Genetics of the Dominant Ataxias

ABSTRACT

The relevant clinical, genetic, and cell biologic aspects of the dominantly inherited spinocerebellar ataxias (SCAs) are reviewed in this article. SCAs are diseases of the entire nervous system; in addition to cerebellar ataxia, the central (but not obligate) disease feature, many noncerebellar complications can be present as well. There are over 35 genetic subtypes: although those caused by expanded CAG repeats are still the more common ones, the majority of the recent SCAs have been caused by more conventional mutations. Genotype–phenotype correlations do exist and are most clear for the repeat expansion, where repeat length partially explains age at onset, disease severity and progression, and the core clinical phenotype. Some common themes within the disease mechanisms seem to emerge, including misfolding and aggregation, impairment of the protein quality control system, abnormal protein interactions, disruption of gene transcription, RNA toxicity, and changes in glutamate and calcium signaling. Yet despite this exciting progress in the molecular genetic background and suggested corresponding pathways, there is still no drug available that is specifically designed for or targeted at the mechanisms at play.

KEYWORDS

Ataxia - cerebellum - polyglutamine - genotype–phenotype correlations

REFERENCES

• 1 Yakura H, Wakisaka A, Fujimoto S, Itakura K. Letter: Hereditary ataxia and HL-A.  N Engl J Med. 1974;  291 (3) 154-155
• 2 Orr HT, Chung MY, Banfi S et al.. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1.  Nat Genet. 1993;  4 (3) 221-226
• 3 David G, Abbas N, Stevanin G et al.. Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion.  Nat Genet. 1997;  17 (1) 65-70
• 4 Imbert G, Saudou F, Yvert G et al.. Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats.  Nat Genet. 1996;  14 (3) 285-291
• 5 Kawaguchi Y, Okamoto T, Taniwaki M et al.. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1  Nat Genet. 1994;  8 (3) 221-228
• 6 Koide R, Kobayashi S, Shimohata T et al.. A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease?.  Hum Mol Genet. 1999;  8 (11) 2047-2053
• 7 Zhuchenko O, Bailey J, Bonnen P et al.. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel.  Nat Genet. 1997;  15 (1) 62-69
• 8 Holmes SE, O'Hearn EE, McInnis MG et al.. Expansion of a novel CAG trinucleotide repeat in the 5′ region of PPP2R2B is associated with SCA12.  Nat Genet. 1999;  23 (4) 391-392
• 9 Koob MD, Moseley ML, Schut LJ et al.. An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8).  Nat Genet. 1999;  21 (4) 379-384
• 10 Matsuura T, Yamagata T, Burgess DL et al.. Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10.  Nat Genet. 2000;  26 (2) 191-194
• 11 Kobayashi H, Abe K, Matsuura T et al.. Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement.  Am J Hum Genet. 2011;  89 (1) 121-130
• 12 Sato N, Amino T, Kobayashi K et al.. Spinocerebellar ataxia type 31 is associated with “inserted” penta-nucleotide repeats containing (TGGAA)n.  Am J Hum Genet. 2009;  85 (5) 544-557
• 13 Schöls L, Bauer I, Zühlke C et al.. Do CTG expansions at the SCA8 locus cause ataxia?.  Ann Neurol. 2003;  54 (1) 110-115
