scholarly journals The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

2021 ◽  
Vol 10 (1) ◽  
pp. 7-33
Author(s):  
Darren G. Monckton
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Human Genetics ◽  
Age At Onset ◽  
Cag Repeat ◽  
Model Systems ◽  
Causative Mutation ◽  
Inverse Association ◽  
Independent Manner ◽  
Dna Mismatch

The discovery in the early 1990s of the expansion of unstable simple sequence repeats as the causative mutation for a number of inherited human disorders, including Huntington’s disease (HD), opened up a new era of human genetics and provided explanations for some old problems. In particular, an inverse association between the number of repeats inherited and age at onset, and unprecedented levels of germline instability, biased toward further expansion, provided an explanation for the wide symptomatic variability and anticipation observed in HD and many of these disorders. The repeats were also revealed to be somatically unstable in a process that is expansion-biased, age-dependent and tissue-specific, features that are now increasingly recognised as contributory to the age-dependence, progressive nature and tissue specificity of the symptoms of HD, and at least some related disorders. With much of the data deriving from affected individuals, and model systems, somatic expansions have been revealed to arise in a cell division-independent manner in critical target tissues via a mechanism involving key components of the DNA mismatch repair pathway. These insights have opened new approaches to thinking about how the disease could be treated by suppressing somatic expansion and revealed novel protein targets for intervention. Exciting times lie ahead in turning these insights into novel therapies for HD and related disorders.

scholarly journals New developments in Huntington’s disease and other triplet repeat diseases: DNA repair turns to the dark side

2020 ◽  
Vol 4 (4) ◽  
Author(s):  
Robert S. Lahue
Keyword(s):  
Dna Repair ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cag Repeat ◽  
Model Systems ◽  
Triplet Repeat ◽  
Maximal Effect ◽  
Huntingtin Protein ◽  
Dna Repair Proteins ◽  
Repeat Expansions

Abstract Huntington’s disease (HD) is a fatal, inherited neurodegenerative disease that causes neuronal death, particularly in medium spiny neurons. HD leads to serious and progressive motor, cognitive and psychiatric symptoms. Its genetic basis is an expansion of the CAG triplet repeat in the HTT gene, leading to extra glutamines in the huntingtin protein. HD is one of nine genetic diseases in this polyglutamine (polyQ) category, that also includes a number of inherited spinocerebellar ataxias (SCAs). Traditionally it has been assumed that HD age of onset and disease progression were solely the outcome of age-dependent exposure of neurons to toxic effects of the inherited mutant huntingtin protein. However, recent genome-wide association studies (GWAS) have revealed significant effects of genetic variants outside of HTT. Surprisingly, these variants turn out to be mostly in genes encoding DNA repair factors, suggesting that at least some disease modulation occurs at the level of the HTT DNA itself. These DNA repair proteins are known from model systems to promote ongoing somatic CAG repeat expansions in tissues affected by HD. Thus, for triplet repeats, some DNA repair proteins seem to abandon their normal genoprotective roles and, instead, drive expansions and accelerate disease. One attractive hypothesis—still to be proven rigorously—is that somatic HTT expansions augment the disease burden of the inherited allele. If so, therapeutic approaches that lower levels of huntingtin protein may need blending with additional therapies that reduce levels of somatic CAG repeat expansions to achieve maximal effect.

Dementia due to Huntington’s disease

2020 ◽  
pp. 448-453
Author(s):  
Russell L. Margolis
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Psychiatric Symptoms ◽  
Cag Repeat ◽  
Causative Mutation ◽  
Clinical Onset ◽  
Key Features ◽  
Neurobiological Research ◽  
Clinical Triad ◽  
Near Future

Huntington’s disease (HD), first described in 1872, is perhaps the prototypical hereditary dementia and movement disorder. Key features include autosomal dominant inheritance, typically mid-life clinical onset, and a clinical triad of abnormal voluntary and involuntary movements, subcortical dementia, and psychiatric symptoms. The disease progresses inevitably, with death typically 15–20 years after onset. Neurodegeneration is most prominent in the striatum and cerebral cortex. The discovery of the causative mutation, an expanded CAG repeat in the gene huntingtin, has led to the development of reliable genetic testing for affected and at-risk individuals and an explosion of neurobiological research into HD pathogenesis. While present treatment of HD is limited to managing symptoms, there is considerable optimism that treatments to prevent, slow, or stop disease progression may be feasible in the near future.

