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PubMed2005

Expanded repeat in canine epilepsy.

Epilepsy afflicts 1% of humans and 5% of dogs. We report a canine epilepsy mutation and evidence for the existence of repeat-expansion disease outside humans. A canid-specific unstable dodecamer repeat in the Epm2b (Nhlrc1) gene recurrently expands, causing a fatal epilepsy and contributing to the high incidence of canine epilepsy. Tracing the repeat origins revealed two successive events, starting 50 million years ago, unique to canid evolution. A genetic test, presented here, will allow carrier and presymptomatic diagnosis and disease eradication. Clinicopathologic characterization establishes affected animals as a model for Lafora disease, the most severe teenage-onset human epilepsy.

Alleles↗
PubMed2025

Prevalence of intronic repeat expansions in the RFC1 gene in Polish patients with cerebellar syndrome.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited neurodegenerative ataxic disorder, which has been associated with intronic biallelic repeat expansions in the RFC1 gene. Our objective was to assess retrospectively the prevalence of CANVAS in Polish population. We screened 2523 Polish patients in whom other repeat expansions were excluded. To determine the repeat expansions in the RFC1 gene in patients, we performed RFC1-flanking PCR and repeat primed PCR (RP-PCR) and to measure the size of the expansion we used Southern blotting and optical genome mapping to compare the results. We have observed the biallelic pathogenic motif/unit AAGGG expansions in 4.6% and expansions of non-pathogenic motifs AAAAG, AAAGG in 25% patients of our studied population. This is the first large-scale cohort study that confirms the relatively frequent occurrence of the CANVAS in Polish population. To increase the current diagnostics of late-onset ataxias within an unexplained molecular background, we suggest involving the RFC1 repeat expansions analysis to the routine diagnostic workflow.

Humans↗
PubMed2003

Repeat expansion and autosomal dominant neurodegenerative disorders: consensus and controversy.

Repeat-expansion mutations cause 13 autosomal dominant neurodegenerative disorders falling into three groups. Huntington's disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxias (SCAs) types 1, 2, 3, 7 and 17 are each caused by a CAG repeat expansion that encodes polyglutamine. Convergent lines of evidence demonstrate that neurodegeneration in these diseases is a consequence of the neurotoxic effects of abnormally long stretches of glutamines. How polyglutamine induces neurodegeneration, and why neurodegeneration occurs in only select neuronal populations, remains a matter of intense investigation. SCA6 is caused by a CAG repeat expansion in CACNA1A, a gene that encodes a subunit of the P/Q-type calcium channel. The threshold length at which the repeat causes disease is much shorter than in the other polyglutamine diseases, and neurodegeneration may arise from expansion-induced change of function in the calcium channel. Huntington's disease-like 2 (HDL2) and SCAs 8, 10 and 12 are rare disorders in which the repeats (CAG, CTG or ATTCT) are not in protein-coding regions. Investigation into these diseases is still at an early stage, but it is now reasonable to hypothesise that the net effect of each expansion is to alter gene expression. The different pathogenic mechanisms in these three groups of diseases have important implications for the development of rational therapeutics.

Chromosome Disorders↗
PubMed2026

Altered neuronal start codon stringency favors cap-independent repeat-associated non-AUG translation.

Intronic GGGGCC repeat expansions in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This expansion supports a non-canonical form of translational initiation known as repeat-associated non-AUG (RAN) translation to produce toxic dipeptide repeat proteins that contribute to neurodegeneration. Here, we find that the efficiency of RAN translation and its dependency on the 5' 7-methylguanosine mRNA cap are variable across cell types, with both rodent neurons and human iNeurons favoring cap-independent RAN translation from two distinct repeats (CGG and GGGGCC) across multiple reading frames. Treatment with an eIF4E inhibitor that blocks cap-dependent translation enhances RAN translation specifically in neurons. Intriguingly, cap-independent RAN translation exhibits less reliance on near-cognate codons for initiation than cap-dependent RAN translation. This finding led us to identify a surprising global alteration in neuronal start codon stringency as a contributor to the relatively higher cap-independent RAN translation in this cell type. This effect correlates with cytoplasmic redistribution of eIF1 in neurons and is reversed with overexpression of the eukaryotic initiation factor eIF5, which relaxes start codon stringency and preferentially enhances cap-dependent RAN translation. Together, these findings reveal several neuron-specific features of translational regulation that favor cap-independent RAN translation with implications for nucleotide repeat expansion disorder pathogenesis.

