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Results for “driver mutations”

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PubMed2026

Co-Occurring EGFR L858R Mutation and HER2 Amplification in NSCLC Identified by Stepwise Molecular Profiling.

BACKGROUND The coexistence of multiple oncogenic drivers in non-small cell lung cancer (NSCLC) is a rare and diagnostically challenging molecular configuration. Conventional polymerase chain reaction (PCR)-based testing may fail to detect co-occurring genomic alterations, potentially limiting therapeutic options, particularly in resource-constrained settings. CASE REPORT We describe the case of a 54-year-old non-smoking woman diagnosed with Stage IIIA lung adenocarcinoma in 2020. Initial PCR-based molecular testing was negative for EGFR mutations. Following disease progression with brain metastases and severe chemotherapy toxicity, stepwise molecular profiling in a resource-limited setting identified HER2 (ERBB2) amplification via fluorescence in situ hybridization (FISH). The patient achieved 23 months of clinical and radiological stabilization on trastuzumab. Subsequent next-generation sequencing (NGS) analysis of archived tissue revealed a previously undetected estimated glomular filtration rate (EGFR) L858R mutation. In late April 2025, new lesions appeared in the lungs, indicating disease progression. Based on the previously verified EGFR L858R mutation, the treatment strategy was revised and gefitinib was initiated in May 2025. CONCLUSIONS This case illustrates that co-occurring EGFR and HER2 alterations can remain undetected following initial limited molecular testing, and that stepwise molecular profiling in a resource-constrained setting can facilitate identification of therapeutically actionable targets. The sequential clinical responses observed are consistent with the biological relevance of both alterations, although broader conclusions regarding diagnostic strategy or driver hierarchy cannot be drawn from a single observation.

Humans↗

PubMed2026

Differential contributions of mt-Tr and Cs variants to developmental cochlear defects and mitochondrial dysfunction in A/J mice.

A/J mice exhibit early-onset hearing loss linked to Cdh23, mitochondrial tRNA-Arg (mt-Tr), and citrate synthase (Cs) variants. Although developmental cochlear defects have been identified in juvenile A/J mice, the hierarchical contributions of mt-Tr versus Cs remain unclear. Using reciprocal intercross-derived strains to decouple mitochondrial haplotypes from nuclear factors, we demonstrate that the mitochondrial background is the primary determinant of auditory dysfunction. Mice with A/J mtDNA (AXB strains) displayed significantly higher ABR thresholds, accelerated hair cell attrition, and severe stereocilia dysmorphology compared to those with B6 mtDNA (BXA strains), occurring largely independently of the Cs genotype. While the Cs mutation exacerbated hearing loss, its impact was secondary to that of the dominant mitochondrial background. Systemic behavioral assessments and mitochondrial assays confirmed that A/J mitochondria exert a more profound metabolic impact than the Cs mutation. Our findings establish that the mitochondrial genomic background, with the mt-Tr locus as a prominent candidate variant, serves as the principal driver of developmental cochlear defects and early-onset hearing loss in A/J mice, while the nuclear Cs mutation acts as a synergistic modifier. This study underscores the critical role of mitonuclear crosstalk in inner ear maturation and provides new insights into the etiology of hereditary hearing loss.

Animals↗

PubMed2025

Mutant RIT1 cooperates with YAP to drive an EMT-like lung cancer state.

Mutations in "Ras-like in all tissues" (RIT1) occur in up to 2% of lung adenocarcinomas and are mutually exclusive with KRAS and EGFR mutations, suggesting that RIT1 may act as a non-canonical driver oncogene in lung cancer. However, the lack of a RIT1-mutant lung cancer model has hindered the development and testing of RIT1-targeted therapeutics. Here, we report a mouse model with conditional regulation of the cancer-associated RIT1M90I variant. We show that autochthonous expression of RIT1M90I and combined inactivation of Nf2 and p53 drives an aggressive lung cancer with 100% penetrance and short latency. Oncogenic cooperation between RIT1M90I and p53/Nf2 loss is driven by synergistic activation of AP-1 transcription factors and can be reversed by the combined inhibition of MEK and TEAD. These data identify YAP/TEAD as a mediator of RIT1's oncogenic capability and nominate TEAD as a potential drug target in RIT1-mutant lung cancer.

