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Spinocerebellar Ataxia Type 17

Synonyms: SCA17, HDL4, Huntington Disease-like 4

, MD, PhD, , MD, PhD, , MD, PhD, , MD, PhD, and , MD, PhD.

Author Information
, MD, PhD
Associate Professor , Department of Pathology
Brain Research Institute
Niigata University
Niigata, Japan
, MD, PhD
Professor, Department of Molecular Neuroscience
Brain Research Institute
Niigata University
Niigata, Japan
, MD, PhD
Department of Clinical Research
Saigata National Hospital
National Hospital Organization
Niigata, Japan
, MD, PhD
Professor, Department of Neurology
University of Tokyo Graduate School of Medicine
Tokyo, Japan
, MD, PhD
Professor, Department of Pathology
Brain Research Institute
Niigata University
Niigata, Japan

Initial Posting: ; Last Update: May 17, 2012.

Summary

Disease characteristics. Spinocerebellar ataxia type 17 (SCA17) is characterized by ataxia, dementia, and involuntary movements, including chorea and dystonia. Psychiatric symptoms, pyramidal signs, and rigidity are common. The age of onset ranges from three to 55 years. Individuals with full-penetrance alleles develop neurologic and/or psychiatric symptoms by age 50 years. Ataxia and psychiatric abnormalities are frequently the initial findings, followed by involuntary movement, parkinsonism, dementia, and pyramidal signs. Brain MRI shows variable atrophy of the cerebrum, brain stem, and cerebellum. The clinical features correlate with the length of the polyglutamine expansion but are not absolutely predictive of the clinical course

Diagnosis/testing. The diagnosis of SCA17 relies on molecular genetic testing to detect an abnormal CAG/CAA repeat expansion in TBP, the only gene in which mutations are known to cause SCA17. Affected individuals usually have more than 42 repeats. Such testing detects 100% of affected individuals. The CAA and CAG codons both encode glutamine residues resulting in a polyglutamine expansion mutation.

Management. Treatment of manifestations: psychotropic medications for psychiatric problems, antiepileptic drugs for seizures (AEDs); botulinum toxin injections for dystonia; and adaptation of the environment to accommodate dementia.

Prevention of secondary complications: Side effects of psychotropic medications and AEDs may require total or intermittent discontinuation of the treatment or reduction in dose.

Surveillance: Annual or semiannual evaluation by a neurologist or more frequently if symptoms are progressing rapidly.

Agents/circumstances to avoid: Sedative/hypnotic agents, such as ethanol or certain medications, may exacerbate incoordination.

Genetic counseling. SCA17 is inherited in an autosomal dominant manner. Offspring of affected individuals are at a 50% risk of inheriting the expanded TBP allele. The age of onset, severity, specific symptoms, and progression of the disease are variable and cannot be precisely predicted by family history or size of expansion. Prenatal diagnosis is possible for fetuses at 50% risk if the diagnosis has been confirmed in at least one relative; requests for prenatal testing of typically adult-onset diseases are uncommon.

Diagnosis

Clinical Diagnosis

Spinocerebellar ataxia type 17 (SCA17) is suspected in individuals with the following:

  • Psychiatric symptoms or dementia
  • Cerebellar ataxia or involuntary movement

Molecular Genetic Testing

Gene. TBP, encoding the TATA-box-binding protein, is the only gene in which mutations are known to cause SCA17. The expansion of an imperfect CAG/CAA repeat is the only mutation observed [Koide et al 1999, Nakamura et al 2001]. Because both codons CAA and CAG encode a glutamine residue, the repeat results in a variable tract of glutamines.

Allele sizes. The structure of the repeat sequence is (CAG)3 (CAA)3 (CAG)x CAA CAG CAA (CAG)y CAA CAG. Allele sizes are determined by counting all triplet repeats; for example, if x=9 in (CAG)x and y=16 for (CAG)y, the total number of CAG/CAA repeats in the example above would be 36, translating to 36 glutamine residues in the protein.

  • Normal alleles. 25 to 40 CAG/CAA repeats
  • Mutable normal alleles. Not reported to date
  • Reduced penetrance alleles. 41 to 48 CAG/CAA repeats. An individual with an allele in this range may or may not develop symptoms. The significance of alleles of 41 and 44 repeats is particularly controversial because penetrance is estimated to be 50%, making genotype-phenotype correlations difficult. One symptomatic individual having 41 repeats and four symptomatic persons having 42 repeats were reported recently [Nanda et al 2007, Nolte et al 2010].
  • Full penetrance alleles. 49 or greater CAG/CAA repeats. The largest repeat size reported to date is 66 [Maltecca et al 2003].

