Trinucleotide-Expansion Diseases 345 Table 3 A n -expansion diseases Disease Gene Affected Protein A n Expansion Synpolydactyly type II (SPD) HOXD13 Transcription factor (15 → 22–29) Cleidocranial dysplasia (CCD) RUNX2 (CBFA1) Transcription factor (17 → 27) Oculopharyngeal muscular dystrophy (OPMD) PABPN1 Polyadenylate-binding protein (10 → 11–17) Holoprosencephaly (HPE5) ZIC2 Transcription factor (15 → 25) Hand–foot–genital syndrome (HFGS) HOXA13 Transcription factor (Tract 1; 14 → 22) (Tract 2; 12 → 18) (Tract 3; 18 → 24–30) Blepharophimosis, ptosis, and epicanthus inversus (BPES) FOXL2 Transcription factor (14 → 22–24) X-linked mental retardation with hypopituitarism (XH) (MRX) SOX3 Transcription factor (15 → 26) X-linked infantile spasm syndrome (ISSX; West syndrome, WS) Partington syndrome (PRTS) X-linked lissencephaly with ambiguous genitalia (XLAG) X-linked mental retardation 36 and 54 (MRX) ARX Transcription factor (Tract 1; 16 → 23) (Tract 2; 12 → 20) Congenital central hypoventilation syndrome (CCHS) Ondine’s curse PMX2B (PHOX2B) Transcription factor (20 → 25–33) Modified from Brown and Brown (2004) and Messaed and Rouleau (2009). (CCD), oculopharyngeal muscular dystrophy (OPMD), hand–foot–genital syn- drome (HFGS), and blepharophimosis, ptosis, and epicanthus inversus (BPES) are inherited in an autosomal dominant fashion. Holoprosencephaly (HPE) is a severe developmental disease resulting in death in infancy and the causative mutation presumably arises de novo. Congenital central hypoventilation syndrome (CCHS; Ondine curse) cases also appear to be due to spontaneous mutations. Two A n - expansion diseases are X-linked. A mutation in the SOX3 gene, giving rise to sex-linked mental retardation (MRX) with growth hormone deficiency, has been described in one large family (Brown and Brown, 2004). A n -Expansion mutations can occur in two different tracts in the expressed protein of the ARX gene, giv- ing rise to nonsyndromic MRX and two syndromic conditions (X-linked infantile spasm syndrome (ISSX) also known as West syndrome (WS) and Partington syn- drome (PRTS)). A n -Expansion mutations can occur in three different tracts in the HOXA13 gene. 5.2 Comparison of A n -Expansion Diseases with Q n -Expansion Diseases Although expansions in Q n and A n domains give rise to disease phenotypes, the characteristics of the diseases are remarkably dissimilar. (1) The number of alanine 346 A.J.L. Cooper and J.P. Blass repeats is fixed at a single value in the normal (nonmutated) A n -containing pro- teins. This number varies between 10 and 18, depending on the protein (Table 3). In contrast, although 10–20 glutamine repeats occur in normal (nonmutated) Q n - containing proteins, the number is not fixed and may vary considerably in the nonmutated protein among the general population. (2) The expansions giving rise to disease phenotypes in the A n -expansion diseases are small, with a maximum exten- sion of 14 alanine residues. In contrast, pathological extensions of Q n domains can be much larger (compare Tables 2 and 3). (3) The A n expansion appears to be meiot- ically and somatically stable, whereas this is not the case with the Q n expansions. (4) The disease phenotypes of the Q n -expansion diseases are almost entirely restricted to neural tissue. In contrast, although severe neurological defects can occur in the A n -expansion diseases, all give rise to extraneural disease phenotypes. (5) The A n - expansion disease phenotypes are present at birth whereas the onset of Q n -expansion diseases is typically in adulthood. (6) The diseases caused by Q n expansions are thought to arise predominantly (but not exclusively) via a toxic gain of function (Section 5). By contrast, the diseases caused by A n expansions are thought to arise by loss of function, gain of function, or by a dominant-negative effect, depending on the disease. (7) All but one of the A n -expansion diseases is associated directly with a transcription factor, whereas only one of the Q n -expansion diseases is associated directly with a known transcription factor. (8) The Q n -expansion disease proteins are usually coded in the genome by “perfect” runs of CAG repeats, and thus slippage mechanisms may account for the meiotic and somatic instabilities of the Q n domain. On the other hand, the A n -expansion disease proteins are usually coded by “imper- fect” runs containing any of the four triplets that code for alanine (CCG, GCA, GCT, and GCC). These differences suggest that Q n tracts are easier to expand than A n tracts (Messaed and Rouleau, 2009). Increases in the length of the A n domain are thought to arise through unequal recombination. However, slippage may occur in BPES and possibly ISSX (Brown and Brown, 2004). 