Evidence for an oligogenic basis of amyotrophic lateral sclerosis

Article (PDF Available)inHuman Molecular Genetics 21(17):3776-84 · May 2012with54 Reads
DOI: 10.1093/hmg/dds199 · Source: PubMed
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a substantial heritable component. In pedigrees affected by its familial form, incomplete penetrance is often observed. We hypothesized that this could be caused by a complex inheritance of risk variants in multiple genes. Therefore, we screened 111 familial ALS (FALS) patients from 97 families, and large cohorts of sporadic ALS (SALS) patients and control subjects for mutations in TAR DNA-binding protein (TARDBP), fused in sarcoma/translated in liposarcoma (FUS/TLS), superoxide dismutase-1 (SOD1), angiogenin (ANG) and chromosome 9 open reading frame 72 (C9orf72). Mutations were identified in 48% of FALS families, 8% of SALS patients and 0.5% of control subjects. In five of the FALS families, we identified multiple mutations in ALS-associated genes. We detected FUS/TLS and TARDBP mutations in combination with ANG mutations, and C9orf72 repeat expansions with TARDBP, SOD1 and FUS/TLS mutations. Statistical analysis demonstrated that the presence of multiple mutations in FALS is in excess of what is to be expected by chance (P = 1.57 × 10−7). The most compelling evidence for an oligogenic basis was found in individuals with a p.N352S mutation in TARDBP, detected in five FALS families and three apparently SALS patients. Genealogical and haplotype analyses revealed that these individuals shared a common ancestor. We obtained DNA of 14 patients with this TARDBP mutation, 50% of whom had an additional mutation (ANG, C9orf72 or homozygous TARDBP). Hereby, we provide evidence for an oligogenic aetiology of ALS. This may have important implications for the interpretation of whole exome/genome experiments designed to identify new ALS-associated genes and for genetic counselling, especially of unaffected family members.

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    • "This hypothesis is exemplified in lineages containing inherited mutations that display incomplete penetrance in phenotypically normal family members, where affected individuals possess risk factor variants in multiple genes. Such oligogenic variants have the potential to influence the neuropathology or phenotype of a more dominant mutation in ALS/FTD, as has been evidenced in several cases [14, 15, 86, 87]. This effect is now recognised in the context of several other diseases [6, 60, 77, 95]. "
    [Show abstract] [Hide abstract] ABSTRACT: Disruptions to genes linked to RNA processing and homeostasis are implicated in the pathogenesis of two pathologically related but clinically heterogeneous neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations in the Fused-in-Sarcoma (FUS) gene encoding a 526 amino-acid RNA-binding protein are found in a small subset of ALS cases, but FUS mutations do not appear to be a direct cause of FTD. Structural and functional similarities between FUS and another ALS-related RNA-binding protein, TDP-43, highlight the potential importance of aberrant RNA processing in ALS/FTD, and this pathway is now a major focus of interest. Recently, several research groups have reported transgenic vertebrate models of FUSopathy, with varying results. Here, we discuss the evidence for FUS pathogenicity in ALS/FTD, review the experimental approaches used and phenotypic features of FUS rodent models reported to date, and outline their contribution to our understanding of pathogenic mechanisms. Further refinement of vertebrate models will likely aid our understanding of the role of FUS in both diseases.
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    • "These results suggest that the sole loss of C9ORF72 or the expression of GGGGCC RNA and DPR in isolation is not sufficient to be pathogenic, but it remains to test whether a reduced expression of C9ORF72 would synergize the toxicity of GGGGCC RNA or DPRs. This synergic model is consistent with the absence of ALS/FTD patients with null alleles or missense mutations in C9ORF72, as well as by increasing genetic evidences of oligogenicity in ALS-FTD (Ferrari et al, 2012; Van Blitterswijk et al, 2012; van Blitterswijk et al, 2013; Cady et al, 2015; Lattante et al, 2015a; Pottier et al, 2015). In conclusion, our results support a double-hit mechanism in ALS-FTD, where the sole decreased expression of C9ORF72 does not explain alone the pathogenicity of the expanded GGGGCC repeats but may synergize other stress such as Ataxin-2 with intermediate polyQ length, while association with other stress such as GGGGCC RNA foci or Ran-translated DPRs remains to be formally tested. "
    [Show abstract] [Hide abstract] ABSTRACT: An intronic expansion ofGGGGCCrepeats within the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). Ataxin-2 with intermediate length of polyglutamine expansions (Ataxin-2 Q30x) is a genetic modifier of the disease. Here, we found that C9ORF72 forms a complex with theWDR41 andSMCR8 proteins to act as aGDP/GTPexchange factor forRAB8a andRAB39b and to thereby control autophagic flux. Depletion of C9orf72 in neurons partly impairs autophagy and leads to accumulation of aggregates ofTDP-43 and P62 proteins, which are histopathological hallmarks ofALS-FTDSMCR8 is phosphorylated byTBK1 and depletion ofTBK1 can be rescued by phosphomimetic mutants ofSMCR8 or by constitutively activeRAB39b, suggesting thatTBK1,SMCR8, C9ORF72, andRAB39b belong to a common pathway regulating autophagy. While depletion of C9ORF72 only has a partial deleterious effect on neuron survival, it synergizes with Ataxin-2 Q30x toxicity to induce motor neuron dysfunction and neuronal cell death. These results indicate that partial loss of function of C9ORF72 is not deleterious by itself but synergizes with Ataxin-2 toxicity, suggesting a double-hit pathological mechanism inALS-FTD.
    Article · Apr 2016
    • "incomplete family history collection and the incomplete penetrance described for some mutations (Andersen and Al-Chalabi 2011; van Blitterswijk, et al. 2012). "
    [Show abstract] [Hide abstract] ABSTRACT: Rapid advances in the genetics of amyotrophic lateral sclerosis (ALS) have dramatically changed the approach of clinicians and researchers to the motor neuron diseases. We report two siblings in whom the genetic study provided conflicting results, hence raising a number of issues which deserve to be considered by clinicians involved in genetic testing for ALS. The first patient died within 2 years of ALS onset, while her brother still manages to walk unaided, 7 years into onset. Genetic analyses, performed on the first patient as part of a research protocol, and as clinical genetic testing on the brother, provided different results. Results for Patient 1 were negative for all investigated genes, thus suggesting that her disease may be a phenocopy, while her brother carried an autosomal dominant TARDBP mutation (p.A382T). A multidisciplinary approach may help patients and clinicians face the emerging dilemmas in such a complex field. Sharing and updating of advances, not to mention uncertainties inherent to current knowledge, with patients and families may prove to be an effective way to support them and to make them aware of the present limits of our knowledge and of the blurred border between research and clinical practice.
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