Animals↗

PubMed2025

Investigating the genomic landscape of mouse models of breast cancer metastasis.

Metastasis remains a major cause of cancer mortality. AbstractThis study, expanding upon previous findings in the MMTV-PyMT model, investigated four independent mouse models, representing luminal (MMTV-PyMT, MMTV-Myc), HER2-amplified (MMTV-Her2) and triple negative (C3(1)TAg) breast cancer subtypes. Consistent with previous results, limited evidence for metastasis-associated somatic point mutations was found for all models. We also found that oncogenic drivers significantly influenced the number and size of metastasis-specific copy number variations (MSCNVs), but common driver-independent MSCNVs were rare. Furthermore, analyzing a cohort with varying genetic backgrounds while maintaining a constant oncogenic driver (PyMT) revealed that genetic background profoundly impacts MSCNVs. Transcriptome analysis demonstrated that oncogenic drivers strongly shaped metastasis-specific gene expression (MSGE), with each driver exhibiting distinct expression profiles. In contrast, MSGE in the PyMT-F1 cohort was more variable across strains. Despite the diversity of MSCNV and MSGE, functional analysis revealed that both mechanisms converge on the modulation of key cellular processes, including immune responses, metabolism, and extracellular matrix interactions. These findings emphasize the complex interplay between oncogenic drivers and genetic background in shaping the genomic and transcriptional landscapes of metastatic lesions.

Journal Article↗

PubMed2006

IL-1 beta breaks tolerance through expansion of CD25+ effector T cells.

IL-1 is a key proinflammatory driver of several autoimmune diseases including juvenile inflammatory arthritis, diseases with mutations in the NALP/cryopyrin complex and Crohn's disease, and is genetically or clinically associated with many others. IL-1 is a pleiotropic proinflammatory cytokine; however the mechanisms by which increased IL-1 signaling promotes autoreactive T cell activity are not clear. Here we show that autoimmune-prone NOD and IL-1 receptor antagonist-deficient C57BL/6 mice both produce high levels of IL-1, which drives autoreactive effector cell expansion. IL-1beta drives proliferation and cytokine production by CD4(+)CD25(+)FoxP3(-) effector/memory T cells, attenuates CD4(+)CD25(+)FoxP3(+) regulatory T cell function, and allows escape of CD4(+)CD25(-) autoreactive effectors from suppression. Thus, inflammation or constitutive overexpression of IL-1beta in a genetically predisposed host can promote autoreactive effector T cell expansion and function, which attenuates the ability of regulatory T cells to maintain tolerance to self.

Animals↗

PubMed2026

Telomere Crisis Shapes Cancer Evolution.

Somatic mutations arise in normal tissues and precursor lesions, often targeting cancer-driver genes involved in cell cycle regulation. Most checkpoint-mutant clones, however, remain dormant throughout an individual's lifetime and seldom progress to malignancy, implying the presence of protective mechanisms that limit their expansion and malignant transformation. One such safeguard is telomere crisis-a potent tumor-suppressive barrier that eliminates cells lacking functional checkpoints and evading p53- and pRb-mediated surveillance. While the genomic instability unleashed during telomere crisis can drive clonal evolution, cell death is typically the dominant outcome, with only a rare subset of cells escaping elimination to initiate malignancy. Recognizing the dual role of telomere crisis-suppressing tumor initiation while enabling clonal evolution-is essential for understanding early cancer development and designing strategies to eliminate tumor-initiating cells.

Neoplasms↗

PubMed2006

Decreased internalisation of erbB1 mutants in lung cancer is linked with a mechanism conferring sensitivity to gefitinib.

A majority of gefitinib (IRESSA)-responsive tumours in non-small cell lung cancer have been found to carry mutations in ErbB1. Previously, it has been observed that internalisation-deficient ErbB1 receptors are strong drivers of oncogenesis. Using a computational model of ErbB1 trafficking and signalling, it is found that a deficiency in ErbB1 internalisation is sufficient to explain the observed signalling phenotype of these gefitinib-responsive ErbB1 mutants in lung cancer cell lines. Experimental tests confirm that gefitinib-sensitive cell lines with and without ErbB1 mutations exhibit markedly slower internalisation rates than gefitinib-insensitive cell lines. Moreover, the computational model demonstrates that reduced ErbB1 internalisation rates are mechanistically linked to upregulated AKT signalling. Experimentally it is confirmed that impaired internalisation of ErbB1 is associated with increased AKT activity, which can be blocked by gefitinib. On the basis of these experimental and computational results, it is surmised that gefitinib sensitivity is a marker of a reliance on AKT signalling for cell survival that may be brought about by impaired ErbB1 internalisation.

