Beyond CAG Repeats: The Multifaceted Role of Genetics in Huntington Disease

被引:5
|
作者
Pengo, Marta [1 ]
Squitieri, Ferdinando [2 ,3 ]
机构
[1] Univ Brescia, Dept Mol & Translat Med, I-25121 Brescia, Italy
[2] Fdn Lega Italiana Ric Huntington LIRH, Ctr Neurol Rare Dis CMNR, I-00161 Rome, Italy
[3] IRCCS Casa Sollievo Sofferenza, Huntington & Rare Dis Unit, I-71013 San Giovanni Rotondo, Italy
关键词
gene modifiers; DNA mismatch repair; loss of interruption; somatic mutations; somatic instability; RNA toxicity; mtDNA; epigenetics; MITOCHONDRIAL-DNA DAMAGE; TRINUCLEOTIDE-REPEAT; MISMATCH REPAIR; RAN TRANSLATION; CTG REPEAT; EXPANSION; AGE; INSTABILITY; ONSET; POLYGLUTAMINE;
D O I
10.3390/genes15060807
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG expansion on the huntingtin (HTT) gene and is characterized by progressive motor, cognitive, and neuropsychiatric decline. Recently, new genetic factors besides CAG repeats have been implicated in the disease pathogenesis. Most genetic modifiers are involved in DNA repair pathways and, as the cause of the loss of CAA interruption in the HTT gene, they exert their main influence through somatic expansion. However, this mechanism might not be the only driver of HD pathogenesis, and future studies are warranted in this field. The aim of the present review is to dissect the many faces of genetics in HD pathogenesis, from cis- and trans-acting genetic modifiers to RNA toxicity, mitochondrial DNA mutations, and epigenetics factors. Exploring genetic modifiers of HD onset and progression appears crucial to elucidate not only disease pathogenesis, but also to improve disease prediction and prevention, develop biomarkers of disease progression and response to therapies, and recognize new therapeutic opportunities. Since the same genetic mechanisms are also described in other repeat expansion diseases, their implications might encompass the whole spectrum of these disorders.
引用
收藏
页数:15
相关论文
共 50 条
  • [41] ANTICIPATION AND INSTABILITY OF IT-15 (CAG)(N) REPEATS IN PARENT-OFFSPRING PAIRS WITH HUNTINGTON DISEASE
    RANEN, NG
    STINE, OC
    ABBOTT, MH
    SHERR, M
    CODORI, AM
    FRANZ, ML
    CHAO, NI
    CHUNG, AS
    PLEASANT, N
    CALLAHAN, C
    KASCH, LM
    GHAFFARI, M
    CHASE, GA
    KAZAZIAN, HH
    BRANDT, J
    FOLSTEIN, SE
    ROSS, CA
    AMERICAN JOURNAL OF HUMAN GENETICS, 1995, 57 (03) : 593 - 602
  • [42] A survey of (CAG)n repeats causing juvenile Huntington disease in an Iranian family with 4 affected members
    Mazdeh, Mehrdokht
    Pour-Jafari, Hamid
    Ghaleiha, Ali
    Pour-Jafari, Bita
    NEUROSCIENCES, 2009, 14 (03) : 273 - 276
  • [43] Normal CAG repeats in the Huntington gene in a family with benign familial chorea
    Meszaros, K
    Brucke, T
    Fuchs, K
    Gerhard, E
    Sieghart, W
    vanDerMeer, CH
    Aschauer, HN
    PSYCHIATRIC GENETICS, 1996, 6 (02) : 91 - 94
  • [44] Comparative semi-automated analysis of (CAG) repeats in the Huntington disease gene: use of internal standards
    Williams, LC
    Hegde, MR
    Herrera, G
    Stapleton, PM
    Love, DR
    MOLECULAR AND CELLULAR PROBES, 1999, 13 (04) : 283 - 289
  • [45] Analysis of PDE10A mutations in suspected Huntington disease patients with normal CAG repeats in Singapore
    Sonu, S. K.
    JOURNAL OF THE NEUROLOGICAL SCIENCES, 2019, 405
  • [46] Continuous and Periodic Expansion of CAG Repeats in Huntington's Disease R6/1 Mice
    Mollersen, Linda
    Rowe, Alexander D.
    Larsen, Elisabeth
    Rognes, Torbjorn
    Klungland, Arne
    PLOS GENETICS, 2010, 6 (12) : 1 - 11
  • [47] The Role of CAG Repeat Size and Parental Sex in Huntington's Disease
    Keller, Eric
    McCormack, Michael
    Hillen, Machteld
    NEUROTHERAPEUTICS, 2018, 15 (01) : 250 - 251
  • [48] The Number of CAG Repeats Within the Normal Allele Does Not Influence the Age of Onset in Huntington's Disease
    Klempir, Jin
    Zidovska, Jana
    Stochl, Jan
    Kebrdlova, Vera
    Uhrova, Tereza
    Roth, Jan
    MOVEMENT DISORDERS, 2011, 26 (01) : 125 - 129
  • [49] Sex contribution to average age at onset of Huntington's disease depends on the number of (CAG)n repeats
    Stanislawska-Sachadyn, Anna
    Krzeminski, Michal
    Zielonka, Daniel
    Krygier, Magdalena
    Zietkiewicz, Ewa
    Slawek, Jaroslaw
    Limon, Janusz
    SCIENTIFIC REPORTS, 2024, 14 (01):
  • [50] Unstable Familial Transmissions of Huntington Disease Alleles With 27-35 CAG Repeats (Intermediate Alleles)
    Semaka, A.
    Collins, J. A.
    Hayden, M. R.
    AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, 2010, 153B (01) : 314 - 320