6 Possible Mechanisms Contributing to A n -Expansion Diseases Disruption of transcription factor function will result in altered expression of down- stream target genes and in abnormal development (Brown and Brown, 2004). But how are the functions of the transcription factors altered by an A n expansion? It has been suggested that the A n domains may (1) have a role in repression, (2) act as spacers or hinges, or (3) play important roles in correct protein–protein interactions and protein–DNA interactions during transcription. Clearly much work needs to be done to elucidate the pathological mechanisms associated with A n -expansion dis- eases (reviewed by Brown and Brown, 2004). A n polypeptides form fibrils through β-sheet formation (Nguyen and Hall, 2004), and it has been shown that transfection of cells with an A n expansion in the aristaless-related homeobox (ARX) protein results in nuclear protein aggregation, filamentous nuclear inclusions, and increased Trinucleotide-Expansion Diseases 347 cell death (Nasrallah et al., 2004). It was suggested that nuclear protein aggregation likely underlies the pathogenesis of diseases caused by A n expansions in the ARX protein and possibly in other A n -containing transcription factors (Nasrallah et al., 2004). The aggregates themselves may be toxic or toxicity may result in loss of transcription function. A summary of possible mechanisms relating to the A n -expansion diseases has been provided by Messaed and Rouleau (2009). These authors point out that in mammalian cells chaperones bind to misfolded proteins produced during transla- tion or later during their aggregation (in the cytosol and/or nuclear compartment) in an attempt to correctly refold/solubilize them. Unsuccessful folding and prolonged association of the misfolded protein with chaperones can stimulate ubiquitination and targeting to the proteasome machinery. However, in the A n -expansion dis- eases this quality-control mechanism may be insufficient. Depending on the disease, aggregates may form i n the cytosol, nucleus, or both compartments. These aggre- gates may sequester essential cellular factors preventing them from reaching their targets. In the case of SPD, HFGS, and XH the essential cellular factor recruited into the deposits may be the wild-type A n -containing protein which may lead to a dominant-negative effect. In addition, expanded A n tracts may result in (a) decreased binding efficiency to DNA, (b) pathological competition with the wild- type protein for binding to DNA, or (c) interfere with cofactors important for DNA binding of the wild-type protein. As summarized by Messaed and Rouleau (2009), in order to delineate the cellular pathways involved in pathogenesis, future work requires an understanding of the mechanism relating to (a) the selective tissue vulnerability of expanded A n domains, (b) the nature of the targeted genes, and (c) the nature of the targeted interaction partners. 7 Other Nucleotide-Expansion Diseases Examples of diseases caused by tetra- and pentanucleotide expansions are known. For example, myotonic dystrophy type 2 (DM2) is caused by a tetranucleotide expansion in the affected gene on chromosome 19q13.3 (Meola and Moxley, 2004; Lee and Cooper, 2009). In this case, an expanded CCTG repeat occurs in intron 1 of the zinc finger 9 (ZFN9) gene (Meola and Moxley, 2004). The expanded repeat in transcribed RNA forms nuclear inclusions in both types of myotonic dystro- phy (Mankodi, 2008). The aberrrant RNA sequesters muscleblind-like protein 1 (MBNL1), a splice regulator protein, and depletes MBNL1 in the nucleus. Loss of MBNL1 results in altered splicing of ClC-1 (chloride channel 1) mRNA, inactive ClC-1 and loss of chloride conductance in muscle membranes (Mankodi, 2008). Spinocerebellar ataxia 10 (SCA 10) is caused by a pentanucleotide (ATTCT) expansion in intron 9 of the SCA10 (ATXN10) gene at chromosome 22q13 encoding an approximately 55-kd protein (ataxin 10) of unknown function (Matsuura et al., 2000; Wakamiya et al., 2006). In experiments with HEK293 cells in culture, it was shown that the SCA10 protein is essential for neuronal survival (März et al., 2004). 