Reports from China found a significantly lower rate of ATXN2 intermediate alleles (1.6, 1.5 and 1.9%) among ALS patients as studies involving patients of European origin [49,50,51]. This comes as no surprise since the population of China vastly differs from European people as far as ancestry is concerned. 1.5% of ALS patients of Korean ancestry carried an intermediate allele [52]. Australian ALS patients also exhibit Asian-like numbers in terms of ATXN2 intermediate alleles: Only 1.6% (10/616) of the patients harbored an intermediate length allele, which is unanticipated since Australia has seen vast number of European immigrants in the past, even though the investigated sample size is rather small [42]. ATXN2 intermediate repeat expansions were seldom identified in African ALS patients and no link could be established between ATXN2 and ALS [28].
Most studies agree that ALS patients with ATXN2 intermediate repeat expansions do not differ in any demographical or clinical variable from patients without an ATXN2 intermediate allele [13, 33, 47, 52]. However, a 2015 paper investigating 672 Italian ALS patients identified a significantly shorter survival in case of ATXN2 positive patients compared to ATXN2 negative patients (2.0 years vs. 3.2 years). Furthermore, a non-significant abundance of spinal onset ALS cases was observed among ATXN2 intermediate allele carriers [35]. The same results with larger effect sizes were confirmed by a paper reporting on the genetic testing of 375 ALS patients from Sardinia [53].
It was recently reported by analyzing an ALS registry that ATXN2 intermediate repeat expansions are not only associated with shorter survival and spinal onset but also with a faster time to diagnosis from onset of symptoms, faster decline of ALSFRS-R (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) score and with the presence of comorbid frontotemporal dementia [54]. It is noteworthy, that reports of ATXN2 intermediate alleles being a phenotype modifier only stem from Italy. This could be explained by the fact that Italian researchers are very active in this field and perform detailed and comprehensive analyses.
NIPA1 GCG repeat expansion
The NIPA1 gene codes the non-imprinted in Prader-Willi/Angelman syndrome region protein 1, a magnesium transporter that has an inhibitory role on the bone morphogenetic protein signaling pathway. This pathway is involved in the development of synapses and axons [55, 56] and NIPA1 mutations have been identified in autosomal dominant spastic paraplegia [8].
In 2010 a CNV analysis study identified NIPA1 rare deletion as a risk factor candidate for ALS [57]. Later the ALS associated role of NIPA1 polymorphic GCG repeat expansions was confirmed in multiple European populations and longer alleles were associated with shorter survival of patients [58]: a large international cohort examining almost 4000 ALS patients found NIPA1 alleles with more than 8 GCG units a risk factor of ALS with an odds ratio of 1.54 [59].
More rapid disease progression was also noted in a Maltese ALS patient with a heterozygous NIPA1 expansion of more than 8 repeats [46]. A non-significant association between spinal onset, and earlier disease onset and NIPA1 alleles of more than 8 repeats was also observed in two unrelated studies [60, 61].
The presence of NIPA1 expansion was also investigated in a C9orf72 positive subgroups of ALS patients [60, 61]. An Italian study did not find a significantly higher proportion of NIPA1 expansion among C9orf72 positive ALS patients (3.5% = 6 patients of C9orf72 positive patients and 4.1% = 15 patients of C9orf72 negative patients). Meanwhile 15.3% = 7 patients of C9orf72 positive patients (46/755 patients, 6.1%) also carried a NIPA1 expansion according to a paper from the Netherlands [60, 61]. As the results of the two studies are significantly diverse, further studies are needed to investigate the role of the joint expansion of NIPA1 and C9orf72 in ALS.
NIPA1 repeats were shorter in populations with African origin compared to Europeans and did not show enrichment among African ALS patients [28].
SMN1 and SMN2 genes
Homozygous deletions and compound heterozygous variants of the survival of motor neuron 1 (SMN1) gene cause spinal muscular atrophy (SMA) [62]. The severity of the SMA symptoms is mainly determined by the copy number of the highly homologous survival of motor neuron 2 (SMN2) gene [63].