CAA CAG CAA interruption. The CAA CAG CAA interruption between (CAG)x and (CAG)y is present in all expanded alleles that are stably transmitted (i.e., the allele size is unchanged during meiosis).

The CAA CAG CAA interruption between (CAG)x and (CAG)y was absent in two families with allele size instability (i.e., change in allele size) during transmission [Zühlke et al 2001, Maltecca et al 2003]. Thus, loss of this interruption may be a prerequisite of instability in SCA17 as in other diseases caused by repeat expansions [Maltecca et al 2003, Zühlke et al 2003b, Zühlke et al 2005].

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 17

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
TBPTargeted mutation analysisCAG/CAA repeat expansion100%

1. The ability of the test method used to detect a mutation that is present in the indicated gene

Testing Strategy

To confirm/establish the diagnosis in a proband, molecular genetic testing must reveal an expanded CAG/CAA repeat in TBP.

Predictive testing for at-risk asymptomatic adult family members requires prior confirmation of the diagnosis in an affected family member.

Prenatal diagnosis for at-risk pregnancies requires prior confirmation of the diagnosis in an affected family member.

Clinical Description

Natural History

The main symptoms of spinocerebellar ataxia type 17 (SCA17) are ataxia (95%), dementia (~90%), and involuntary movements (~70%), including chorea and dystonia (blepharospasm, torticollis, writer's cramp, foot dystonia) [Toyoshima et al 2004b]. Psychiatric symptoms, pyramidal signs, and rigidity are common.

Onset ranges from age three to 75 years (mean: 34.6 years) [Stevanin & Brice 2008]. All individuals with full penetrance alleles develop neurologic and/or psychiatric symptoms by age 50 years [Koide et al 1999; Fujigasaki et al 2001; Nakamura et al 2001; Zühlke et al 2001; Silveira et al 2002; Maltecca et al 2003; Stevanin et al 2003; Zühlke et al 2003b; Bauer et al 2004; Hagenah et al 2004; Oda et al 2004; Toyoshima, personal observation].

Although the disease course is variable, ataxia and psychiatric abnormalities are frequently the initial findings followed by involuntary movement, parkinsonism, dementia, and pyramidal signs.

Brain MRI shows variable atrophy of the cerebrum, brain stem, and cerebellum (Figure 1). Most people present with cerebellar atrophy. The age of the individual and the length of CAG/CAA repeat influence the degree of atrophy. For example, in older individuals – even those with a small full-penetrance allele – severe atrophy is present on brain MRI. High-intensity T2-weighted images and selective atrophy on caudate nucleus are not observed. Some correlation of region of brain atrophy with clinical characteristics is seen [Lasek et al 2006].

Figure 1

Figure

Figure 1. Number of CAG/CAA repeats versus age of individuals with SCA17

Neuropathology. The brain shows atrophy of the striatum (more apparent in the caudate nucleus) and cerebellum. Histologically, neuronal loss is observed in the striatum and Purkinje cell layer. Loss of cerebral cortical neurons is seen in some individuals.

Immunohistochemistry for the expanded polyglutamine (polyQ) tracts shows diffuse labeling of the neuronal nucleoplasm.

Note: Intranuclear inclusions are a much less common finding than diffuse labeling. No labeling is detectable in the cytoplasm or in the neuropil. Glial cell involvement is occasionally seen.

In individuals who are homozygous for an expanded allele in the full-penetrance range, nuclear polyQ pathology involves other CNS regions including the cerebral cortex, thalamus, and brain stem [Toyoshima et al 2004a]. The abundant nuclear accumulation of polyQ in the cerebral cortices and subcortical nuclei (e.g., dorsomedian thalamic nucleus) are possibly associated with the prominent cognitive and behavioral decline in affected individuals.

Genotype-Phenotype Correlations

Heterozygotes

Clinical features. The length of the CAG/CAA repeat in TBP correlates with the clinical features based on data available from 52 individuals (50 from the literature and two unreported) (Table 2, Figure 2). As the information reported in the literature was incomplete, the percentage of each symptom may be underestimated [Koide et al 1999, Fujigasaki et al 2001, Nakamura et al 2001, Zühlke et al 2001, Silveira et al 2002, Maltecca et al 2003, Rolfs et al 2003, Stevanin et al 2003, Zühlke et al 2003a, Bauer et al 2004, Hagenah et al 2004, Oda et al 2004]. Of note is the high proportion of individuals with psychiatric problems and chorea.

Figure 2

Figure

Figure 2. The clinical features in SCA17 depend on the length of CAG/CAA repeats. The clinical features of SCA17 in each case are denoted by letter. For example, A-E denotes ataxia with parkinsonism.
A = ataxia
D = dementia or psychiatric (more...)