348 A.J.L. Cooper and J.P. Blass Spinocerebellar ataxia type 31 is associated with pentanucleotide repeat [(TGGAA) n ] expansion at chromosme 16g22.1 in introns of the TK2 (thymidine kinase) and BEAN (brain expressed, associated with Nedd4) genes (Sato et al., 2009). The length of the pentanucleotide repeat correlates inversely with the age of onset of symptoms. Purkinje cells in the cerebellum are affected. Aberrant RNA foci may result in disrupted splicing factors in these cells (Sato et al., 2009). A mutation in the junctophilin-3 (JPH3) gene at chromosome 16q24.3 in a vari- ably spliced exon gives rise to an autosomal dominantly inherited disease that is clinically indistinguishable from HD (Margolis et al., 2004). The disease appears to be restricted largely, if not exclusively, to families of African descent, and is referred to as Huntington disease-like 2 (HDL2) (Margolis et al., 2004; Rodrigues et al., 2008). The mutation results from an expansion in a CTG/CAG repeat. Although the expansion is in an exon (exon 2A), junctophilin-3 protein containing a domain with increased Q residues does not appear to be produced, suggesting that the pathological phenotype is due to loss of JPH3 protein and/or to aberrant RNA processing/metabolism (Margolis et al., 2004). 8 Conclusions Before the advent of modern genetic analyses, precise classification of many inher- ited neurodegenerative diseases, especially among those that exhibited closely related disease phenotypes, was difficult and often resulted in contentious debate. Beginning in the early 1990s, the genetic basis of a large number of inherited neurodegenerative diseases began to be elucidated. Many of the inherited neurode- generative diseases were found to be caused by trinucleotide expansions either in a noncoding region of the affected gene or in a coding region (Q n -expansion diseases; A n -expansion diseases). This genetic underpinning has essentially brought order out of anarchy and chaos (Margolis, 2002). Many inherited neurodegenerative diseases can now be classified on a rational nosology based on well-defined genetic muta- tions. A n -expansions in mutated proteins result in neurological damage, but these diseases are invariably accompanied by cranial and somatic morphological defects. There are still many inherited neurodegenerative diseases for which a mutation has not yet been described. For example, there are many inherited SCAs whose genetic basis has not yet been determined. Possibly, at least some of these neurodegenera- tive diseases will be shown to be due to nucleotide-expansions. It will be interesting to determine whether some forms of purely psychiatric disease also can be firmly assigned to trinucleotide-expansion diseases. Among the trinucleotide-expansion diseases, it is still not yet clear what accounts for the sensitivity of nervous tissue to the altered genotype and what accounts for the selective vulnerability of different brain regions among the various diseases. However, some progress is being made. A feature of the Q n -expansion diseases and A n -expansion diseases, is the presence of (or propensity to form) aberrant protein deposits in affected brain regions. In this respect, these diseases are similar to the Trinucleotide-Expansion Diseases 349 more common neurodegenerative diseases such as PD and AD, which also exhibit aberrant protein deposits. To what extent these deposits play a role in the pathogen- esis of AD and PD is still under debate. An understanding of the origin of aberrant protein deposits in the Q n - and A n -expansion diseases may suggest possible ther- apeutic strategies not only for these diseases, but also for the more common AD and PD. Acknowledgments We thank Dr. John T. Pinto for helpful suggestions. Part of the