• 14 Worth PF, Houlden H, Giunti P, Davis MB, Wood NW. Large, expanded repeats in SCA8 are not confined to patients with cerebellar ataxia.  Nat Genet. 2000;  24 (3) 214-215
• 15 Izumi Y, Maruyama H, Oda M et al.. SCA8 repeat expansion: large CTA/CTG repeat alleles are more common in ataxic patients, including those with SCA6.  Am J Hum Genet. 2003;  72 (3) 704-709
• 16 Sobrido MJ, Cholfin JA, Perlman S, Pulst SM, Geschwind DH. SCA8 repeat expansions in ataxia: a controversial association.  Neurology. 2001;  57 (7) 1310-1312
• 17 Sulek A, Hoffman-Zacharska D, Zdzienicka E, Zaremba J. SCA8 repeat expansion coexists with SCA1—not only with SCA6.  Am J Hum Genet. 2003;  73 (4) 972-974
• 18 Moseley ML, Schut LJ, Bird TD, Koob MD, Day JW, Ranum LP. SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance.  Hum Mol Genet. 2000;  9 (14) 2125-2130
• 19 Chen DH, Brkanac Z, Verlinde CL et al.. Missense mutations in the regulatory domain of PKC gamma: a new mechanism for dominant nonepisodic cerebellar ataxia.  Am J Hum Genet. 2003;  72 (4) 839-849
• 20 van de Warrenburg BP, Verbeek DS, Piersma SJ et al.. Identification of a novel SCA14 mutation in a Dutch autosomal dominant cerebellar ataxia family.  Neurology. 2003;  61 (12) 1760-1765
• 21 Wang JL, Yang X, Xia K et al.. TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing.  Brain. 2010;  133 (Pt 12) 3510-3518
• 22 Chen DH, Cimino PJ, Ranum LP et al.. The clinical and genetic spectrum of spinocerebellar ataxia 14.  Neurology. 2005;  64 (7) 1258-1260
• 23 Oda M, Maruyama H, Komure O et al.. Possible reduced penetrance of expansion of 44 to 47 CAG/CAA repeats in the TATA-binding protein gene in spinocerebellar ataxia type 17.  Arch Neurol. 2004;  61 (2) 209-212
• 24 Raskin S, Ashizawa T, Teive HA et al.. Reduced penetrance in a Brazilian family with spinocerebellar ataxia type 10.  Arch Neurol. 2007;  64 (4) 591-594
• 25 van de Warrenburg BP, Frenken CW, Ausems MG et al.. Striking anticipation in spinocerebellar ataxia type 7: the infantile phenotype.  J Neurol. 2001;  248 (10) 911-914
• 26 van de Warrenburg BP, Sinke RJ, Verschuuren-Bemelmans CC et al.. Spinocerebellar ataxias in the Netherlands: prevalence and age at onset variance analysis.  Neurology. 2002;  58 (5) 702-708
• 27 Moretti P, Blazo M, Garcia L et al.. Spinocerebellar ataxia type 2 (SCA2) presenting with ophthalmoplegia and developmental delay in infancy.  Am J Med Genet A. 2004;  124A (4) 392-396
• 28 Globas C, du Montcel ST, Baliko L et al.. Early symptoms in spinocerebellar ataxia type 1, 2, 3, and 6.  Mov Disord. 2008;  23 (15) 2232-2238
• 29 Schneider SA, van de Warrenburg BP, Hughes TD et al.. Phenotypic homogeneity of the Huntington disease-like presentation in a SCA17 family.  Neurology. 2006;  67 (9) 1701-1703
• 30 Shan DE, Soong BW, Sun CM, Lee SJ, Liao KK, Liu RS. Spinocerebellar ataxia type 2 presenting as familial levodopa-responsive parkinsonism.  Ann Neurol. 2001;  50 (6) 812-815
• 31 Visser JE, Bloem BR, van de Warrenburg BP. PRKCG mutation (SCA-14) causing a Ramsay Hunt phenotype.  Mov Disord. 2007;  22 (7) 1024-1026
• 32 Yamashita I, Sasaki H, Yabe I et al.. A novel locus for dominant cerebellar ataxia (SCA14) maps to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter.  Ann Neurol. 2000;  48 (2) 156-163