Antineoplastic Agents↗

PubMed2026

Landscape of genetic alterations affecting cancer genes in primary and advanced malignant phyllodes tumours.

BACKGROUND: Malignant phyllodes tumours (MPT) are aggressive breast fibroepithelial neoplasms. Their rarity has limited their genetic characterization, and associations with genetic ancestry and progression drivers remain poorly understood. Prior studies suggest two evolutionary pathways according to MED12 mutational status. We sought to determine the repertoire of somatic genetic alterations in cancer genes in primary versus metastatic/recurrent MPTs, and according to MED12 mutational status and genetic ancestry. MATERIALS AND METHODS: We analysed the paired tumour-normal targeting sequencing data (up to 505 cancer-related genes) of 31 MPTs (primary, n = 20; metastatic/recurrent, n = 11). RESULTS: Metastatic/recurrent MPTs harboured a numerically higher frequency of genetic alterations in CDKN2A/2B (55% vs. 25%). Moreover, analysis of an MPT case with paired primary and metastatic samples revealed a CDKN2A/2B homozygous deletion restricted to the metastatic sample, suggesting a role for CDKN2A/2B in progression. Compared with MED12-wild type MPTs, MED12-mutant MPTs had higher tumour mutation burden (P = 0.002), frequency of TERT promoter (82% vs. 35%; P = 0.02) and RB1 mutations (45% vs. 5%; P = 0.01). Genetic alterations in the PI3K pathway, including PIK3CA and PTEN, were only present in MED12-wild type MPTs, and absent in MED12-mutant cases (15% vs. 0%; P > 0.05). Furthermore, genetic alterations in EGFR were restricted to MPTs from patients of European genetic ancestry and absent in those of Asian ancestry (43% vs. 0%; P > 0.05). CONCLUSIONS: Taken together, the repertoire of genetic alterations in primary and metastatic/recurrent MPTs shows overlap, and CDKN2A/2B homozygous deletions may play a role in progression. Additionally, molecular profiles of MPTs may vary according to genetic ancestry and MED12 mutational status.

Humans↗

PubMed2026

HLA class I escape drives the evolution of SARS-CoV-2 in human populations.

The role of escape from the cytotoxic T cell (CTL) response in Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) evolution remains controversial. Here, we study the origin and spread of SARS-CoV-2 variants whose mutations reduce presentation by the human leukocyte antigen (HLA) class I alleles common in human populations. We find that 35% of mutations that are characteristic of the variants of concern, and 39% of all subsequent viral mutations, facilitate escape of viral epitopes from presentation. Mutations allowing escape from more common HLA alleles reach higher frequencies, particularly in those countries where these HLA alleles are more frequent, indicating that escape is selected by the local genetic composition of the human host population. We also show that viral mutations that accumulated in general-population transmission chains matched population HLA class I allele frequencies as well as, or better than, mutations acquired during persistent infections, suggesting that selection in favor of escape mutations is not limited to immunocompromised individuals. Together, these data reveal CTL escape as a facet of selection, a driver of evolution, and an epidemiological concern for SARS-CoV-2.

Humans↗

PubMed2026

Integrated clinicogenomic analysis reveals the evolution and metastatic tropisms of advanced colorectal cancer.

We performed an integrated clinical and genomic analysis of over 7,000 consecutively sequenced colorectal cancer (CRC) samples to comprehensively characterize genetic drivers and metastatic tropisms of CRC. We find that genomic evolutionary changes, such as clonal mutations and oncogenic mutant allelic imbalance, selectively enhance the impact of recurrent oncogenic alterations. We identify the relative timing of organ-specific metastasis, showing sequential metastatic progression in microsatellite stable CRC with brain and adrenal metastases as late events; metastatic sites that cluster together, such as lung, bone, and brain metastases; and genomic events that enhance or decrease risk for each metastatic site, with WNT pathway activation as overall protective while RAS pathway activation increased risk for spread to all metastatic sites. Our data suggest that despite the heterogeneity in CRC, genomic evolution increases the impact of recurrent alterations, and integrating information about tumor primary location and genomics can be used to predict organ-specific metastasis risk.