work cited from the authors’ laboratory was supported by NIH grant 2P01 AG14930. References Amato AA, Prior TW, Barohn RJ, Snyder P, Papp A, Mendell JR (1993) Kennedy’s disease: a clinicopathologic correlation with mutations in the androgen receptor gene. Neurology 43: 791–794 Andreassen OA, Dedeoglu A, Ferrante RJ, Jenkins BG, Ferrante KL, Thomas M, Friedlich A, Browne SE, Schilling G, Borchelt DR, Hersch SM, Ross CA, Beal MF (2001) Creatine increases survival and delays motor symptoms in a transgenic mouse model of Huntington’s disease. Neurobiol Dis 8:479–491 Bahl S, Virdi K, Mittal U, Sachdeva MP, Kalla AK, Holmes SE, O’Hearn E, Margolis RL, Jain S, Srivastava AK, Mukerji M (2005) Evidence of a common founder for SCA12 in the Indian population. Ann Hum Genet 69:528–534 Bailey CDC, Johnson GVW (2006) The protective effects of cystamine in the R6/2 Huntington’s disease mouse involve mechanisms other than the inhibition of transglutaminase. Neurobiol Aging 27:871–879 Banno H, Katsuno M, Suzuki K, Takeuchi Y, Kawashima M, Suga N, Takamori M, Ito M, Nakamura T, Matsuo K, Yamada S, Oki Y, Adachi H, Minamiyama M, Waza M, Atsuta N, Watanabe H, Fujimoto Y, Nakashima T, Tanaka F, Doyu M, Sobue G (2009) Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy. Ann Neurol 65:140–150 Bates G (2003) Huntingtin aggregation and toxicity in Huntington’s disease. Lancet 361: 1642–1644 Bauer PO, Nukina N (2009) The pathogenic mechanisms of polyglutamine diseases and current therapeutic strategies. J Neurochem 110:1737–1765 Beal MF, Kowall NW, Ellison DW, Mazurek MF, Swartz KJ, Martin JB (1986) Replication of the neurochemical characteristics of Huntington’s disease by quinolinic acid. Nature 321:168–171 Bithell A, Johnson R, Buckley NJ (2009) Transcriptional dysregulation of coding and non-coding genes in cellular models of Huntington’s disease. Biochem Soc Trans 37:1270–1275 Bitoun E, Davies KE (2009) The robotic mouse: understanding the role of AF4, a cofactor of transcriptional elongation and chromatin remodelling, in Purkinje cell function. Cerebellum 8:175–183 Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, Stanton VP, Thirion JP, Hudson T, et al (1992) Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3 end of a transcript encoding a protein kinase family member. Cell 68:799–808 Brown LY, Brown SA (2004) Alanine tracts: the expanding story of human illness and trinucleotide repeats. Trends Genet 20:51–58 Browne SE (2008) Mitochondria and Huntington’s disease pathogenesis: insight from genetic and chemical models. Ann N Y Acad Sci 1147:358–382 Browne SE, Beal MF (2004) The energetics of Huntington’s disease. Neurochem Res 29:531–546 Browne SE, Bowling AC, MacGarvey U, Baik MJ, Berger SC, Muqit MMK, Bird ED, Beal MF (1997) Oxidative damage and metabolic dysfunction in Huntington’s disease: selective vulnerability of the basal ganglia. Ann Neurol 41:646–653 350 A.J.L. Cooper and J.P. Blass Brustovetsky N, Brustovetsky T, Purl KJ, Capano M, Crompton M, Dubinsky JM (2003) Increased susceptibility of striatal mitochondria to calcium-induced permeability transition. J Neurosci 23:4858–4867 Campuzano A, Montermini L, Moltò MD, Pianese L, Cossée M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A, Zara F, Cañizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, De Michele G, Filla A, De Frutos R, Palau F, Patel PI, Di Donato S, Mandel JL, Cocozza S, Koenig M, Pandolfo M (1996) Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271:1423–1427 Cary GA, La Spada AR (2008) Androgen receptor function in motor neuron survival and degeneration. Phys Med Rehabil Clin N Am 19:479–494, viii Caviston JP, Holzbaur EL (2009) Huntingtin as an essential integrator of intracellular vesicular trafficking. Trends Cell Biol 19:147–155 Chakrabarti L, Bristulf J, Foss GS, Davies KE (1998) Expression of the murine homologue of FMR2 in mouse brain and during development. Hum Mol Genet 7:441–448 Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L, Farrell LA, Hersch SM, Hobbs W, Vonsattel J-P, Cha JH, Friedlander RM (2000) Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 6:797–801 Chow MK, Mackay JP, Whisstock JC, Scanlon MJ, Bottomley SP (2004) Structural analysis of the Josephin domain of the