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

Donaldson, Jasmine; Powell, Sophie; Rickards, Nadia; Holmans, Peter; Jones, Lesley

doi:10.3233/jhd-200445

Cited by 41 publications

(27 citation statements)

References 277 publications

(240 reference statements)

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“…Such diseases include HD (OMIM#143100), spinocerebellar ataxia type 1 (SCA1 OMIM#164400), SCA2 (OMIM#183090), SCA3 (OMIM#109150), SCA6 (OMIM#183086), SCA7 (OMIM#164500), SCA17 (OMIM#607136), and others. The age of onset of symptoms correlates with the length of the inherited CAG tract at the disease locus [132]. For the same inherited CAG size a broad range of onset age can occur, but less so within a given family [133], suggesting genetic modifiers of disease onset, independent of CAG tract size, must exist.…”

Section: Genetic Modifiers Of Cag/polyq Expansion Disease Onsetmentioning

confidence: 99%

FAN1, a DNA Repair Nuclease, as a Modifier of Repeat Expansion Disorders

Deshmukh

Porro

Mohiuddin

et al. 2021

JHD

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FAN1 encodes a DNA repair nuclease. Genetic deficiencies, copy number variants, and single nucleotide variants of FAN1 have been linked to karyomegalic interstitial nephritis, 15q13.3 microdeletion/microduplication syndrome (autism, schizophrenia, and epilepsy), cancer, and most recently repeat expansion diseases. For seven CAG repeat expansion diseases (Huntington’s disease (HD) and certain spinocerebellar ataxias), modification of age of onset is linked to variants of specific DNA repair proteins. FAN1 variants are the strongest modifiers. Non-coding disease-delaying FAN1 variants and coding disease-hastening variants (p.R507H and p.R377W) are known, where the former may lead to increased FAN1 levels and the latter have unknown effects upon FAN1 functions. Current thoughts are that ongoing repeat expansions in disease-vulnerable tissues, as individuals age, promote disease onset. Fan1 is required to suppress against high levels of ongoing somatic CAG and CGG repeat expansions in tissues of HD and FMR1 transgenic mice respectively, in addition to participating in DNA interstrand crosslink repair. FAN1 is also a modifier of autism, schizophrenia, and epilepsy. Coupled with the association of these diseases with repeat expansions, this suggests a common mechanism, by which FAN1 modifies repeat diseases. Yet how any of the FAN1 variants modify disease is unknown. Here, we review FAN1 variants, associated clinical effects, protein structure, and the enzyme’s attributed functional roles. We highlight how variants may alter its activities in DNA damage response and/or repeat instability. A thorough awareness of the FAN1 gene and FAN1 protein functions will reveal if and how it may be targeted for clinical benefit.

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Section: Genetic Modifiers Of Cag/polyq Expansion Disease Onsetmentioning

confidence: 99%

FAN1, a DNA Repair Nuclease, as a Modifier of Repeat Expansion Disorders

Deshmukh

Porro

Mohiuddin

et al. 2021

JHD

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“…The autosomal-dominant neurodegenerative disorder Huntington’s disease (HD) is caused by the expansion of a CAG repeat tract at the 5′ of the huntingtin gene above a critical threshold of ~35 repeats 1 . CAG tract expansion corresponds to an expanded polyglutamine tract of the Huntingtin (HTT) protein, which functions aberrantly compared to its unexpanded form 2 .…”

Section: Introductionmentioning

confidence: 99%

Huntingtin structure is orchestrated by HAP40 and shows a polyglutamine expansion-specific interaction with exon 1

et al. 2021

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Huntington’s disease results from expansion of a glutamine-coding CAG tract in the huntingtin (HTT) gene, producing an aberrantly functioning form of HTT. Both wildtype and disease-state HTT form a hetero-dimer with HAP40 of unknown functional relevance. We demonstrate in vivo and in cell models that HTT and HAP40 cellular abundance are coupled. Integrating data from a 2.6 Å cryo-electron microscopy structure, cross-linking mass spectrometry, small-angle X-ray scattering, and modeling, we provide a near-atomic-level view of HTT, its molecular interaction surfaces and compacted domain architecture, orchestrated by HAP40. Native mass spectrometry reveals a remarkably stable hetero-dimer, potentially explaining the cellular inter-dependence of HTT and HAP40. The exon 1 region of HTT is dynamic but shows greater conformational variety in the polyglutamine expanded mutant than wildtype exon 1. Our data provide a foundation for future functional and drug discovery studies targeting Huntington’s disease and illuminate the structural consequences of HTT polyglutamine expansion.

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“…Somatic instability in the cortex in HD brains is a predictor of age of onset 63 and increases with age 66 . Recently, it has been observed that individuals who lack a CAA interruption in the CAG repeat have a significantly earlier age of onset in HD as well as increased somatic instability 58 , 59 , 60 , 67 . Somatic instability is often linked to an altered DNA damage response.…”

Section: Somatic Instability and Dna Handling In Hdmentioning

confidence: 99%

“…* Line may have a slightly different name depending on the study or publication. ** The CAG repeat size listed here is an estimate of the number of contiguous CAG triplets and does not include CAA interruptions, which are likely to occur and have been identified in human 58 , 59 and mouse models 60 . *** To generate this list, we focused on the most prominent phenotypes reported between 2012 and 2022.…”

Section: Introductionmentioning

confidence: 99%

Huntington’s disease iPSC models—using human patient cells to understand the pathology caused by expanded CAG repeats

Kaye¹,

Reisine²,

Finkbeiner³

2022

Fac Rev

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A major advance in the study of Huntington’s disease (HD) has been the development of human disease models employing induced pluripotent stem cells (iPSCs) derived from patients with HD. Because iPSCs provide an unlimited source of cells and can be obtained from large numbers of HD patients, they are a uniquely valuable tool for investigating disease mechanisms and for discovering potential disease-modifying therapeutics. Here, we summarize some of the important findings in HD pathophysiology that have emerged from studies of patient-derived iPSC lines. Because they retain the genome and actual disease mutations of the patient, they provide a cell source to investigate genetic contributions to the disease. iPSCs provide advantages over other disease models. While iPSC-based technology erases some epigenetic marks, newly developed transdifferentiation methods now let us investigate epigenetic factors that control expression of mutant huntingtin (mHTT). Human HD iPSC lines allow us to investigate how endogenous levels of mHTT affect cell health, in contrast to other models that often rely on overexpressing the protein. iPSCs can be differentiated into neurons and other disease-related cells such as astrocytes from different brain regions to study brain regional differences in the disease process, as well as the cell-cell dependencies involved in HD-associated neurodegeneration. They also serve as a tissue source to investigate factors that impact CAG repeat instability, which is involved in regional differences in neurodegeneration in the HD brain. Human iPSC models can serve as a powerful model system to identify genetic modifiers that may impact disease onset, progression, and symptomatology, providing novel molecular targets for drug discovery.

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

Cited by 41 publications

References 277 publications

FAN1, a DNA Repair Nuclease, as a Modifier of Repeat Expansion Disorders

FAN1, a DNA Repair Nuclease, as a Modifier of Repeat Expansion Disorders

Huntingtin structure is orchestrated by HAP40 and shows a polyglutamine expansion-specific interaction with exon 1

Huntington’s disease iPSC models—using human patient cells to understand the pathology caused by expanded CAG repeats

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