• 33 Robitaille Y, Lopes-Cendes I, Becher M, Rouleau G, Clark AW. The neuropathology of CAG repeat diseases: review and update of genetic and molecular features.  Brain Pathol. 1997;  7 (3) 901-926
• 34 Schulz JB, Borkert J, Wolf S et al.. Visualization, quantification and correlation of brain atrophy with clinical symptoms in spinocerebellar ataxia types 1, 3 and 6.  Neuroimage. 2010;  49 (1) 158-168
• 35 van de Warrenburg BP, Notermans NC, Schelhaas HJ et al.. Peripheral nerve involvement in spinocerebellar ataxias.  Arch Neurol. 2004;  61 (2) 257-261
• 36 Varrone A, Salvatore E, De Michele G et al.. Reduced striatal [123 I]FP-CIT binding in SCA2 patients without parkinsonism.  Ann Neurol. 2004;  55 (3) 426-430
• 37 Durr A. Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond.  Lancet Neurol. 2010;  9 (9) 885-894
• 38 Trujillo-Martín MM, Serrano-Aguilar P, Monton-Alvarez F, Carrillo-Fumero R. Effectiveness and safety of treatments for degenerative ataxias: a systematic review.  Mov Disord. 2009;  24 (8) 1111-1124
• 39 Ilg W, Synofzik M, Brötz D, Burkard S, Giese MA, Schöls L. Intensive coordinative training improves motor performance in degenerative cerebellar disease.  Neurology. 2009;  73 (22) 1823-1830
• 40 Fonteyn EM, Schmitz-Hübsch T, Verstappen CC et al.. Falls in spinocerebellar ataxias: Results of the EuroSCA Fall Study.  Cerebellum. 2010;  9 (2) 232-239
• 41 van de Warrenburg BP, Hendriks H, Dürr A et al.. Age at onset variance analysis in spinocerebellar ataxias: a study in a Dutch-French cohort.  Ann Neurol. 2005;  57 (4) 505-512
• 42 Dürr A, Stevanin G, Cancel G et al.. Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features.  Ann Neurol. 1996;  39 (4) 490-499
• 43 Cancel G, Gourfinkel-An I, Stevanin G et al.. Somatic mosaicism of the CAG repeat expansion in spinocerebellar ataxia type 3/Machado-Joseph disease.  Hum Mutat. 1998;  11 (1) 23-27
• 44 Schmitz-Hübsch T, Coudert M, Bauer P et al.. Spinocerebellar ataxia types 1, 2, 3, and 6: disease severity and nonataxia symptoms.  Neurology. 2008;  71 (13) 982-989
• 45 Charles P, Camuzat A, Benammar N French Parkinson's Disease Genetic Study Group et al. Are interrupted SCA2 CAG repeat expansions responsible for parkinsonism?.  Neurology. 2007;  69 (21) 1970-1975
• 46 Kim JY, Kim SY, Kim JM et al.. Spinocerebellar ataxia type 17 mutation as a causative and susceptibility gene in parkinsonism.  Neurology. 2009;  72 (16) 1385-1389
• 47 Zoghbi HY, Orr HT. Glutamine repeats and neurodegeneration.  Annu Rev Neurosci. 2000;  23 217-247
• 48 van Ham TJ, Holmberg MA, van der Goot AT et al.. Identification of MOAG-4/SERF as a regulator of age-related proteotoxicity.  Cell. 2010;  142 (4) 601-612
• 49 Cummings CJ, Mancini MA, Antalffy B, DeFranco DB, Orr HT, Zoghbi HY. Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1.  Nat Genet. 1998;  19 (2) 148-154
• 50 Schmidt T, Lindenberg KS, Krebs A et al.. Protein surveillance machinery in brains with spinocerebellar ataxia type 3: redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions.  Ann Neurol. 2002;  51 (3) 302-310
• 51 Gidalevitz T, Ben-Zvi A, Ho KH, Brignull HR, Morimoto RI. Progressive disruption of cellular protein folding in models of polyglutamine diseases.  Science. 2006;  311 (5766) 1471-1474