polyglutamine protein ataxin-3. Biochem Biophys Res Commun 322:387–394 Conneally PM (1984) Huntington’s disease: genetics and epidemiology. Am J Hum Genet 36: 506–526 Cooper AJL, Jeitner TM, Gentile V, Blass JP (2002) Cross linking of polyglutamine domains catalyzed by tissue transglutaminase is greatly favored with pathological length repeats: does transglutaminase activity play a role in (CAG) n /Q n -expansion diseases? Neurochem Int 40: 53–67 Cooper JM, Schapira AH (2003) Friedreich’s ataxia: disease mechanisms, antioxidants and coenzyme Q 10 therapy. Biofactors 18:163–171 Cornett J, Cao F, Wang CE, Ross CA, Bates GP, Li SH, Li XJ (2005) Polyglutamine expansion of huntingtin impairs nuclear export. Nat Genet 37:198–204 Cummings CJ, Reinstein E, Sun Y, Antalffy B, Jiang Y, Ciechanover A, Orr HT, Beaudet AL, Zoghbi HY (1998) Mutations of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice. Neuron 24: 879–892 Cummings CJ, Zoghbi HY (2000) Fourteen and counting: unraveling trinucleotide repeat disor- ders. Human Mol Genet 9:909–916 Cummings CJ, Zoghbi HY (2001) Trinucleotide repeats: mechanisms and pathophysiology. Annu Rev Genomics Hum Genet 1:281–328 Cusimano A, D’Adamo MC, Pessia M (2004) An episodic ataxia type-1 mutation in the S1 segment sensitizes the hKv1.1 potassium channel to extracellular Zn 2+ . FEBS Lett 576: 237–244 Daughters RS, Tuttle DL, Gao W, Ikeda Y, Moseley ML, Ebner TJ, Swanson MS, Ranum LP (2009) RNA gain-of-function in spinocerebellar ataxia type 8. PLoS Genet 5(8):e1000600. Epub 2009 Aug 14 David G, Abbas N, Stevanin G, Dürr A, Yvert G, Cancel G, Weber C, Imbert G, Saudou F, Antoniou E, Drabkin H, Gemmill R, Giunti P, Benomar A, Wood N, Ruberg M, Agid Y, Mandel JL, Brice A (1997) Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet 17:65–70 Dedeoglu AD, Kubilus JK, Jeitner TM, Matson SA, B ogdanov M, Kowall NW, Matson WR, Cooper AJL, Ratan RR, Beal MF, Hersch SM, Ferrante RJ (2002) Therapeutic effects of the transglutaminase inhibitor, cystamine, in a murine model of Huntington’s disease. J Neurosci 22:8942–8950 Trinucleotide-Expansion Diseases 351 D’Huist C, Kooy RF (2009) Fragile X syndrome: from molecular genetics to therapy. J Med Genet 46:577–584 Di Prospero NA, Fischbeck KH (2005) Therapeutic development for triplet repeat expansion diseases. Nat Rev Genet 6:756–765 Dürr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, Mandel JL, Brice A, Koenig M (1996) Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N Eng J Med 335:1169–1175 Emamian ES, Kaytor MD, Duvick LA, Zu T, Tousey SK, Zoghbi HY, Clark HB, Orr HT (2003) Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice. Neuron 38:375–387 Figueroa KP, Farooqi S, Harrup K, Frank J, O’Rahilly S, Pulst SM (2009) Genetic variance in the spinocerebellar ataxia type 2 (ATXN2) gene in children with severe early onset obesity. PLoS One 4:e8280 Foster TC, Kumar A (2002) Calcium dysregulation in the aging brain. Neuroscientist 8:297–301 Frints SG, Froyen G, Marynen P, Fryns JP (2002) X-linked mental retardation: vanishing bound- aries between non-specific (MRX) and syndromic (MRXS) forms. Clin Genet 62:423–432 Gårseth M, Sonnewald U, White LR, Rød M, Zwart JA, Nygaard O, Aasly J (2000) Proton mag- netic resonance spectroscopy of cerebrospinal fluid in neurodegenerative disease: indication of glial energy impairment in Huntington chorea, but not Parkinson disease. J Neurosci Res 60:779–782 Gatchel JR, Zoghbi HY (2005) Diseases of unstable repeat expansions. Nature Rev Genet 6: 743–755 Gécz J, Gedeon AK, Sutherland GR, Mulley JC (1996) Identification of the gene FMR2, associated with FRAXE mental retardation. Nat Genet 13:105–108 Greenamyre JT, Shoulson I (1994) Huntington’s disease. In neurodegenerative diseases. In: Calne DB (ed) Neurodegenerative diseases. W. B. Saunders Company, New York, NY, pp 685–704 Gu Y, Nelson DL (2003) FMR2 function: insight from a mouse knockout model. Cytogenet Genome Res 100:129–139 Guidetti P, Luthi-Carter RE, Augood SJ, Schwarcz R (2004) Neostriatal and cortical quinolinate levels are increased in early grade Huntington’s disease. Neurobiol Dis 17:455–461 Gunawardena S, Goldstein LSB (2005) Polyglutamine diseases and transport problems. Deadly traffic jams and