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Spinocerebellar Ataxia Type 14

Synonym: SCA14

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

Author Information

Initial Posting: ; Last Update: April 18, 2013.

Summary

Clinical characteristics.

Spinocerebellar ataxia type 14 (SCA14) is characterized by slowly progressive cerebellar ataxia, dysarthria, and nystagmus. Axial myoclonus, cognitive impairment, tremor, and sensory loss may also be observed. Parkinsonian features including rigidity and tremor have been described in some families. Findings seen in other ataxia disorders (e.g., dysphagia, dysphonia) may also occur in SCA14. Age of onset ranges from childhood to the sixth decade. Life span is not shortened.

Diagnosis/testing.

The diagnosis of SCA14 relies on the use of molecular genetic testing to identify a pathogenic variant in PRKCG.

Management.

Treatment of manifestations: Clonazepam or valproic acid to help improve axial myoclonus; canes and walkers to help prevent falls; modification of the home (grab bars, raised toilet seats, ramps for motorized chairs); weighted eating utensils and dressing hooks to maintain independence; speech therapy and communication devices for those with dysarthria.

Prevention of secondary complications: Dietary modifications when dysphagia becomes troublesome to reduce the risk for aspiration and maintain caloric intake.

Surveillance: Annual evaluation of gait, coordination, and speech.

Agents/circumstances to avoid: Obesity can exacerbate difficulties with ambulation and mobility.

Other: Tremor-controlling drugs do not work well for cerebellar tremors.

Genetic counseling.

SCA14 is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting the PRKCG pathogenic variant. Prenatal testing is possible if the pathogenic variant in the family has been identified; however, requests for prenatal diagnosis of (typically) adult-onset diseases are not common.

Diagnosis

Clinical Diagnosis

No features of spinocerebellar ataxia type 14 (SCA14) are pathognomonic; therefore, diagnosis depends on molecular genetic testing.

Molecular Genetic Testing

Gene. The only gene in which pathogenic variants are known to cause SCA14 is PRKCG, which encodes protein kinase C gamma type (PCKγ) [Chen et al 2003].

Clinical testing

Table 1.

Summary of Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 14

Gene 1Test MethodVariants Detected 2Variant Detection Frequency by Test Method 3
PRKCGSequence analysis 4Sequence variantsUnknown 5
Sequence analysis of select exonsSequence variants in exon6Unknown 5
Deletion/duplication analysis 7(Multi)exon or whole-gene deletions/duplicationsUnknown 8
1.
2.

See Molecular Genetics for information on allelic variants

3.

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

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

The prevalence of SCA14 and the full spectrum of pathogenic variants are unknown. To date, large-scale screening for pathogenic variants has been limited to methods that preferentially detect single-nucleotide variants and other small pathogenic variants in the coding region. However, it is possible that intron changes, duplications, and deletions that can only be identified using other test methods exist.

6.

Exons may vary by laboratory; it is estimated that about 50% of pathogenic variants may be in exon 4.

7.

Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

8.

No deletions or duplications involving PRKCG as causative of SCA14 have been reported; diagnostic yield may be very low.

Testing Strategy

To confirm/establish the diagnosis in a proband. Establishing the diagnosis in a proband relies on molecular genetic testing.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the pathogenic variant in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant in the family.

Clinical Characteristics

Clinical Description

Clinical features of spinocerebellar ataxia type 14 (SCA14) are summarized in Table 2 (pdf). The initial finding is almost always subtle unsteadiness of gait that slowly worsens. Accurate age of onset is often difficult to determine. The usual onset is in early adult life, typically in the 30s (age range: 3-70 years) [Yamashita et al 2000, Brkanac et al 2002, Chen et al 2003, Hiramoto et al 2006, Vlak et al 2006].

Mild to moderate dysarthria is common. Findings seen in other ataxia disorders (e.g., dysphagia, dysphonia) may also occur in SCA14.

More than half of individuals have horizontal jerk nystagmus or saccadic intrusions.

One third of affected families show mild or moderate sensory loss, mostly decreased vibration sense.

Tendon reflexes vary from decreased to normal to hyperactive. Extensor plantar reflexes are present in a few cases.

Five persons in a Japanese family with early onset had episodic axial myoclonus manifest as irregular tremulous movements of the trunk and head lasting minutes to hours [Yamashita et al 2000]. Although this feature has not been observed in most families with SCA14, mild persistent multifocal myoclonus has been reported in a person with early onset [Vlak et al 2006] and a few other cases [van de Warrenburg et al 2003, Klebe et al 2005, Foncke et al 2010]. An individual homozygous for a deletion that results in extension of the protein by 13 amino acids had early onset and developed generalized myoclonus in late teenage years [Asai et al 2009]. Identification of PRKCG pathogenic variants in persons with phenotypes similar to progressive myoclonic ataxia (Ramsay Hunt syndrome) [Visser et al 2007] and myoclonus-dystonia [Foncke et al 2010] suggest that SCA14 should be considered in individuals with these clinical syndromes.