scholarly journals Promotion of somatic CAG repeat expansion by Fan1 knock-out in Huntington’s disease knock-in mice is blocked by Mlh1 knock-out

2020 ◽  
Vol 29 (18) ◽  
pp. 3044-3053 ◽  
Author(s):  
Jacob M Loupe ◽  
Ricardo Mouro Pinto ◽  
Kyung-Hee Kim ◽  
Tammy Gillis ◽  
Jayalakshmi S Mysore ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Genetic Interaction ◽  
Age At Onset ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Genome Wide Association Studies ◽  
Knock Out ◽  
Cag Repeat Expansion ◽  
Dna Instability

Abstract Recent genome-wide association studies of age-at-onset in Huntington’s disease (HD) point to distinct modes of potential disease modification: altering the rate of somatic expansion of the HTT CAG repeat or altering the resulting CAG threshold length-triggered toxicity process. Here, we evaluated the mouse orthologs of two HD age-at-onset modifier genes, FAN1 and RRM2B, for an influence on somatic instability of the expanded CAG repeat in Htt CAG knock-in mice. Fan1 knock-out increased somatic expansion of Htt CAG repeats, in the juvenile- and the adult-onset HD ranges, whereas knock-out of Rrm2b did not greatly alter somatic Htt CAG repeat instability. Simultaneous knock-out of Mlh1, the ortholog of a third HD age-at-onset modifier gene (MLH1), which suppresses somatic expansion of the Htt knock-in CAG repeat, blocked the Fan1 knock-out-induced acceleration of somatic CAG expansion. This genetic interaction indicates that functional MLH1 is required for the CAG repeat destabilizing effect of FAN1 loss. Thus, in HD, it is uncertain whether the RRM2B modifier effect on timing of onset may be due to a DNA instability mechanism. In contrast, the FAN1 modifier effects reveal that functional FAN1 acts to suppress somatic CAG repeat expansion, likely in genetic interaction with other DNA instability modifiers whose combined effects can hasten or delay onset and other CAG repeat length-driven phenotypes.

Correlations between molecular and clinical data in Huntington's disease and implications for predictive testing

1995 ◽  
Vol 7 (1) ◽  
pp. 7-12
Author(s):  
S. Claes ◽  
M. Decruyenaere ◽  
R. Dom ◽  
M. Malfroid ◽  
G. Evers-Kiebooms ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Clinical Data ◽  
Human Genetics ◽  
Age At Onset ◽  
Genetic Defect ◽  
Biological Marker ◽  
Predictive Testing ◽  
Testing Procedure ◽  
Autosomal Dominant Disorder

SummaryHuntington's disease (HD) is an autosomal dominant disorder of the central nervous system, characterised by neurological, cognitive and psychiatric pathology. Recently the causative genetic defect was discovered. We present a retrospective study of 59 HD patients, investigating correlations between molecular and clinical data.The correlation between CAG-repeatlength and age at onset is confirmed. No correlations between this biological marker and other clinical features are found (symptoms at onset, mode of progression of the disease).The consequences of these findings for predictive testing are discussed. Furthermore, a short overview of the predictive testing procedure in the Center for Human Genetics in Leuven (Belgium) is given.

scholarly journals Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases

2017 ◽  
Vol 114 (52) ◽  
pp. E11293-E11302 ◽  
Author(s):  
Renee R. Handley ◽  
Suzanne J. Reid ◽  
Rudiger Brauning ◽  
Paul Maclean ◽  
Emily R. Mears ◽  
...  
Keyword(s):  
Human Brain ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Cag Repeat ◽  
Causative Mutation ◽  
Striatal Neurons ◽  
Psychological Disturbance ◽  
Postmortem Human Brain ◽  
Sheep Model