• 52 Chai Y, Berke SS, Cohen RE, Paulson HL. Poly-ubiquitin binding by the polyglutamine disease protein ataxin-3 links its normal function to protein surveillance pathways.  J Biol Chem. 2004;  279 (5) 3605-3611
• 53 Mao Y, Senic-Matuglia F, Di Fiore PP, Polo S, Hodsdon ME, De Camilli P. Deubiquitinating function of ataxin-3: insights from the solution structure of the Josephin domain.  Proc Natl Acad Sci U S A. 2005;  102 (36) 12700-12705
• 54 Helmlinger D, Hardy S, Sasorith S et al.. Ataxin-7 is a subunit of GCN5 histone acetyltransferase-containing complexes.  Hum Mol Genet. 2004;  13 (12) 1257-1265
• 55 Klement IA, Skinner PJ, Kaytor MD et al.. Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice.  Cell. 1998;  95 (1) 41-53
• 56 Kordasiewicz HB, Thompson RM, Clark HB, Gomez CM. C-termini of P/Q-type Ca2+ channel alpha1A subunits translocate to nuclei and promote polyglutamine-mediated toxicity.  Hum Mol Genet. 2006;  15 (10) 1587-1599
• 57 Helmlinger D, Hardy S, Abou-Sleymane G et al.. Glutamine-expanded ataxin-7 alters TFTC/STAGA recruitment and chromatin structure leading to photoreceptor dysfunction.  PLoS Biol. 2006;  4 (3) e67
• 58 Lin X, Antalffy B, Kang D, Orr HT, Zoghbi HY. Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1.  Nat Neurosci. 2000;  3 (2) 157-163
• 59 Shah AG, Friedman MJ, Huang S, Roberts M, Li XJ, Li S. Transcriptional dysregulation of TrkA associates with neurodegeneration in spinocerebellar ataxia type 17.  Hum Mol Genet. 2009;  18 (21) 4141-4152
• 60 Tsai CC, Kao HY, Mitzutani A et al.. Ataxin 1, a SCA1 neurodegenerative disorder protein, is functionally linked to the silencing mediator of retinoid and thyroid hormone receptors.  Proc Natl Acad Sci U S A. 2004;  101 (12) 4047-4052
• 61 Tsuda H, Jafar-Nejad H, Patel AJ et al.. The AXH domain of Ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/Senseless proteins.  Cell. 2005;  122 (4) 633-644
• 62 Tait D, Riccio M, Sittler A et al.. Ataxin-3 is transported into the nucleus and associates with the nuclear matrix.  Hum Mol Genet. 1998;  7 (6) 991-997
• 63 Li F, Macfarlan T, Pittman RN, Chakravarti D. Ataxin-3 is a histone-binding protein with two independent transcriptional corepressor activities.  J Biol Chem. 2002;  277 (47) 45004-45012
• 64 Dick KA, Margolis JM, Day JW, Ranum LP. Dominant non-coding repeat expansions in human disease.  Genome Dyn. 2006;  1 67-83
• 65 Li LB, Yu Z, Teng X, Bonini NM. RNA toxicity is a component of ataxin-3 degeneration in Drosophila.  Nature. 2008;  453 (7198) 1107-1111
• 66 Hsu RJ, Hsiao KM, Lin MJ et al.. Long tract of untranslated CAG repeats is deleterious in transgenic mice.  PLoS ONE. 2011;  6 (1) e16417
• 67 Wang LC, Chen KY, Pan H et al.. Muscleblind participates in RNA toxicity of expanded CAG and CUG repeats in Caenorhabditis elegans .  Cell Mol Life Sci. 2011;  68 (7) 1255-1267
• 68 Daughters RS, Tuttle DL, Gao W et al.. RNA gain-of-function in spinocerebellar ataxia type 8.  PLoS Genet. 2009;  5 (8) e1000600
• 69 Chen IC, Lin HY, Lee GC et al.. Spinocerebellar ataxia type 8 larger triplet expansion alters histone modification and induces RNA foci.  BMC Mol Biol. 2009;  10 9