  • CAG/CAA repeat size from 43 to 50. More than 75% of individuals have intellectual deterioration; in some individuals intellectual problems and involuntary movements are the only signs. Psychiatric problems or dementia, parkinsonism, and chorea, a clinical constellation resembling Huntington disease, are more frequently observed in individuals with CAG/CAA repeats in this range than in individuals with larger repeats [Stevanin et al 2003, Bauer et al 2004, Toyoshima et al 2004a].
  • CAG/CAA repeat size from 43-47. Individuals with 43-47 repeat size tend to have a parkisonian phenotype [Kim et al 2009, Chen et al 2010].
  • CAG/CAA repeat size from 50-60. All individuals have ataxia and 75% have reduced intellectual function. Pyramidal signs (e.g., increased deep tendon reflexes) and dystonia are more common than in those with smaller repeats.
  • CAG/CAA repeat size greater than 60. Two individuals with repeats in this size range have been reported. The largest CAG/CAA repeat is 66 repeats, observed in a familial case [Maltecca et al 2003]. The child developed gait disturbance at age three years followed by spasticity, dementia, and psychiatric symptoms. The other child, who had a de novo CAG repeat expansion of 63 repeats, developed ataxia and intellectual deterioration at age six years followed later by spasticity [Koide et al 1999]. Brain MRI showed severe atrophy in the cerebrum, cerebellum, and brain stem.

Table 2. Frequency of Clinical Features in SCA17 Correlated with Repeat Size

CAG/CAA Repeat SizeAtaxiaDementia / Psychiatric SymptomsIncreased DTRs 1 DystoniaParkinsonismChorea
43-4993%90%45%7%42%39%
≥50100%75%55%40%25%10%

1. DTR = deep tendon reflex

Homozygotes

Four homozygous individuals and one compound heterozygous individual have been reported [Zühlke et al 2003b, Oda et al 2004, Toyoshima et al 2004a, Hire et al 2010]. Four individuals who were homozygous for 47 and 48 CAG/CAA repeats had onset in the fourth decade, not unlike the onset age predicted for heterozygotes [Zühlke et al 2003b, Toyoshima et al 2004a]. Their symptoms were severe and rapidly progressive, and in one individual differed from those of his parents, suggesting that the presence of two expanded alleles influences the severity and rate of progression of symptoms.

Penetrance

The penetrance of alleles of 41 to 44 repeats is estimated at 50% and the penetrance of alleles of 45 to 48 repeats is estimated at greater than 80% [Toyoshima et al 2004a].

Age of onset. The correlation between the size of the CAG/CAA repeat and the age of onset in SCA17 (Figure 3) is not as strong as in other disorders (SCA1, SCA2, SCA3, SCA6, SCA7, Huntington disease, DRPLA, SBMA [Kennedy disease]) caused by expansion of a polyglutamine tract [Rolfs et al 2003, Toyoshima et al 2004a].

Figure 3

Figure

Figure 3. Correlation in SCA17 between age at onset and length of CAG/CAA repeat

Anticipation

Instability of the CAG repeat in germline transmission is not clear in SCA17 [Fujigasaki et al 2001, Nakamura et al 2001, Shatunov et al 2004]. CAG repeats in TBP have two distinct configurations, which are differentiated by the absence or presence of CAA interruptions. In German and Italian families, an absence of CAA interruptions resulting in longer pure tracts of CAG repeats was detected. It is of note that intergenerational instability and anticipation were documented in these families[ Zühlke et al 2001, Maltecca et al 2003] CAA interruptions may serve as a limiting element for further expansion of CAG repeats in TBP [Gao et al 2008].

The phenomenon termed anticipation, a trend toward an earlier age at onset and more severe disease manifestations in offspring of an affected individual, is infrequently documented in families with SCA17. In addition, because of low penetrance of the intermediate alleles (41 to 48 repeats), the age of onset, severity, specific symptoms, and progression of the disease are variable and cannot be predicted by family history or size of expansion.

Prevalence

Fewer than 100 families with SCA17 have been reported.

The prevalence of SCA17 in the Japanese population is estimated at 0.47:1,000,000. SCA17 accounts for approximately 0.3% of autosomal dominant SCA [Maruyama et al 2002].

The minimum prevalence of SCA17 in northeast England is 0.16:100,000 [Craig et al 2005].

In a study of the Yugoslav population, none of the 115 individuals with autosomal dominant cerebellar ataxia or simplex cases of adult-onset ataxia had SCA17 [Alendar et al 2004].