Humans↗

PubMed2005

The purine synthesis gene Prat2 is required for Drosophila metamorphosis, as revealed by inverted-repeat-mediated RNA interference.

PRAT (phosphoribosylamidotransferase; E.C. 2.4.2.14) catalyzes the first reaction in de novo purine nucleotide biosynthesis. In Drosophila melanogaster, the Prat and Prat2 genes are both highly conserved with PRAT sequences from prokaryotes and eukaryotes. However, Prat2 organization and expression during development is different from Prat. We used RNA interference (RNAi) to knock down expression of both Prat and Prat2 to investigate their functions. Using the GAL4-UAS system, Prat RNAi driven by Act5c-GAL4 or tubP-GAL4 causes variable pupal lethality (48-100%) and approximately 50% female sterility, depending on the transgenic strains and drivers used. This observation agrees with the phenotype previously observed for Prat EMS-induced mutations. Prat2 RNAi driven by Act5C-GAL4 or tubP-GAL4 also results in variable pupal lethality (61-93%) with the different transgenic strains, showing that Prat2 is essential for fly development. However, Prat2 RNAi-induced arrested pupae have a head eversion defect reminiscent of the "cryptocephal" phenotype, whereas Prat RNAi-induced arrested pupae die later as pharate adults. We conclude that Prat2 is required during the prepupal stage while Prat is more important for the pupal stage. In addition, Prat and Prat2 double RNAi results in more severe pupal lethal phenotypes, suggesting that Prat and Prat2 have partially additive functions during Drosophila metamorphosis.

Amidophosphoribosyltransferase↗

PubMed2024

The Genetic Determinants and Genomic Consequences of Non-Leukemogenic Somatic Point Mutations.

Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as point mutations or mosaic chromosomal alterations (mCAs) in genes associated with hematologic malignancy, are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic lesions. To characterize CH without known driver genetic lesions, we used 51,399 deeply sequenced whole genomes from the NHLBI TOPMed sequencing initiative to perform simultaneous germline and somatic mutation analyses among individuals without leukemogenic point mutations (LPM), which we term CH-LPMneg. We quantified CH by estimating the total mutation burden. Because estimating somatic mutation burden without a paired-tissue sample is challenging, we developed a novel statistical method, the Genomic and Epigenomic informed Mutation (GEM) rate, that uses external genomic and epigenomic data sources to distinguish artifactual signals from true somatic mutations. We performed a genome-wide association study of GEM to discover the germline determinants of CH-LPMneg. After fine-mapping and variant-to-gene analyses, we identified seven genes associated with CH-LPMneg (TCL1A, TERT, SMC4, NRIP1, PRDM16, MSRA, SCARB1), and one locus associated with a sex-associated mutation pathway (SRGAP2C). We performed a secondary analysis excluding individuals with mCAs, finding that the genetic architecture was largely unaffected by their inclusion. Functional analyses of SMC4 and NRIP1 implicated altered HSC self-renewal and proliferation as the primary mediator of mutation burden in blood. We then performed comprehensive multi-tissue transcriptomic analyses, finding that the expression levels of 404 genes are associated with GEM. Finally, we performed phenotypic association meta-analyses across four cohorts, finding that GEM is associated with increased white blood cell count and increased risk for incident peripheral artery disease, but is not significantly associated with incident stroke or coronary disease events. Overall, we develop GEM for quantifying mutation burden from WGS without a paired-tissue sample and use GEM to discover the genetic, genomic, and phenotypic correlates of CH-LPMneg.

Journal Article↗

PubMed2003

Increased plasma homocysteine levels in shift working bus drivers.