neuronal highways. Arch Neurol 62:46–51 Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J, Grigsby J, Gage B, Hagerman PJ (2001) Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 57:127–130 Han JA, Park SC (2000) Transglutaminase-dependent modulation of transcription factor Sp1 activity. Mol Cells 10:612–618 Helmlinger D, Hardy S, Eberlin A, Devys D, Tora L (2006b) Both normal and polyglutamine- expanded ataxin-7 are components of TFTC-type GCN5 histone acetyltransferase-containing complexes. Biochem Soc Symp 73:155–163 Helmlinger D, Hardy S, Sasorith S, Klein F, Robert F, Weber C, Miguet L, Potier N, van-Dorsselaer A, Wurtz JM, Mandel JL, Tora L, Devys D (2004) Ataxin-7 is a subunit of GCN5 histone acetyltransferase-containing complexes. Hum Mol Genet 13:1257–1267 Helmlinger D, Tora L, Devys D (2006a) Transcriptional alterations and chromatin remodeling in polyglutamine diseases. Trends Genet 22:562–570 Hilditch-Maguire. P, Trettel F, Passsani LA, Auerbach A, Persichetti F, MacDonald ME (2000) Huntingtin: an iron-regulated protein essential for normal nuclear and perinuclear organelles. Hum Mol Genet 9:2789–2797 Holmes SE, O’Hearn E, Margolis RL (2003) Why is SCA12 different from other SCAs? Cytogenet Genome Res 100:189–197 Holmes SE, O’Hearn EE, McInnis MG, Gorelick-Feldman DA, Kleiderlein JJ, Callahan C, Kwak NG, Ingersoll-Ashworth RG, Sherr M, Sumner AJ, Sharp AH, Ananth U, Seltzer WK, Boss MA, Vieria-Saecker AM, Epplen JT, Riess O, Ross CA, Margolis RL (1999) Expansion of a 352 A.J.L. Cooper and J.P. Blass novel CAG trinucleotide repeat in the 5 region of PPP2R2B is associated with SCA12. Nat Genet 23:391–392 Ikeda Y, Dalton JC, Moseley ML, Gardner KL, Bird TD, Ashizawa T, Seltzer WK, Pandolfo M, Milunsky A, Potter NT, Shoji M, Vincent JB, Day JW, Ranum LP (2004) Spinocrebellar ataxia type 8: molecular genetic comparisons and haplotype analysis of 37 families with ataxia. Am J Hum Genet 75:3–16 Jiang H, Mankodi A, Swanson MS, Moxley RT, Thornton CA (2004) Myotonic dystrophy type I associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins, and deregulated alternative splicing in neurons. Hum Mol Genet 13:3079–3088 Kahlem P, Green H, Djian P (1998) Transglutaminase action imitates Huntington’s disease: selec- tive polymerization of Huntingtin containing expanded polyglutamine. Mol Cell 1:595–601 Karpuj MV, Becher MW, Springer JE, Chabas D, Youssef S, Pedotti R, Mitchell D, Steinman L (2002) Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine. Nat Med 8:143–149 Karpuj MV, Garren H, Slunt H, Price DL, Gusella J, Becher MW, Steinman L (1999) Transglutaminase aggregates huntingtin into nonamyloidogenic polymers, and its enzymatic activity increases in Huntington’s disease nuclei. Proc Natl Acad Sci USA 96:7388–7393 Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, Kawakami H, Nakamura S, Nishimura M, Akiguchi I, et al (1994) CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 8:221–228 Kaytor MD, Wilkinson KD, Warren ST (2004) Modulating huntingtin half-life alters polyglutamine-dependent aggregate formation and cell toxicity. J Neurochem 89:962–973 Koide R, Ikeuchi T, Onodera O, Tanaka H, Igarishi S, Endo K, Takahashi H, Kondo R, Ishikawa A, Hayashi T (1994) Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet 6:9–13 Koide R, Kobayashi S, Shimohata T, Ikeuchi T, Maruyama M, Saito M, Yamada M, Takahashi H, Tsuji S (1999) A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease? Hum Mol Genet 8: 2047–2053 Koob MD, Moseley ML, Schut LJ, Benzow KA, Bird TD, Day JW, Ranum LP (1999) An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nat Genet 21:379–384 Korade-Mirnics Z, Babitzke P, Hoffman E (1998) Myotonic dystrophy: molecular windows on a complex etiology. Nucleic Acids Res 26:1363–1368 Koroshetz WJ, Martin JB (1997) Huntington’s disease. In: Rosenberg RN, Prusiner SB, DiMauro S, Barchi RL (eds) The molecular and genetic basis of neurological disease. Butterworth- Heinemann, Boston, MA, pp 545–564 Kremer EJ, Pritchard M, Lynch M, Yu S, Holman K, Baker E, Warren ST, Schlessinger D, Sutherland GR, Richards RI (1991) Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG) n . Science 252:1711–1714 Kuemmerle S, Gutekanst C-A, Klein AM, Li X-J, Li