The prevalence of SCA17 may be underestimated because some individuals with SCA17 have a phenotype similar to that of Huntington disease.

Differential Diagnosis

The differential diagnosis of spinocerebellar ataxia type 17 (SCA17) includes many of the other hereditary ataxias that are summarized in the Hereditary Ataxia Overview and described in detail for specific ataxias, including SCA1, SCA2, SCA3, and SCA7.

DRPLA is a progressive disorder of ataxia, choreoathetosis, and dementia or character changes in adults and ataxia, myoclonus, epilepsy, and progressive intellectual deterioration in children.

Huntington disease (HD) also needs to be considered [Rolfs et al 2003]. HD is a progressive disorder of motor, cognitive, and psychiatric disturbances. The mean age of onset is 35 to 44 years and the median survival is 15 to 18 years after onset.

Bauer et al [2004] reported nine individuals with TBP alleles larger than 45 CAG/CAA repeats among 1,712 individuals with Huntington disease-like (HDL), and observed that CAG/CAA repeat expansions in TBP represented a more common monogenic cause for a HD-like phenotype than Huntington disease-like 1 (HDL-1) [Xiang et al 1998] or Huntington disease-like 2 (HDL-2) [Margolis et al 2001]. Therefore SCA17 is also referred to as Huntington disease-like disorder 4 (HDL-4) [Stevanin et al 2003, Schneider et al 2007, Harbo et al 2009].

Lin et al [2007] reported an individual with SCA17 whose findings of ataxia, autonomic dysfunction, parkinsonism, supranuclear palsy, and cognitive impairment resembled multiple system atrophy.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 17 (SCA17), the following evaluations are recommended:

  • Neuropsychological testing to evaluate for dementia and/or psychiatric disturbance
  • Brain MRI to evaluate areas and degree of atrophy
  • Neurology consultation, if not completed prior to initial diagnosis
  • Medical genetics consultation

Treatment of Manifestations

The following are appropriate:

  • Treatment of psychiatric problems with appropriate psychotropic medications
  • Treatment of seizures with antiepileptic drugs (AEDs)
  • Adaptation of environment and care to the level of dementia
  • Treatment of dystonia with local injections of botulinum toxin

Prevention of Secondary Complications

The side effects of psychotropic medications and AEDs (e.g., depression, sedation, nausea, restlessness, headache, neutropenia, and tardive dsykinesia) can be major secondary complications in persons with SCA17. For some individuals, the side effects of certain therapeutics may be worse than the symptoms of the disease; such individuals may benefit from total or intermittent discontinuation of the treatment or reduction in dose.

Surveillance

Affected individuals should be followed annually or semiannually by a neurologist or more frequently if symptoms are progressing rapidly, as may happen in the advanced stages [Toyoshima et al 2004a].

Agents/Circumstances to Avoid

Agents with sedative/hypnotic properties, such as ethanol or certain medications, may markedly increase incoordination.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Affected women may be on medications (e.g., antiepileptics) to control the symptoms of SCA17. Because some medications can have adverse effects on the developing fetus, a thorough discussion of the medical benefits vs. risks to the fetus of such medications before pregnancy (or, in the case of an unplanned pregnancy, immediately after pregnancy is determined) is appropriate.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Spinocerebellar ataxia type 17 (SCA17) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband *

  • Approximately 50% of individuals diagnosed with SCA17 have an affected parent.
  • Thirty-eight percent of individuals with SCA17 are simplex cases (i.e., only one affected person in the family). In most cases, molecular genetic testing of the parents has not been performed.
  • A proband with SCA17 may have the disorder as a result of a de novo expansion in TBP. The proportion of cases caused by de novo expansions is unknown [Koide et al 1999, Shatunov et al 2004].
  • If an expansion (>42 CAG/CAA repeats) of TBP cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo expansion in the proband. Expansion from a mutable normal allele in the parent is also a possibility, although no instances have been reported.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing of TBP.

Note: Although approximately 50% of individuals diagnosed with SCA17 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members because of its extremely variable phenotype, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance in a parent.