BACKGROUND: Previous studies have indicated an association between shift work and cardiovascular disease. There is also considerable epidemiological evidence that hyperhomocysteinemia is an independent risk factor for cardiovascular disorders. AIMS: To analyse plasma homocysteine levels in shift work bus drivers, and to investigate possible relations with sleep parameters and other biochemical factors. METHODS: Blood samples were collected from 30 male shift working long-haul bus drivers in a Brazilian sample and analysed for plasma levels of homocysteine, folic acid, vitamin B(12), and serum lipids. A group of 22 daytime workers, matched for age and body mass index served as controls. The incidence of mutations in the gene coding for methylene tetrahydrofolate, an enzyme which is related to hyperhomocysteinemia, was also assessed. Polysomnographic recordings were obtained from the target group. RESULTS: Bus drivers showed significantly higher levels of plasma homocysteine than the control group (18.57 v 9.43 micro M). Most of the other biochemical, behavioural, and molecular parameters did not differ between groups. Likewise, sleep parameters appeared to be within the normal range. CONCLUSIONS: The significantly increased plasma homocysteine levels in long-haul bus drivers did not appear to be secondary to other biochemical or behavioural problems in this group. These results suggest that hyperhomocysteinemia may be involved in the increased incidence of cardiovascular diseases observed in shift workers.

Adult↗

PubMed2026

Mutation timing, accumulation, and selection in the male germline shape inheritance risk for developmental disorders.

De novo mutations (DNMs) in the paternal germline are a major cause of developmental disorders, but how mutation timing, paternal age, and spermatogonial selection jointly shape transmissible risk within individual fathers is unclear. We combined trio whole-genome sequencing from 167 families with deep targeted NanoSeq profiling of sperm from 127 fathers of children with confirmed pathogenic DNMs. Transmitted DNM burden and paternal sperm mutation burden, spectra, and selection landscape were indistinguishable from population reference cohorts. Six fathers carried pathogenic early mosaic variants detectable in sperm at variant allele fractions (VAFs) of 0.7%-14.8%, creating individual recurrence-risk outliers. However, early mosaics accounted for ∼8% of the cohort-aggregated pathogenic burden exome-wide, compared with ∼18% from known positively selected drivers and ∼74% from other rare variants accumulating with paternal age. Thus, paternal de novo disease risk is shaped primarily by universal age-associated mutation and selection, while early mosaicism creates uncommon but clinically important high-risk individuals.

DNMs↗

PubMed2002

Molecular and genetic toxicology of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).

The heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), formed when meat containing food is cooked, induces cancer of the colon, prostate and mammary gland of rats, tumours that are strongly associated with a Western diet. After consumption of a meat meal, PhIP is rapidly absorbed, metabolised and bioactivated to DNA damaging species. Thus, PhIP should be considered as a candidate etiological agent for human cancer. Studies in vitro in model mammalian cell culture systems, and in vivo in transgenic animals, have shown that mutation induced by PhIP is dose dependent and describes a mutational "fingerprint" that is characteristic of the chemical. This genetic toxicity is dependent upon CYP1 family metabolic activation and is detectable in these model systems at micro M concentrations. At early time points, PhIP treated cells show subtle signs of toxicity that lead to altered growth and cycling. Using co-culture systems where one cell line bioactivates PhIP with a second cell line as target, we showed in human lymphoblastoid target cells that PhIP induced a dose- and time-dependent S-phase delay of the cell cycle. With time, the cell population became increasingly apoptotic with remaining survivors carrying a mutated gene set. Transcript profiling of treated cells indicated differential expression of genes involved in cell cycle regulation, stress response, receptors and tumour related genes. Prominent was elevation of p21(cip1/waf1) transcript and Western blot analysis confirmed induction of p21(cip1/waf1) and p53 proteins. The dose dependency and temporal aspects of these changes indicate that manipulation of the cell cycle and growth in response to PhIP is a precursor to mutant selection. Reduction of the PhIP dose allows dissection of a different battery of cellular responses that favour cell growth rather than inhibition. This pro-growth stimulus is oestrogen-like and encompasses altered gene expression, proliferation and cell behaviour. In human breast cell lines, these PhIP-mediated pro-oestrogenic responses are inhibited by the anti-oestrogen ICI 182780. This range of molecular and genetic responses induced in cells by PhIP is quite remarkable. Its ability to activate S-phase cell cycle checkpoint, alter gene expression leading to apoptosis and an increased frequency of mutation are probably direct consequences of its genetic toxicity. In contrast, its pro-oestrogenic activity is likely to be a driver of clonal expansion. We suggest that these PhIP-induced genomic and cellular events contrive to manipulate cell cycle and survival. Understanding these molecular processes as well as the genetic toxicology of the chemical will help to define the involvement of PhIP in carcinogenesis and shed light upon its tissue specificity.