Neurons↗
PubMed2025

nf-core/pacvar: a pipeline for analyzing long-read PacBio whole genome and repeat expansion sequencing data.

MOTIVATION: Pacific Biosciences (PacBio) single-molecule, long-read sequencing enables whole genome annotation and the characterization of 20 complex repetitive repeat regions, especially relevant to neurodegenerative diseases, through their PureTarget panel. Long-read whole-genome sequencing (WGS) also allows for the detection of structural variants that would be difficult to detect with traditional short-read sequencing. However, the raw unaligned Binary Alignment Map data need to be processed before analysis. There is a need for an intuitive comprehensive bioinformatic pipeline that can analyze these data. RESULTS: We present nf-core/pacvar, a comprehensive pipeline for analyzing both PacBio single-molecule PureTarget and WGS data that demultiplexes and parallelizes pre-processing, variant calling and repeat characterization. nf-core/pacvar is compatible with little configuration and has few dependencies. This pipeline enables rapid end-to-end, parallel processing of PacBio single-molecule whole genome and targeted repeat expansion sequencing. AVAILABILITY AND IMPLEMENTATION: nf-core/pacvar is available on nf-core website (https://nf-co.re/pacvar/) and on github (https://github.com/nf-core/pacvar) under MIT License (DOI: 10.5281/zenodo.14813048).

Software↗
PubMed2006

Transcriptional alterations and chromatin remodeling in polyglutamine diseases.

Transcriptional dysregulation is now thought to be a common feature of polyglutamine disorders, including the spinocerebellar ataxias (SCAs). However, the precise causes of transcriptional alterations and how they relate to the observed phenotype remain elusive. Transcriptional impairment differs in different diseases, possibly reflecting the specific functions of the disease-causing proteins. The SCA7 gene product, ataxin-7, is a subunit of a transcriptional coactivator complex (called STAGA or TFTC) that has histone acetyltransferase activity. Studies on the effect of mutant ataxin-7 on STAGA function suggest that chromatin remodeling and transcriptional alterations are key pathologic events in SCA type 7. These studies could reveal how polyglutamine expansions alter the transcriptional regulation of genes required for neuronal function.

Animals↗
PubMed2025

First clinical diagnosis of FAME3 via commercial Long-Read sequencing reveals mosaic repeat expansion in MARCHF6 gene.

Familial Adult Myoclonic Epilepsy type 3 (FAME3) is a rare autosomal dominant disorder characterized by cortical tremor and epilepsy, caused by a noncoding pentanucleotide repeat expansion (TTTTA/TTTCA)n in the MARCHF6 gene. Conventional genetic testing often fails to detect this expansion due to its repetitive structure and intronic location. We evaluated a 61-year-old woman with refractory myoclonic and generalized tonic-clonic seizures, whose prior genetic testing-including exome and genome sequencing-was non-diagnostic. Using PacBio HiFi long-read whole-genome sequencing and the tandem repeat genotyping tool TRGT, we identified a pathogenic MARCHF6 intronic expansion. The proband harbored one allele with 15 TTTTA repeats and a second allele with a compound expansion of 661 TTTTA and 12 TTTCA repeats. Three affected relatives shared similarly expanded alleles, but with increasing repeat size in the latter generations. Importantly, analysis using TRGT-instability revealed repeat mosaicism in all affected individuals, reflected by variability in motif counts across individual sequencing reads. This somatic heterogeneity may contribute to the phenotypic penetrance, variable expressivity and pleiotropism seen in FAME3 disease expression. To our knowledge, this is the first clinical diagnosis of FAME3 using a commercially available long-read sequencing platform, underscoring its diagnostic utility in resolving complex repeat expansion disorders and uncovering biologically relevant mosaicism.

Humans↗
PubMed2006

Mechanisms of tandem repeat instability in bacteria.