The neurodegenerative disorder Huntington’s disease (HD) is typically characterized by extensive loss of striatal neurons and the midlife onset of debilitating and progressive chorea, dementia, and psychological disturbance. HD is caused by a CAG repeat expansion in the Huntingtin (HTT) gene, translating to an elongated glutamine tract in the huntingtin protein. The pathogenic mechanism resulting in cell dysfunction and death beyond the causative mutation is not well defined. To further delineate the early molecular events in HD, we performed RNA-sequencing (RNA-seq) on striatal tissue from a cohort of 5-y-old OVT73-line sheep expressing a human CAG-expansion HTT cDNA transgene. Our HD OVT73 sheep are a prodromal model and exhibit minimal pathology and no detectable neuronal loss. We identified significantly increased levels of the urea transporter SLC14A1 in the OVT73 striatum, along with other important osmotic regulators. Further investigation revealed elevated levels of the metabolite urea in the OVT73 striatum and cerebellum, consistent with our recently published observation of increased urea in postmortem human brain from HD cases. Extending that finding, we demonstrate that postmortem human brain urea levels are elevated in a larger cohort of HD cases, including those with low-level neuropathology (Vonsattel grade 0/1). This elevation indicates increased protein catabolism, possibly as an alternate energy source given the generalized metabolic defect in HD. Increased urea and ammonia levels due to dysregulation of the urea cycle are known to cause neurologic impairment. Taken together, our findings indicate that aberrant urea metabolism could be the primary biochemical disruption initiating neuropathogenesis in HD.

scholarly journals Somatic CAG expansion in Huntington’s disease is dependent on the MLH3 endonuclease domain, which can be excluded via MLH3 splice redirection to suppress expansion

2020 ◽  
Author(s):  
Jennie C. L. Roy ◽  
Antonia Vitalo ◽  
Marissa A. Andrew ◽  
Eduarda Mota-Silva ◽  
Marina Kovalenko ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mismatch Repair ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Peripheral Tissues ◽  
Dna Mismatch ◽  
Cag Expansion ◽  
Endonuclease Domain ◽  
Primary Fibroblasts

AbstractSomatic expansion of the CAG repeat tract that causes Huntington’s disease (HD) is thought to contribute to the rate of disease pathogenesis. Therefore, factors influencing repeat expansion are potential therapeutic targets. Genes in the DNA mismatch repair pathway are critical drivers of somatic expansion in HD mouse models. Here, we have tested, using genetic and pharmacological approaches, the role of the endonuclease domain of the mismatch repair protein MLH3 in somatic CAG expansion in HD mice and patient cells. A point mutation in the MLH3 endonuclease domain completely eliminated CAG expansion in the brain and peripheral tissues of a HD knock-in mouse model (HttQ111). To test whether the MLH3 endonuclease could be manipulated pharmacologically, we delivered splice switching oligonucleotides in mice to redirect Mlh3 splicing to exclude the endonuclease domain. Splice redirection to an isoform lacking the endonuclease domain was associated with reduced CAG expansion. Finally, CAG expansion in HD patient-derived primary fibroblasts was also significantly reduced by redirecting MLH3 splicing to the endogenous endonuclease domain-lacking isoform. These data indicate the potential of targeting the MLH3 endonuclease domain to slow somatic CAG repeat expansion in HD, a therapeutic strategy that may be applicable across multiple repeat expansion disorders.

scholarly journals FAN1 nuclease activity affects CAG expansion and age at onset of Huntington’s disease

2021 ◽  
Author(s):  
Branduff McAllister ◽  
Jasmine Donaldson ◽  
Caroline S. Binda ◽  
Sophie Powell ◽  
Uroosa Chughtai ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cell Model ◽  
Association Studies ◽  
Age At Onset ◽  
Nuclease Activity ◽  
Cag Repeat ◽  
Genome Wide Association Studies ◽  
Knock Out ◽  
Cag Expansion