The function of SMN1 and SMN2 genes in ALS is quite controversial. The first study linking ALS to SMN1 and SMN2 genes stems from 2001 [64]. In this report the authors found that homozygous deletions of the SMN2 gene were 4 times more frequent in ALS patients than in controls (16% = 18/110 patients vs. 4% = 4/100 patients). In terms of clinical parameters, only the median time of survival seemed to differ, which was 1.9 year shorter in patients with SMN2 homozygous deletions than in patients with 2 copies of SMN2 [64]. A complete opposite finding was published by Corcia et al. In Swedish ALS patients with homozygous SMN2 deletion the duration of the disease was more than 3 months longer compared to a formerly investigated unrelated cohort of French patients. Thereby, SMN2 homozygous deletions were described to be protective in ALS [65].
A paper from 2002 described that both heterozygous deletions and heterozygous SMN1 duplications are more common among ALS patients than in control subjects. Interestingly, spinal onset of ALS symptoms was quite common (71%) among ALS patients with one copy of SMN1. The authors proposed that the abnormal alleles could point to a linkage disequilibrium with the neuronal apoptosis inhibitor protein (NAIP) gene, which is located in close proximity to the SMN1–2 locus [66].
In the subsequent years many replica studies were conducted. In 2005, a study from the Netherlands found that heterozygous SMN1 deletion carriership was 3.8 times more frequent among ALS patients than in controls. Less copies of SMN2 were also enriched in ALS patients. These data suggest that the total level of full-length wild type SMN protein level could be the key regarding ALS pathogenesis. Fewer SMN2 copies and mortality rate showed a directly proportional relationship, while in case of fewer SMN1 copies the correlation did not reach the level of significance [67].
In a large study in 2012, using firm methodology, three copies of the SMN1 gene was found to increase susceptibility to ALS with an odds ratio of 2.07. The authors proposed that the heterozygous duplications of SMN1 might play a more remarkable role than it was formerly indicated [16].
Although a meta-analysis from 2014 [68] confirmed the role of SMN1 duplications as a risk factor of ALS, a recent bioinformatics study, using the DNA sequences of Project MinE (https://www.projectmine.com/) found no association between ALS and the copy number variations of either the SMN1 or the SMN2 gene [69].
In 25 Korean patients with motor neuron disease it was confirmed that SMN2 homozygous deletions are a susceptibility factors for lower motor neuron disease. Later the association was also confirmed in sporadic ALS patients of Korean descent. Furthermore, ALS patients with homozygous SMN2 deletions were found to have an earlier age at onset and a lower initial score on the Medical Research Council scale [70].
Since only European and Korean populations have been studied so far, there is a lack of population specific data regarding the connection of SMN genes and ALS. To settle the debate further studies, involving not yet studied populations, are needed. Moreover, the pathological processes in which copy number variations of SMN1 and SMN2 may be involved remain elusive. Designing functional studies and thus understanding the pathophysiology could bring solution to this two-decade-long debate.
Conclusions
Amyotrophic lateral sclerosis is a diverse disease with defects of many genes implicated in diverse pathways contributing to faulty functioning of multiple mutually non-exclusive pathological processes. With the advent of high-throughput sequencing methods the focus of investigations has shifted from causal genes towards genetic risk factors in ALS genetics research. Uncovering the genetic background of ALS from disease causing genes to risk factors holds the key to understanding the pathomechanism of the disease in detail.
Although, based on a large genome scan study, rare CNVs with larger effect sizes do not play an essential role in ALS [57], investigating copy number variants in ALS might be prosperous. In other neurodegenerative diseases such as Alzheimer’s dementia and Parkinson’s disease the role of copy number variants has been extensively studied with convincing positive results [71, 72].
As we have summarized these genetic risk factors show variability from one population to another, thus characterization of different populations represents huge value. Even though there is not a huge phenotype modifying effect of any of the described ALS risk factors, according on the oligogenic disease theory of ALS, these small-effect repeat expansions and CNVs might be the final straw that broke the camel’s back and led to the emergence of the disease.
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Conceptualization: ZsFN, MP, MSz. Investigation: ZsFN. Writing - Original Draft: ZsFN, MP. Writing - Review & Editing: MP, JIE, MMJ, PK, MSZ. Supervision: PK, MSz.
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Nagy, Z.F., Pál, M., Engelhardt, J.I. et al. Beyond C9orf72: repeat expansions and copy number variations as risk factors of amyotrophic lateral sclerosis across various populations. BMC Med Genomics 17, 30 (2024). https://doi.org/10.1186/s12920-024-01807-9
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DOI: https://doi.org/10.1186/s12920-024-01807-9