Hypermutable tandem repeat sequences (TRSs) are present in the genomes of both prokaryotic and eukaryotic organisms. Numerous studies have been conducted in several laboratories over the past decade to investigate the mechanisms responsible for expansions and contractions of microsatellites (a subset of TRSs with a repeat length of 1-6 nucleotides) in the model prokaryotic organism Escherichia coli. Both the frequency of tandem repeat instability (TRI), and the types of mutational events that arise, are markedly influenced by the DNA sequence of the repeat, the number of unit repeats, and the types of cellular pathways that process the TRS. DNA strand slippage is a general mechanism invoked to explain instability in TRSs. Misaligned DNA sequences are stabilized both by favorable base pairing of complementary sequences and by the propensity of TRSs to form relatively stable secondary structures. Several cellular processes, including replication, recombination and a variety of DNA repair pathways, have been shown to interact with such structures and influence TRI in bacteria. This paper provides an overview of our current understanding of mechanisms responsible for TRI in bacteria, with an emphasis on studies that have been carried out in E. coli. In addition, new experimental data are presented, suggesting that TLS polymerases (PolII, PolIV and PolV) do not contribute significantly to TRI in E. coli.

Base Sequence↗
PubMed2006

Genetic background modifies nuclear mutant huntingtin accumulation and HD CAG repeat instability in Huntington's disease knock-in mice.

Genetically precise models of Huntington's disease (HD), Hdh CAG knock-in mice, are powerful systems in which phenotypes associated with expanded HD CAG repeats are studied. To dissect the genetic pathways that underlie such phenotypes, we have generated Hdh(Q111) knock-in mouse lines that are congenic for C57BL/6, FVB/N and 129Sv inbred genetic backgrounds and investigated four Hdh(Q111) phenotypes in these three genetic backgrounds: the intergenerational instability of the HD CAG repeat and the striatal-specific somatic HD CAG repeat expansion, nuclear mutant huntingtin accumulation and intranuclear inclusion formation. Our results reveal increased intergenerational and somatic instability of the HD CAG repeat in C57BL/6 and FVB/N backgrounds compared with the 129Sv background. The accumulation of nuclear mutant huntingtin and the formation of intranuclear inclusions were fastest in the C57BL/6 background, slowest in the 129Sv background and intermediate in the FVB/N background. Inbred strain-specific differences were independent of constitutive HD CAG repeat size and did not correlate with Hdh mRNA levels. These data provide evidence for genetic modifiers of both intergenerational HD CAG repeat instability and striatal-specific phenotypes. Different relative contributions of C57BL/6 and 129Sv genetic backgrounds to the onset of nuclear mutant huntingtin and somatic HD CAG repeat expansion predict that the initiation of each of these two phenotypes is modified by different genes. Our findings set the stage for defining disease-related genetic pathways that will ultimately provide insight into disease mechanism.

Animals↗
PubMed2004

Homozygosity for CCTG mutation in myotonic dystrophy type 2.

Myotonic dystrophy type 2 (DM2) is caused by a dominantly transmitted CCTG repeat expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene on chromosome 3q. DM2 patients with two mutant alleles have not been reported so far. In one large consanguineous family from Afghanistan, we found three homozygotes for the DM2 mutation. The oldest patient was clinically more severely affected, compared with the two younger homozygotes, but for the clinical course of symptoms all three homozygotes were within the range expected for heterozygotes. Further investigations, such as mutation repeat length, muscle histology, anti-muscleblind-like 1 stainings or brain imaging studies, at least at short-term observation, showed no differences between heterozygotes and homozygotes. Twenty of 24 children, aged 2-21 years, were available for clinical examination. None of these children have signs or symptoms of disease until the age of 18 years. Homozygosity for the DM2 expansion does not seem to alter the disease phenotype as compared with the heterozygous state.

Adolescent↗
PubMed2005

Effect of the [CCTG]n repeat expansion on ZNF9 expression in myotonic dystrophy type II (DM2).

Myotonic dystrophy is caused by two different mutations: a (CTG)n expansion in 3' UTR region of the DMPK gene (DM1) and a (CCTG)n expansion in intron 1 of the ZNF9 gene (DM2). The most accredited mechanism for DM pathogenesis is an RNA gain-of-function. Other findings suggest a contributory role of DMPK-insufficiency in DM1. To address the issue of ZNF9 role in DM2, we have analyzed the effects of (CCTG)n expansion on ZNF9 expression in lymphoblastoid cell lines (n=4) from DM2 patients. We did not observe any significant alteration in ZNF9 mRNA and protein levels, as shown by QRT-PCR and Western blot analyses. Additional RT-PCR experiments demonstrated that ZNF9 pre-mRNA splicing pattern, which includes two isoforms, is unmodified in DM2 cells. Our results indicate that the (CCTG)n expansion in the ZNF9 intron does not appear to have a direct consequence on the expression of the gene itself.