SummaryThe age at onset of motor symptoms in Huntington’s disease (HD) is driven by HTT CAG repeat length but modified by other genes. We used exome sequencing of 683 HD patients with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We identified damaging coding variants in candidate modifier genes from prior genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier onset HD. Nuclease activities of these variants correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion comparable to those observed with complete FAN1 knock out. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.

scholarly journals A critical window of CAG repeat-length correlates with phenotype severity in the R6/2 mouse model of Huntington's disease

2012 ◽  
Vol 107 (2) ◽  
pp. 677-691 ◽  
Author(s):  
Damian M. Cummings ◽  
Yasaman Alaghband ◽  
Miriam A. Hickey ◽  
Prasad R. Joshi ◽  
S. Candice Hong ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Age At Onset ◽  
Human Condition ◽  
Repeat Length ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Drug Trials ◽  
Electrophysiological Properties

The R6/2 mouse is the most frequently used model for experimental and preclinical drug trials in Huntington's disease (HD). When the R6/2 mouse was first developed, it carried exon 1 of the huntingtin gene with ∼150 cytosine-adenine-guanine (CAG) repeats. The model presented with a rapid and aggressive phenotype that shared many features with the human condition and was particularly similar to juvenile HD. However, instability in the CAG repeat length due to different breeding practices has led to both decreases and increases in average CAG repeat lengths among colonies. Given the inverse relationship in human HD between CAG repeat length and age at onset and to a degree, the direct relationship with severity of disease, we have investigated the effect of altered CAG repeat length. Four lines, carrying ∼110, ∼160, ∼210, and ∼310 CAG repeats, were examined using a battery of tests designed to assess the basic R6/2 phenotype. These included electrophysiological properties of striatal medium-sized spiny neurons, motor activity, inclusion formation, and protein expression. The results showed an unpredicted, inverted “U-shaped” relationship between CAG repeat length and phenotype; increasing the CAG repeat length from 110 to 160 exacerbated the R6/2 phenotype, whereas further increases to 210 and 310 CAG repeats greatly ameliorated the phenotype. These findings demonstrate that the expected relationship between CAG repeat length and disease severity observed in humans is lost in the R6/2 mouse model and highlight the importance of CAG repeat-length determination in preclinical drug trials that use this model.

scholarly journals What is the Pathogenic CAG Expansion Length in Huntington’s Disease?

2021 ◽  
Vol 10 (1) ◽  
pp. 175-202
Author(s):  
Jasmine Donaldson ◽  
Sophie Powell ◽  
Nadia Rickards ◽  
Peter Holmans ◽  
Lesley Jones
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Confidence Intervals ◽  
Age At Onset ◽  
Cag Repeat ◽  
Genetic Modifiers ◽  
Tract Length ◽  
Cag Expansion ◽  
Age Dependent ◽  
Step Mechanism

Huntington’s disease (HD) (OMIM 143100) is caused by an expanded CAG repeat tract in the HTT gene. The inherited CAG length is known to expand further in somatic and germline cells in HD subjects. Age at onset of the disease is inversely correlated with the inherited CAG length, but is further modulated by a series of genetic modifiers which are most likely to act on the CAG repeat in HTT that permit it to further expand. Longer repeats are more prone to expansions, and this expansion is age dependent and tissue-specific. Given that the inherited tract expands through life and most subjects develop disease in mid-life, this implies that in cells that degenerate, the CAG length is likely to be longer than the inherited length. These findings suggest two thresholds— the inherited CAG length which permits further expansion, and the intracellular pathogenic threshold, above which cells become dysfunctional and die. This two-step mechanism has been previously proposed and modelled mathematically to give an intracellular pathogenic threshold at a tract length of 115 CAG (95% confidence intervals 70– 165 CAG). Empirically, the intracellular pathogenic threshold is difficult to determine. Clues from studies of people and models of HD, and from other diseases caused by expanded repeat tracts, place this threshold between 60– 100 CAG, most likely towards the upper part of that range. We assess this evidence and discuss how the intracellular pathogenic threshold in manifest disease might be better determined. Knowing the cellular pathogenic threshold would be informative for both understanding the mechanism in HD and deploying treatments.

Sign in / Sign up

Export Citation Format

Share Document