* Based on the family history of the 37 reported families with affected individuals and an unreported family with two affected individuals [Koide et al 1999; Fujigasaki et al 2001; Nakamura et al 2001; Zühlke et al 2001; Silveira et al 2002; Maltecca et al 2003; Rolfs et al 2003; Stevanin et al 2003; Zühlke et al 2003a; Bauer et al 2004; Hagenah et al 2004; Oda et al 2004; Toyoshima, personal observations]

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If one of the parents of the proband has an expanded TBP allele, the risk to the sibs of inheriting the expanded CAG/CAA allele is 50%. The age of onset, severity, specific symptoms, and progression of the disease are variable and cannot be precisely predicted by family history or size of expansion.
  • If an expansion (>42 CAG/CAA repeats) of TBP cannot be detected in the DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband

  • Each child of an individual with SCA17 has a 50% chance of inheriting the expanded TBP allele.
  • The age of onset, severity, specific symptoms, and progression of the disease are variable and cannot be precisely predicted by family history or size of expansion.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected or has an expanded TBP allele, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has gene expansion or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Testing of at-risk asymptomatic adults at risk for SCA17 is possible using the techniques described in Molecular Genetic Testing. Such testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. When testing at-risk individuals for SCA17, an affected family member should be tested first to confirm the molecular diagnosis of SCA17 in the family.

Testing for the disease-causing expansion in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply "the need to know."

Testing of asymptomatic at-risk adult family members usually involves pretest interviews in which the motives for requesting the test, the individual's knowledge of SCA17, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Another issue to consider is the implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and genetic counseling.

Testing of at-risk asymptomatic individuals younger than age 18 years. Consensus holds that individuals younger than age 18 years at risk for adult-onset disorders should not have testing in the absence of symptoms. The principal arguments against such testing are that it removes the individual's choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications. Individuals younger than 18 years of age who are symptomatic usually benefit from having a specific diagnosis established. See also the National Society of Genetic Counselors points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for (typically) adult-onset conditions such as SCA17 are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified in an affected family member.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • NCBI Genes and Disease
  • Spinocerebellar Ataxia: Making an Informed Choice about Genetic Testing
    Booklet providing information about Spinocerebellar Ataxia
  • Ataxia UK
    Lincoln House
    1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: 0845 644 0606 (helpline); 020 7582 1444 (office); +44 (0) 20 7582 1444 (from abroad)
    Email: helpline@ataxia.org.uk; office@ataxia.org.uk
  • euro-ATAXIA (European Federation of Hereditary Ataxias)
    Ataxia UK
    9 Winchester House
    Kennington Park
    London SW9 6EJ
    United Kingdom
    Phone: +44 (0) 207 582 1444
    Email: marco.meinders@euro-ataxia.eu
  • International Network of Ataxia Friends (INTERNAF)
    Email: internaf-owner@yahoogroups.com
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org
  • Spanish Ataxia Federation (FEDAES)
    Spain
    Phone: 34 983 278 029; 34 985 097 152; 34 634 597 503
    Email: sede.valladolid@fedaes.org; sede.gijon@fedaes.org; sede.bilbao@fedaes.org
  • CoRDS Registry for the National Ataxia Foundation
    Sanford Research
    2301 East 60th Street North
    Sioux Falls SD 57104
    Phone: 605-312-6423
    Email: Cords@sanfordhealth.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Spinocerebellar Ataxia Type 17: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
TBP6q27TATA-box-binding proteinTBP homepage - Mendelian genesTBP

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Spinocerebellar Ataxia Type 17 (View All in OMIM)

600075TATA BOX-BINDING PROTEIN; TBP
607136SPINOCEREBELLAR ATAXIA 17; SCA17

Normal allelic variants. TBP has eight exons (NM_003194.4); the CAG/CAA repeat tract is in exon 3. Two transcript variants encoding different protein isoforms were identified (Table A, Gene Symbol TBP). Normal allelic variants have between 25 to 42 CAG/CAA repeats.

Pathologic allelic variants. The CAG/CAA repeat length in individuals with TBP ranges from 43 to 66 repeats.

Normal gene product. TATA-box-binding protein (TBP) is also called transcription factor IID (TFIID). Human TBP has 339 amino acids (NP_003185.1) and a molecular size of 37.8 kd. TBP is an important general transcription initiation factor and is the DNA-binding subunit of RNA polymerase II transcription factor D, the multi-subunit complex crucial for the expression of most genes.

Abnormal gene product. Because TBP is a fundamental transcription factor expressed ubiquitously in all organs including the CNS, the question of whether loss of TBP function plays a role in the pathogenesis of SCA17 remains to be addressed. In a homozygote, however, no abnormality was observed in growth, and pathologic examination showed no specific changes in the visceral organs [Toyoshima et al 2004a]. Taking into consideration the ubiquitous presence of TBP, the selective neuronal degeneration suggests no significant loss of protein function in individuals with SCA17.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

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Chapter Notes

Revision History

  • 17 May 2012 (me) Comprehensive update posted live
  • 1 August 2007 (me) Comprehensive update posted to live Web site
  • 29 March 2005 (me) Review posted to live Web site
  • 24 August 2004 (yt) Original submission
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