Table 2.
Characteristics of selected disease-causing repeat loci.
| Neurological abnormalities | Disease | Gene | Repeat sequence | Somatic expansion | DNA repair factors involved in diseases | Replication and repair pathways | Neurological abnormalities caused by impaired pathways |
|---|---|---|---|---|---|---|---|
| Autism; Intellectual Disability (ID) Syndrome (Hagerman et al., 2017) | Fragile X syndrome/ ataxia syndrome | FMR1 | CGG | M, H | N | mRNA translation | N |
| Action tremor; Bradykinesia; Cerebellar signs, including ataxia; Hyperreflexia; Paucity of movement; Babinski present; Decreased tone; Psychiatric symptoms; Focal dystonia; Dementia; Incontinence (Klockgether et al., 2019) | Spinocerebellar ataxia 12 | PPP2R2B | CAG | Rare | PP2A | • NHEJ (Wang et al., 2009) • HR (Ambjørn et al., 2021) |
A-T (Li et al., 2012; Teive et al., 2015): Movement disorders and motor disturbances; Cerebellar ataxia; Oculo-cutaneous telangiectasia |
| Focal atrophy; Motor neuron degeneration; Muscle weakness; Paralysis (Abramzon et al., 2020) | Frontotemporal dementia and amyotrophic lateral sclerosis | C9ORF72 | GGGGCC | H | • TP53 (Maor-Nof et al., 2021) • P62, RNA Pol (Haeusler et al., 2014) • ATM (Walker et al., 2017) |
oxidative stress DNA repair (Lopez-Gonzalez et al., 2016; Yuva-Aydemir et al., 2018) | HD (Hyeon et al., 2021): Motor impairment; Cognitive impairment; Depression; Anxiety AD (Shen et al., 2021): Dementia |
| Ataxia; Choreoathetosis; Dementia (Sugiyama et al., 2020) | Dentatorubral-pallidoluysian atrophy | ATN1 | CAG | H, M | • P21 • P62 |
NHEJ (Deguise et al., 2016) | N |
| Involuntary movement; Cognitive impairment; Depression; Anxiety, Neuropsychiatric changes, Physical pain (Underwood et al., 2017) | Huntington's disease | HTT | CAG | H, M | • FAN1, MLH3, MSH3, DHFR (Ciosi et al., 2019) MLH1 (Lee et al., 2015) • APEX1 (Mollica et al., 2016) • PNKP (Gao et al., 2019) |
• Oxidative DNA damage repair (Ayala-Peña, 2013) • BER • MMR (Goold et al., 2021) • TC-NER • NHEJ |
Cerebellar ataxia; Axonal neuropathy; Cognitive impairment; Hypercholesterolemia; Hypoalbuminemia; Hyperkinetic dyskinesia; Microcephaly. |
| Muscular dystrophy; dysarthria; dysphagia; muscle atrophy (Hashizume and Katsuno, 2018) | Spinal and bulbar muscular atrophy | AR | CAG | H, M | • IGF (Hashizume and Katsuno, 2018) • HDAC6 (Grunseich et al., 2014) • P53 (Malik et al., 2019) |
• Mitochondrial dysfunction • Transcription dysfunction (Malik et al., 2019) • BER (Vasquez et al., 2020) |
Parkinsonism; Flexed posture; Extremity hyperreflexia; Dementia; Polyproteinopathy |
| Progressive ataxia; Cerebellar atrophy; axonal sensor motor neuropathy; Hypercholesterolemia; cognitive impairment (Martins et al., 2017) | Spinocerebellar ataxia 1 | ATXN1 | CAG | H, M | • ATM (Suart et al., 2021), MRE11A, MSH2, WRN (Spence and Wallihan, 2012) • RpA1 (Bosso Taniguchi et al., 2016) |
• ATM mediated DNA repair (Suart et al., 2021) • Mitochondrial DNA damage repair (Ito et al., 2015) |
Radiosensitivity, Immunodeficiency Learning difficulties; Movement disorders and motor disturbances; Cerebellar ataxia; Oculo-cutaneous telangiectasia |
| Symptoms of amyotrophic lateral sclerosis; Extraocular muscle palsy; Severe tremor and myoclonus (Egorova and Bezprozvanny, 2019) | Spinocerebellar ataxia 2 | ATXN2 | CAG | H, M | MTHFR (Almaguer-Mederos et al., 2020) mTORC1 (Auburger et al., 2017) TDP-43 | TC-NER | Cerebellum cerebrum, neurons loss; Parkinsonism; Flexed posture; Extremity hyperreflexia; Dementia; Polyproteinopathy |
| Cerebellar ataxia; Extraocular muscle palsy; Dysarthria; dysphagia; Dystonia; Distal muscular dystrophy (Zhang et al., 2021) | Spinocerebellar ataxia 3 | ATXN3 | CAG | H, M | • TP53 (Liu et al., 2016) • CHK1 (Tu et al., 2017) • PNKP (Chatterjee et al., 2015; Gao et al., 2015; Chakraborty et al., 2020) • MDC1 |
• NHEJ (Chakraborty et al., 2020) • DSBR • NER |
Cocaine syndrome, sulfur dystrophy, brain-eye-skeletal syndrome |
| Dysphagia; delayed progressive cerebellar ataxia; nystagmus; language disorder (Tamura et al., 2017) | Spinocerebellar ataxia 6 | CACNA1A | CAG | Rare meiotic | ATM, APTX (Kashimada et al., 2019) | N | Movement disorders and motor disturbances; Cerebellar ataxia; Oculo-cutaneous telangiectasia |
| Permanent blindness, dysarthria, difficulty swallowing; brain-eye-skeletal syndrome (Klockgether et al., 2019) | Spinocerebellar ataxia 7 | ATXN7 | CAG | H, M | • FUS (Niss et al., 2021) • H2B (Ramachandran et al., 2016) |
N | N |
| Progressive gait and limb ataxia; Auditory and optic neuropathy; Cardiomyopathy; scoliosis; Dysarthria; Dysphagia (Keage et al., 2017) | Friedreich's ataxia | FXN | GAA | H, M | MSH2, MSH3 (Halabi et al., 2012) | • NER (Moreno-Lorite et al., 2021) • BER (Moreno-Lorite et al., 2021) • SSBR (Moreno-Lorite et al., 2021) • MMR (Neil et al., 2021) • DSBR (Neil et al., 2021) |
Peripheral axonal neuropathy; Oculomotor apraxia; Hypoalbuminemia |
| Sleep apnea; Central and obstructive sleep apnea (Harley et al., 1992) | Myotonic dystrophy 1 | DMPK | CTG | H, M | N | N | N |
| Gait ataxia; Parkinson; language disorder (Klockgether et al., 2019) | Spinocerebellar ataxia 8 | ATXN8 | (CTA)n (CTG)n | H | N | N | N |
Only parts of disease-causing repeat loci are included, so many rare diseases caused by expansion of repeat codons, including those giving rise to shorter polyalanine tracts are not shown. H, seen in human tissues; M, seen in mouse model tissues; N, no literature has reported relevant cases.
Red font: The symptom shared by TNR diseases and general symptom caused by impaired DNA pathway.