SH, Beal MF, Hersch SM, Ferrante RJ (1999) Huntingtin aggregates may not predict neuronal death in Huntington’s disease. Ann Neurol 46:842–849 La Spada AR, Roling DB, Harding AE, Warner CL, Spiegel R, Hausmanowa-Petrusewicz I, Yee WC, Fischbeck KH (1992) Meiotic stability and genotype-phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy. Nat Genet 2: 301–304 La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH (1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352:77–79 Lai TS, Tucker T, Burke JR, Strittmatter WJ, Greenberg CS (2004) Effect of tissue transglutam- inase on the solubility of proteins containing expanded polyglutamine repeats. J Neurochem 88:1253–1260 Trinucleotide-Expansion Diseases 353 Lane DJ, Richardson DR (2010) Frataxin, a molecule of mystery: trading stability for function in its iron-binding site. Biochem J 426:e1–3 Lee JE, Cooper TA (2009) Pathogenic mechanisms of myotonic dystrophy. Biochem Soc Trans 37:1281–1286 Lee WW, Kim SY, Kim JY, Kim HJ, Park SS, Jeon BS (2009) Extrapyramidal signs are a common feature of spinocerebellar ataxia type 17. Neurology 73:1708–1709 Lesca G, Biancalana V, Brunel MJ, Quack B, Calender A, Lespinasse J (2003) Clinical, cytogenetic, and molecular description of a FRAXE French family. Psychiatr Genet 13: 43–46 Lesort M, Lee M, Tucholski J, Johnson GVW (2003) Cystamine inhibits caspase activity. Implications for the treatment of polyglutamine disorders. J Biol Chem 278:3825–3830 Li SH, Li XJ (2004) Huntingtin-protein interactions and the pathogenesis of Huntington’s disease. Trends Genet 20:146–154 Limprasert P, Nouri N, Heyman RA, Nopparatana C, Kamonslip M, Deininger PL, Keats BJ (1996) Analysis of CAG repeat of the Machado-Joseph gene in human, chimpanzee and monkey pop- ulations: a variant nucleotide is associated with the number of CAG repeats. Hum Mol Genet 5:207–213 Liu J, Tang TS, Tu H, Nelson O, Herndon E, Huynh DP, Pulst SM, Bezprozvanny I (2009) Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 2. J Neurosci 29:9148–9962 Lodi R, Schapira AH, Manners D, Styles P, Wood NW, Taylor DJ, Warner TT (2000) Abnormal in vivo skeletal muscle energy metabolism in Huntington’s disease and dentatorubralpalli- doluysian atrophy. Ann Neurol 48:72–76 Lukusa T, Fryns JP (2008) Human chromosome fragility. Biochim Biophys Acta 1779:3–16 Maldonado PD, Molina-Jijón E, Villeda-Hernández J, Galván-Arzate S, Santamaría A, Pedraza- Chaverrí J (2010) NAD(P)H oxidase contributes to neurotoxicity in an excitotoxic/prooxidant model of Huntington’s disease in rats: protective role of apocynin. J Neurosci Res 88: 620–629 Mandrusiak LM, Beitel LK, Wang X, Scanlon TC, Chevalier-Larsen E, Merry DE, Trifiro MA (2003) Transglutaminase potentiates ligand-dependent proteasome dysfunction induced by polyglutamine-expanded androgen receptor. Hum Mol Genet 12:1497–1506 Mankodi A (2008) Myotonic dystrophies. Neurol India 56:298–304 Margolis RL (2002) The spinocerebellar ataxias: order emerges from chaos. Curr Neurol Sci Rep 2:447–456 Margolis RL, Holmes SE, Rosenblatt A, Gourley L, O’Hearn E, Ross CA, Seltzer WK, Walker RH, Ashizawa T, Rasmussen A, Hayden M, Almqvist EW, Harris J, Fahn S, Macdonald ME, Mysore J, Shimohata T, Tsuji S, Potter N, Nakaso K, Adachi Y, Nakashima K, Bird T, Krause A, Greenstein P (2004) Huntington’s disease like 2 (HDL-2) in North America and Japan. Ann Neurol 56:670–674 Margolis RL, Li SH, Young WS, Wagster MV, Stine OC, Kidwai AS, Ashworth RG, Ross CA (1996) DRPLA gene (atrophin-1) sequence and mRNA expression in human brain. Brain Res Mol Brain Res 36:219–226 März P, Probst A, Lang S, Schwager M, Rose-John S, Otten U, Ozbek S (2004) Ataxin-10, the spinocerebellar ataxia type 10 neurodegenerative disorder protein, is essential for survival of cerebellar neurons. J Biol Chem 279:35542–35550 Mastroberardino PG, Iannocola C, Nardacci R, Bernassola F, De Lurenzi V, Melino G, Moreno S, Pavone F, Oliverio S, Fésüs L, Piacentini M (2002) ‘Tissue’ transglutaminase ablation reduces neuronal death and prolongs survival in a mouse model of Huntington’s disease. Cell Death Differ 9:873–880 Matsuura T, Yamagata T, Burgess DL, Rasmussen A, Grewal RP, Watase K, Khajavi M, McCall AE, Davis CF, Zu L, Achari M, Pulst SM, Alonso