Base Sequence↗
PubMed2004

Clinical and genetic analysis of a family with PROMM.

PROMM (proximal myotonic myopathy) and DM2 (myotonic dystrophy Type 2) are autosomal dominant multisystem disorders that have both been linked to chromosome 3q. Recently, the genetic basis of DM2 has been defined by a '(CCTG)(n)' expansion mutation in intron 1 of the ZNF9 gene. We identified and studied a multigenerational family in which five members had clinical features consistent with PROMM. Two affected members were available for detailed clinical, electrophysiological, radiological and genetic analysis. Our study confirms that the PROMM phenotype is associated with DM2-(CCTG)(n) expansion mutations. In addition, our results may extend the clinical spectrum of manifestations to include vestibular symptoms.

DNA Mutational Analysis↗
PubMed2005

HnRNP H inhibits nuclear export of mRNA containing expanded CUG repeats and a distal branch point sequence.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disorder associated with a (CUG)n expansion in the 3'-untranslated region of the DMPK (DM1 protein kinase) gene. Mutant DMPK mRNAs containing the trinucleotide expansion are retained in the nucleus of DM1 cells and form discrete foci. The nuclear sequestration of RNA binding proteins and associated factors binding to the CUG expansions is believed to be responsible for several of the splicing defects observed in DM1 patients and could ultimately be linked to DM1 muscular pathogenesis. Several RNA binding proteins capable of co-localizing with the nuclear-retained mutant DMPK mRNAs have already been identified but none can account for the nuclear retention of the mutant transcripts. Here, we have employed a modified UV crosslinking assay to isolate proteins bound to mutant DMPK-derived RNA and have identified hnRNP H as an abundant candidate. The specific binding of hnRNP H requires not only a CUG repeat expansion but also a splicing branch point distal to the repeats. Suppression of hnRNP H expression by RNAi rescued nuclear retention of RNA with CUG repeat expansions. The identification of hnRNP H as a factor capable of binding and possibly modulating nuclear retention of mutant DMPK mRNA may prove to be an important link in our understanding of the molecular mechanisms that lead to DM1 pathogenesis.

3' Untranslated Regions↗
PubMed2007

Multiple system atrophy in a patient with the spinocerebellar ataxia 3 gene mutation.

The cerebellar variant of multiple system atrophy (MSA-C) has overlapping clinical features with the hereditary spinocerebellar ataxias (SCAs), but can usually be distinguished on a clinical basis. We describe a patient who developed a sporadic, late-onset, rapidly progressive neurodegenerative disorder consistent with MSA-C. Genetic testing, however, showed an abnormal expansion of one allele of the spinocerebellar ataxia 3 (SCA3) gene. The clinical impression of MSA-C was confirmed by identification of numerous alpha-synuclein-containing glial cytoplasmic inclusions on autopsy. These findings suggest that abnormal expansion of the SCA3 gene may be a risk factor for the development of MSA-C.

Alleles↗
PubMedDate not supplied

Biomolecular identification of (CCTG)n mutation in myotonic dystrophy type 2 (DM2) by FISH on muscle biopsy.

Myotonic dystrophy type 2 (DM2) is a dominantly inherited disorder with multisystemic clinical features, caused by a CCTG repeat expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene. The mutant transcripts are retained in the nucleus forming multiple discrete foci also called ribonuclear inclusions. The size and the somatic instability of DM2 expansion complicate the molecular diagnosis of DM2. In our study fluorescence-labeled CAGG-repeat oligonucleotides were hybridized to muscle biopsies to investigate if fluorescence in situ hybridization (FISH), a relatively quick and simple procedure, could be used as a method to diagnose DM2. When FISH was performed with (CAGG)5 probe, nuclear foci of mutant RNA were present in all genetically confirmed DM2 patients (n=17) and absent in all patients with myotonic dystrophy type 1 (DM1; n=5) or with other muscular disease (n=17) used as controls. In contrast, foci were observed both in DM1 and DM2 myonuclei when muscle tissue were hybridized with (CAG)6CA probe indicating that this probe is not specific for DM2 identification. The consistent detection of ribonuclear inclusions in DM2 muscles and their absence in DM1, in agreement with the clinical diagnosis and with leukocyte (CCTG)n expansion, suggests that fluorescence in situ hybridization using (CAGG)5 probes, may be a specific method to distinguish between DM1 and DM2. Moreover, the procedure is simple, and readily applicable in any pathology laboratory.