Stevanin et al [2004] reported facial fasciculations and/or myokymia in several individuals in one family.

Parkinsonian features including rigidity and tremor were described in some families [Stevanin et al 2004, van de Warrenburg et al 2004, Fahey et al 2005, Klebe et al 2005, Dalski et al 2006, Vlak et al 2006, Nolte et al 2007, Visser et al 2007, Asai et al 2009 ].

Other extrapyramidal findings such as dystonia have also been reported [Nolte et al 2007, Visser et al 2007, Miura et al 2009, Foncke et al 2010].

Cognitive deficits may be part of the SCA14 phenotype [Stevanin et al 2004]. Intellectual impairment, attention deficit, and deficient executive function were identified in 13 of 18 (72%) individuals in a French family [Stevanin et al 2004] and in a few families in another French study [Klebe et al 2005]. Two studies in Japanese families found severe intellectual disability in one individual with early onset [Hiramoto et al 2006] and mild cognitive deficits in two members with adult-onset disease from another family [Miura et al 2009]. Three affected individuals in a Norwegian family were described to have learning difficulty with IQ in the normal to low range [Koht et al 2012].

Memory loss after age 70 years observed in several affected individuals may be coincidentally occurring age-related dementia [Chen et al 2005]. Depression found in some families with SCA14 [Chen et al 2003, Chen et al 2005, Nolte et al 2007, Wieczorek et al 2007, Miura et al 2009] may reflect general dysfunction in progressive diseases, rather than a feature specific to SCA14.

Hearing impairment was observed in two persons with SCA14 [Stevanin et al 2004, Klebe et al 2005], but it is not clear if the impairment results from PRKCG pathogenic variants.

One person with intractable epilepsy was reported in a Japanese family [Hiramoto et al 2006].

Almost all persons remain ambulatory, but many fall frequently and require the assistance of stair railings and canes. Some people require a wheelchair late in life. Life span is not shortened and many persons live beyond age 70 years.

Neuroimaging. Brain MRI in all affected persons has shown mild to moderately severe cerebellar atrophy that is primarily midline. Atrophy of the brain stem or cerebral cortex is not observed.

Genotype-Phenotype Correlations

Because all reported features have not been assessed in detail in all affected individuals, evidence is currently insufficient to establish a specific correlation between genotypes and phenotypes.

Some individuals with SCA14, particularly those with younger age of onset, exhibit axial myoclonus [Yamashita et al 2000, Yabe et al 2003, Klebe et al 2005], multifocal myoclonus [Vlak et al 2006, Visser et al 2007, Asai et al 2009], or myokymia [Stevanin et al 2004]. However, the clinical phenotype in these families is not identical and the PRKCG pathogenic variants involved do not cluster in one region.

Cognitive deficits have been reported in a French family with a pathogenic variant in exon 18 affecting the C4 domain [Stevanin et al 2004] and in several French and Japanese families with different pathogenic variants in exon 4 affecting the C1 domain. In the American families with pathogenic variants in other PRKCG regions, two persons have had normal neuropsychological testing and two have developed dementia in older age [Chen et al 2005]; however, most affected persons have not had detailed cognitive testing. The true prevalence of this problem in SCA14 is yet to be determined.

For the most part, pathogenic variants have been described in single families only, although compiled results of clinical testing have not been made public.

Pathogenic variants that have occurred in more than one family include p.His101Tyr [Chen et al 2003, Nolte et al 2007], the founder p.Gly118Asp variant in the Dutch population [van de Warrenburg et al 2003, Verbeek et al 2005b, Visser et al 2007], p.Phe643Leu in two French families, and p.Gly128Asp [Chen et al 2003, Morita et al 2006, Miura et al 2009]. Features such as myoclonus, cognitive deficits, tremor, and dystonia can differ between families that have the same pathogenic variant.

Similarly, different pathogenic variants affecting the same residues (i.e., p.His101Tyr, p.His101Gln, and deletion p.Lys100His101del; p.Ser119Pro and p.Ser119Phe; p.Gly123Arg and p.Gly123Glu; and p.Cys131Arg and p.Cys131Tyr) may produce different extracerebellar symptoms (see Table 2).

Penetrance

Too few families have been studied to specify the penetrance or to determine if decreased penetrance is related to specific pathogenic variants. However, clinically unaffected individuals with PRKCG pathogenic variants who are older than age 60 years have been described in at least two families [Yabe et al 2003, Chen et al 2005]. In general, penetrance is high when late-onset cases are included [Klebe et al 2005].

Anticipation

SCA14 is not caused by an expansion of a nucleotide repeat. Earlier onset of disease in later generations suggestive of anticipation [Brkanac et al 2002, van de Warrenburg et al 2004] most likely reflects either heightened awareness in families known to have ataxia or stochastic influences that contribute to the extreme variation in age of onset.