E, Noebels JL, Nelson DL, Zoghbi HY, Ashizawa T (2000) Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nat Genet 26:191–194 354 A.J.L. Cooper and J.P. Blass Matsuyama Z, Yanagisawa NK, Aoki Y, Black JL 3rd, Lennon VA, Mori Y, Imoto K, Inuzuka T (2004) Polyglutamine repeats of spinocerebellar ataxia 6 impair the cell-death-preventing effect of CaV2.1 Ca 2+ channel – loss of-function cellular model of SCA6. Neurobiol Dis 17: 198–204 Meola G, Moxley RT 3rd (2004) Myotonic dystrophy type 2 and related myotonic disorders. J Neurol 251:1173–1182 Messaed C, Rouleau GA (2009) Molecular mechanisms underlying polyalanine diseases. Neurobiol Dis 34:397–405 Miller RC, Tewari A, Miller JA, Garbern J, Van Stavern GP (2009) Neuro-ophthalmologic features of spinocerebellar ataxia type 7. J Neuroophthalmol 29:180–186 Milnerwood AJ, Gladding CM, Pouladi MA, Kaufman AM, Hines R M, Boyd JD, Ko RW, Vasuta OC, Graham RK, Hayden MR, Murphy TH, Raymond LA (2010) Early increase in extrasy- naptic NMDA receptor s ignaling and expression contributes to phenotype onset in Huntington’s disease mice. Neuron 65:178–190 Mitra S, Tsvetkov AS, Kinkbeiner S (2009) Protein turnover and inclusion body formation. Autophagy 5:1037–1038 Mizutani A, Wang L, Rajan H, Vig PJ, Alaynick WA, Thaler JP, Tsai CC (2005) Boat, an AXH domain protein, suppresses the cytotoxicity of mutant ataxin-1. EMBO J 24:3339–3351 Mutsuddi M, Marshall CM, Benzow KA, Koob MD, Rebay I (2004) The Spinocerebellar ataxia 8 noncoding RNA causes neurodegeneration and associates with stauffen in Drosphila.CurrBiol 14:302–308 Nagafuchi S, Yanagisawa H, Sato K, Shirayama T, Ohsaki E, Bundo M, Takeda T, Tadokoro K, Kondo I, Murayama N, et al (1994) Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nat Genet 6:14–18 Nasrallah IM, Minarcik JC, Golden JA (2004) A polyalanine tract expansion in Arx forms intranuclear inclusions and results in increased cell death. J Cell Biol 167:411–416 Nguyen HD, Hall CK (2004) Molecular dynamics of spontaneous fibril formation by random-coil peptides. Proc Natl Acad Sci USA 101:16180–16185 Nicholls DG (2009) Mitochondrial calcium function and dysfunction in the central nervous system. Biochim Biophys Acta 1787:1416–1424 Obrietan K, Hoyt KR (2004) CRE-mediated transcription is increased in Huntington’s disease transgenic mice. J Neurosci 24:791–796 Ona VO, Li M, Vonsatell J-P, Andrews LJ, Khan SQ, Chung WM, Frey AS, Menon AS, Li XJ, Stieg PE, Yuan J, Penney JB, Young AB, Cha JH, Friedlander RM (1999) Inhibition of caspase-1 slows disease progression in a mouse model of Huntington’s disease. Nature 399: 263–267 Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, Frants RR (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca 2+ channel gene CACNL1A4. Cell 87:543–552 Orr HT, Chung MY, Banfi S, Kwiatkowski TJ, Jr Servadio A, Beaudet AL, McCall AE, Duvick LA, Ranum LP, Zoghbi HY (1993) Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet 4:221–226 Ortega Z, Díaz-Hernández M, Lucas JJ (2007) Is the ubiquitin-proteasome system impaired in Huntington’s disease? Cell Mol Life Sci 64:2245–2257 Pandolfo M, Pastore A (2009) The pathogenesis of Friedreich ataxia and the structure and function of frataxin. J Neurol 256(Suppl 1):9–17 Panov AV, Burke JR, Strittmatter WJ, Greenamayre JT (2003) In vitro effects of polyglu- tamine tracts on Ca 2+ -dependent depolarization of rat and human mitochondria: relevance to Huntington’s disease. Arch Biochem Biophys 410:1–6 Panov AV, Gutekunst CA, Leavitt BR, Hayden MR, Burke JR, Strittmatter WJ, Greenamayre JT (2002) Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat Neurosci 5:731–736 . the A n domains may (1) have a role in repression, (2) act as spacers or hinges, or (3) play important roles in correct protein–protein interactions and protein–DNA interactions during transcription ptosis, and epicanthus inversus (BPES) are inherited in an autosomal dominant fashion. Holoprosencephaly (HPE) is a severe developmental disease resulting in death in infancy and the causative. 2009). A mutation in the junctophilin-3 (JPH3) gene at chromosome 16q24.3 in a vari- ably spliced exon gives rise to an autosomal dominantly inherited disease that is clinically indistinguishable from