• 70 Lin CH, Chen CM, Hou YT et al.. The CAG repeat in SCA12 functions as a cis element to up-regulate PPP2R2B expression.  Hum Genet. 2010;  128 (2) 205-212
• 71 Rudrabhatla P, Pant HC. Role of protein phosphatase 2A in Alzheimer's disease.  Curr Alzheimer Res. 2011;  8 (6) 623-632
• 72 Grady DL, Ratliff RL, Robinson DL, McCanlies EC, Meyne J, Moyzis RK. Highly conserved repetitive DNA sequences are present at human centromeres.  Proc Natl Acad Sci U S A. 1992;  89 (5) 1695-1699
• 73 Bakalkin G, Watanabe H, Jezierska J et al.. Prodynorphin mutations cause the neurodegenerative disorder spinocerebellar ataxia type 23.  Am J Hum Genet. 2010;  87 (5) 593-603
• 74 Wang Y, Qin ZH. Molecular and cellular mechanisms of excitotoxic neuronal death.  Apoptosis. 2010;  15 (11) 1382-1402
• 75 Hollmann M, Heinemann S. Cloned glutamate receptors.  Annu Rev Neurosci. 1994;  17 31-108
• 76 Perkel DJ, Hestrin S, Sah P, Nicoll RA. Excitatory synaptic currents in Purkinje cells.  Proc Biol Sci. 1990;  241 (1301) 116-121
• 77 Saegusa H, Wakamori M, Matsuda Y et al.. Properties of human Cav2.1 channel with a spinocerebellar ataxia type 6 mutation expressed in Purkinje cells.  Mol Cell Neurosci. 2007;  34 (2) 261-270
• 78 Watase K, Barrett CF, Miyazaki T et al.. Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant CaV2.1 channels.  Proc Natl Acad Sci U S A. 2008;  105 (33) 11987-11992
• 79 Knöpfel T, Grandes P. Metabotropic glutamate receptors in the cerebellum with a focus on their function in Purkinje cells.  Cerebellum. 2002;  1 (1) 19-26
• 80 Hirai H. Modification of AMPA receptor clustering regulates cerebellar synaptic plasticity.  Neurosci Res. 2001;  39 (3) 261-267
• 81 Adachi N, Kobayashi T, Takahashi H et al.. Enzymological analysis of mutant protein kinase Cgamma causing spinocerebellar ataxia type 14 and dysfunction in Ca2+ homeostasis.  J Biol Chem. 2008;  283 (28) 19854-19863
• 82 Ikeda Y, Dick KA, Weatherspoon MR et al.. Spectrin mutations cause spinocerebellar ataxia type 5.  Nat Genet. 2006;  38 (2) 184-190
• 83 Knight MA, Hernandez D, Diede SJ et al.. A duplication at chromosome 11q12.2-11q12.3 is associated with spinocerebellar ataxia type 20.  Hum Mol Genet. 2008;  17 (24) 3847-3853
• 84 Serra HG, Byam CE, Lande JD, Tousey SK, Zoghbi HY, Orr HT. Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice.  Hum Mol Genet. 2004;  13 (20) 2535-2543
• 85 Figueroa KP, Minassian NA, Stevanin G et al.. KCNC3: phenotype, mutations, channel biophysics-a study of 260 familial ataxia patients.  Hum Mutat. 2010;  31 (2) 191-196
• 86 Shakkottai VG, Xiao M, Xu L et al.. FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons.  Neurobiol Dis. 2009;  33 (1) 81-88
• 87 Maltecca F, Magnoni R, Cerri F, Cox GA, Quattrini A, Casari G. Haploinsufficiency of AFG3L2, the gene responsible for spinocerebellar ataxia type 28, causes mitochondria-mediated Purkinje cell dark degeneration.  J Neurosci. 2009;  29 (29) 9244-9254
• 88 Jeitner TM, Muma NA, Battaile KP, Cooper AJ. Transglutaminase activation in neurodegenerative diseases.  Future Neurol. 2009;  4 (4) 449-467
• 89 Van Damme P, Veldink JH, van Blitterswijk M et al.. Expanded ATXN2 CAG repeat size in ALS identifies genetic overlap between ALS and SCA2.  Neurology. 2011;  76 (24) 2066-2072