Interrupting sequence variants and age of onset in Huntington's disease: clinical implications and emerging therapies

Wright, Galen E.B.; Black, Hailey Findlay; Collins, Jennifer A.; Gall-Duncan, Terence; Caron, Nicholas S.; Pearson, Christopher; Hayden, Michael R.

doi:10.1016/s1474-4422(20)30343-4

Cited by 54 publications

(50 citation statements)

References 82 publications

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“…The common ground for all these models is aberrant DNA structures formed by the expanded sequence, called slipped-DNAs, as intermediates of the expanded mutations [202,204,205]. Unusual non-B-DNA structures can form in vitro and in vivo at each of the unstable repeats (reviewed in [205][206][207][208][209][210]). In addition, all models of repeat instability require nucleases to Fig.…”

Section: Fan1 Variants Modify Disease By Modifying Repeat Expansionsmentioning

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: Fan1 Variants Modify Disease By Modifying Repeat Expansionsmentioning

confidence: 99%

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

Deshmukh

Porro

Mohiuddin

et al. 2021

JHD

View full text Add to dashboard Cite

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“…In conclusion, the genetic and clinical features of the populations examined in the present study were in accordance with the previous Hungarian study as well as with international literature data, except for the higher frequency of intermediate alleles and individuals with reduced penetrance alleles. The presence of these alleles is gaining importance in light of increasing evidence of disease modifying genetic factors, such as the loss of interruption variants, which have been extensively investigated in the past 2 years [ 31 , 32 ], owing to developments in analytic technologies. They are considered to cause CAG repeat length underestimation with the currently, most widely, used diagnostic methods.…”

Section: Discussionmentioning

confidence: 99%

“…They are considered to cause CAG repeat length underestimation with the currently, most widely, used diagnostic methods. Additionally, some authors suggest that these variants not only influence the age of onset, but, in individuals carrying reduced penetrance alleles, they might play a major role in the manifestation of the disease [ 31 , 32 ]. These factors have not yet been thoroughly analysed in individuals carrying intermediate alleles and presenting neurological symptoms, which could serve as a target for future studies.…”

Section: Discussionmentioning

confidence: 99%

Genetic epidemiological characteristics of a Hungarian subpopulation of patients with Huntington’s disease

et al. 2021

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Background Recent advances in therapeutic options may prevent deterioration related to Huntington’s disease (HD), even at the pre-symptomatic stage. Be that as it may, a well-characterized patient population is essential for screening and monitoring outcome. Accordingly, the aim of this study was to describe the characteristics of a Hungarian subpopulation of HD patients and mutation carriers diagnosed at the University of Szeged. Methods We conducted a search for International Classification of Diseases (ICD) code G10H0 in the local medical database for the period of 1 January 1998 to 31 December 2018. Results We identified 90 HD cases (male: 45, female: 45) and 34 asymptomatic carriers (male: 15, female: 19). The median age of onset was 45 years (range: 16–79). There were 3 cases of juvenile onset (3.3%), and 7 of late disease onset (7.8%). The median repeat length was 43 (range: 36–70) for the pathological and 19 for the non-pathological alleles (range: 9–35). 17.5% of the pathological alleles were in the decreased penetrance range, while 7% of non-pathological alleles were intermediate. Conclusions The genetic and clinical features of the population examined in the present study were in line with the previous Hungarian study, as well as with international literature. The exceptions were the higher ratio of reduced penetrance and intermediate alleles.

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“…In conclusion, the genetic and clinical features of the populations examined in the present study were in accordance with the previous Hungarian study as well as with international literature data, except for the higher frequency of intermediate alleles and individuals with reduced penetrance alleles. The presence of these alleles is gaining importance in light of increasing evidence of disease modifying genetic factors, such as the loss of interruption variants, which have been extensively investigated in the past two years [31,32], owing to developments in analytic technologies. They are considered to cause CAG repeat length underestimation with the currently, most widely, used diagnostic methods.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genetic epidemiological characteristics of a Hungarian subpopulation of patients with Huntington’s Disease

Despotov

Zádori

Veres

et al. 2021

Preprint

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Background: Recent advances in therapeutic options may prevent deterioration related to Huntington’s disease (HD), even at the pre-symptomatic stage. Be that as it may, a well-characterized patient population is essential for screening and monitoring outcome. Accordingly, the aim of this study was to describe the characteristics of a Hungarian subpopulation of HD patients and mutation carriers diagnosed at the University of Szeged. Methods: We conducted a search for International Classification of Diseases (ICD) code G10H0 in the local medical database for the period of 1 January 1998 to 31 December 2018. Results: We identified 90 HD cases (male: 45, female: 45) and 34 asymptomatic carriers (male: 15, female: 19). The median age of onset was 45 years (range: 16-79). There were 3 cases of juvenile onset (3.3%), and 7 of late disease onset (7.8%). The median repeat length was 43 (range: 36-70) for the pathological and 19 for the non-pathological alleles (range: 9-35). 17.5% of the pathological alleles were in the decreased penetrance range, while 7% of non-pathological alleles were intermediate. Conclusions: The genetic and clinical features of the population examined in the present study were in line with the previous Hungarian study, as well as with international literature. The exceptions were the higher ratio of reduced penetrance and intermediate alleles.

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Interrupting sequence variants and age of onset in Huntington's disease: clinical implications and emerging therapies

Cited by 54 publications

References 82 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

Genetic epidemiological characteristics of a Hungarian subpopulation of patients with Huntington’s disease

Genetic epidemiological characteristics of a Hungarian subpopulation of patients with Huntington’s Disease

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