Animals↗

PubMed2025

A prognostic signature for lung adenocarcinoma in people who have never smoked.

Knowledge of tumor cell dynamics can inform prognosis and treatment yet is largely lacking for lung adenocarcinoma in people who have never smoked (NS-LUAD). With RNA-seq data from 684 NS-LUAD and validation in an independent dataset, we identified three subtypes with distinct phenotypic traits and cell compositions. Additional genomic and histological data further characterized the subtypes. 'Steady', marked by low proliferation, high alveolar cell fraction, moderate-to-well differentiation, and fewer driver genes' alterations, is linked to prolonged survival and low immune evasion. 'Proliferative' shows high proliferation markers, TP53 mutations, and gene fusions. 'Chaotic', with high epithelial-to-mesenchymal transition markers, has the worst prognosis even within stage I tumors. Lacking known molecular or histological characteristics, this aggressive subtype is solely identified by transcriptomic data. A 60-gene signature recapitulates the overall classification and strongly predicts survival even within subgroups based on tumor stage or known genomic features, emphasizing its potential for improving NS-LUAD prognostication in clinical settings.

Journal Article↗

PubMed2025

Phylogenomic signatures of repeat-induced point mutations across the fungal kingdom.

Fungal genome sizes exhibit more than a 100-fold variation, largely driven by the expansion of repetitive sequences such as transposable elements (TEs). Silencing mechanisms targeting TEs at the epigenetic or transcript level have independently evolved in many lineages. In fungi, repeat-induced point mutation (RIP) targets TEs by recognizing repetitive sequences and inducing mutagenesis. However, the prevalence of RIP across the fungal kingdom and the fidelity of the canonical C-to-T mutation signatures remain unclear. In this study, we address these gaps by tracking shifts in genome architecture across the fungal kingdom. We find that a striking approximately 30-fold increase in genome size within a clade of leotiomycetes is associated with the absence of several RIP-related genes, suggesting a relaxation of genome defense mechanisms during this expansion. To track the impact of genome defenses, we designed a quantitative screen for RIP-like mutation signatures. The phylum of ascomycetes was unique in showing enrichment in mutation signatures in non-coding and repetitive sequences, consistent with a phylogenetically restricted occurrence of RIP-like genome defense systems. Then, we performed a phylogeny-aware association study to identify gene functions associated with RIP-like mutation signatures. We identified a zinc-finger protein as the strongest candidate underpinning a novel mechanism of genome defenses. Our findings reveal the multifaceted drivers of genome defense systems and their close ties to genome size evolution in fungi, particularly in lineages with evidence for recent RIP activity, highlighting how proximate molecular mechanisms can shape genome evolution on deep phylogenetic scales.

Genome, Fungal↗

PubMed1994

The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function.

Some transcription factors contain stretches of polyglutamine encoded by repeats of the trinucleotide CAG. Expansion of the CAG repeat in the androgen receptor (AR) has been correlated with the incidence and severity of X-linked spinal and bulbar muscular atrophy (Kennedy's disease). In order to understand the relationship of this mutation to AR function, we constructed ARs that varied in the position and size of the polyglutamine tract, and assayed for the abilities of these mutant receptors to bind androgen and to activate transcription of several different AR-responsive reporter genes. Elimination of the tract in both human and rat AR resulted in elevated transcriptional activation activity, strongly suggesting that the presence of the polyglutamine tract is inhibitory to transactivation. Progressive expansion of the CAG repeat in human AR caused a linear decrease of transactivation function. Importantly, expansion of the tract did not completely eliminate AR activity. We postulate that this residual AR activity may be sufficient for development of male primary and secondary sex characteristics, but may fall below a threshold level of activity necessary for normal maintenance of motor neuron function. This functional abnormality may be representative of other genetic diseases that are associated with CAG expansion mutations in open reading frames, such as spinocerebellar ataxia type I and Huntington's disease.

Animals↗