Adult↗
PubMed2003

Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum.

BACKGROUND: Myotonic dystrophy types 1 (DM1) and 2 (DM2/proximal myotonic myopathy PROMM) are dominantly inherited disorders with unusual multisystemic clinical features. The authors have characterized the clinical and molecular features of DM2/PROMM, which is caused by a CCTG repeat expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene. METHODS: Three-hundred and seventy-nine individuals from 133 DM2/PROMM families were evaluated genetically, and in 234 individuals clinical and molecular features were compared. RESULTS: Among affected individuals 90% had electrical myotonia, 82% weakness, 61% cataracts, 23% diabetes, and 19% cardiac involvement. Because of the repeat tract's unprecedented size (mean approximately 5,000 CCTGs) and somatic instability, expansions were detectable by Southern analysis in only 80% of known carriers. The authors developed a repeat assay that increased the molecular detection rate to 99%. Only 30% of the positive samples had single sizeable expansions by Southern analysis, and 70% showed multiple bands or smears. Among the 101 individuals with single expansions, repeat size did not correlate with age at disease onset. Affected offspring had markedly shorter expansions than their affected parents, with a mean size difference of -17 kb (-4,250 CCTGs). CONCLUSIONS: DM2 is present in a large number of families of northern European ancestry. Clinically, DM2 resembles adult-onset DM1, with myotonia, muscular dystrophy, cataracts, diabetes, testicular failure, hypogammaglobulinemia, and cardiac conduction defects. An important distinction is the lack of a congenital form of DM2. The clinical and molecular parallels between DM1 and DM2 indicate that the multisystemic features common to both diseases are caused by CUG or CCUG expansions expressed at the RNA level.

Adolescent↗
PubMed2026

RFC1 Repeat Expansions in Chronic Idiopathic Axonal Polyneuropathy: Prevalence, Phenotype, and Diagnostic Implications.

BACKGROUND AND AIMS: Chronic idiopathic axonal polyneuropathy (CIAP) accounts for approximately 20%-30% of adult-onset axonal polyneuropathies. Pathogenic RFC1 repeat expansions have emerged as a frequent cause of idiopathic sensory neuropathy, but their recognition in routine clinical practice may be challenging, particularly in the presence of potentially confounding comorbidities. We aimed to determine the prevalence of pathogenic RFC1 repeat expansions in a well-defined CIAP cohort, characterize the associated clinical and electrophysiological phenotype, and evaluate whether coexisting well-controlled diabetes mellitus (DM) or monoclonal gammopathy of undetermined significance (MGUS) may hinder recognition of RFC1-related neuropathy. METHODS: We performed a retrospective observational study of adult patients with CIAP followed at a tertiary neuromuscular unit. All patients underwent RFC1 genetic testing. Clinical and electrophysiological features were compared between RFC1+ and RFC1- patients in the full cohort and after exclusion of patients with DM or MGUS. RESULTS: Ninety patients met CIAP criteria and were analyzed. Twenty-four (27%) carried biallelic pathogenic AAGGG repeat expansions in RFC1, of whom 6 (25%) had coexisting DM or MGUS. Compared with RFC1- patients, RFC1+ individuals more frequently exhibited dysautonomic symptoms, unsteadiness, history of falls, need for walking support, chronic cough, impaired vibration sense in the upper limbs and up to the knees in the lower limbs, brisk upper-limb reflexes, mild cerebellar signs, an abnormal head-impulse test, and a positive Romberg's test. Most of these differences persisted after exclusion of DM or MGUS. Electrophysiological studies in RFC1+ patients showed widespread sensory nerve involvement, including the upper limbs, with relative motor sparing, whereas RFC1- patients exhibited a more typical length-dependent pattern. INTERPRETATION: Biallelic AAGGG repeat expansions in RFC1 were identified in 27% of patients with CIAP. Specific clinical and electrophysiological features may help distinguish RFC1-related disease from other forms of CIAP and identify candidates for genetic testing, even in the presence of potentially confounding comorbidities such as well-controlled DM or MGUS.

Humans↗