Nomenclature

The term olivopontocerebellar atrophy (OPCA) was used to denote SCA in the past. Prior to the discovery of the genes that differentiate members of the group, the autosomal dominant cerebellar ataxias (ADCA) were divided into subgroups depending on the presence of clinical features in addition to ataxia. ADCA III, to which SCA14 would belong, referred to a pure form of late-onset cerebellar ataxia without additional features.

Prevalence

SCA14 probably accounts for fewer than 1% of unselected cases of autosomal dominant ataxia. With the exception of the index family in which linkage to the SCA14 locus was first demonstrated, no other PRKCG pathogenic variant was identified in 113 individuals of Japanese heritage with autosomal dominant SCA [Basri et al 2007].

In two studies involving a total of 310 individuals with ataxia not caused by expansions in the genes for SCA1, 2, 3, 6, 7, and 8, four familial and two simplex cases (i.e., individuals with no family history of ataxia) were found to have pathogenic missense variants or deletions in PRKCG [Chen et al 2005].

A founder variant (p.Gly118Asp) has been reported in the Dutch population [Verbeek et al 2005b].

Differential Diagnosis

Persons with spinocerebellar ataxia type 14 (SCA14) may present with ataxia that is indistinguishable from other adult-onset inherited or acquired ataxias (see Ataxia Overview). SCA14 should particularly be considered if the proband or an affected relative displays axial myoclonus or cognitive impairment.

SCA14 may mimic other disorders that are characterized by myoclonus including progressive myoclonus epilepsy with ataxia caused by pathogenic variants in PRICKLE1 [Bassuk et al 2008] and myoclonus-dystonia caused by pathogenic variants in SGCE (formerly DYT11) [Foncke et al 2010]. Conversely, these other diagnoses can be considered if a diagnosis of SCA14 is entertained because of the presence of myoclonus, but a pathogenic variant is not detected in PRKCG.

In the absence of linkage assignment to a specific SCA locus, the most pragmatic and cost-effective testing strategy is to test first for pathogenic variants in the genes causing the more prevalent autosomal dominant SCAs (i.e., SCA1, 2, 3, 6, 7, and 8) and if none are found, to proceed with testing for a PRKCG pathogenic variant.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 14 (SCA14), the following evaluations are recommended:

  • Medical history
  • Neurologic examination
  • Brain MRI
  • Clinical genetics consultation

Treatment of Manifestations

Axial myoclonus may be improved by clonazepam or valproic acid [Yamashita et al 2000].

Although neither exercise nor physical therapy has been shown to stem the progression of incoordination or muscle weakness, individuals should continue to be active.

Canes and walkers help prevent falls. Modification of the home with such conveniences as grab bars, raised toilet seats, and ramps to accommodate motorized chairs may be necessary. Weighted eating utensils and dressing hooks help maintain a sense of independence.

Speech therapy and communication devices such as writing pads and computer-based devices may benefit those with dysarthria.

When dysphagia becomes troublesome, video esophagram can identify the consistency of food least likely to trigger aspiration.

Prevention of Secondary Complications

No dietary factor has been shown to curtail symptoms; however, vitamin supplements are recommended, particularly if caloric intake is reduced.

Weight control is important because obesity can exacerbate difficulties with ambulation and mobility.

Surveillance

Gait, coordination, and speech should be evaluated annually.

Agents/Circumstances to Avoid

Alcohol and sedation may make gait and coordination worse.

Evaluation of Relatives at Risk

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

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.

Other

Tremor-controlling drugs do not work well for cerebellar tremors.

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 14 (SCA14) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Many individuals diagnosed with SCA14 have an affected parent.
  • As most PRKCG pathogenic variants reported to date are private, occurring in only a single family, it is clear that de novo pathogenic variants may arise in this gene. Too few unselected cases have been studied to derive a reliable estimate of the proportion of cases that result from a de novo variant, and in none of the apparently simplex cases have both parents been available for evaluation.
  • It is recommended that both parents of a proband with an apparent de novo pathogenic variant be evaluated using molecular genetic testing.

Note: Although most individuals diagnosed with SCA14 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents.

  • If a parent of the proband is affected or has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
  • When the parents are clinically unaffected and a pathogenic variant cannot be detected in the DNA of either parent, the risk to the sibs of a proband is probably low; however, very few cases have been studied to date. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with SCA14 has a 50% chance of inheriting the pathogenic variant.

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 a pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo variant. Possible non-medical explanations including alternate paternity or undisclosed adoption or maternity (e.g., with assisted reproduction) 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.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the PRKCG pathogenic variant has been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis for SCA14 are possible.

Given that almost no reported PRKCG variants have been associated with functional evidence for pathogenicity, and that a rare benign polymorphism cannot be ruled out, results from molecular genetic testing should be used with extreme caution for prenatal diagnosis at the present time.

Requests for prenatal testing for adult-onset conditions such as SCA14 are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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.

  • 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
    Lincoln House, Kennington Park, 1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: +44 (0) 207 582 1444
    Email: smillman@ataxia.org.uk
  • 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
    Sanford Research
    2301 East 60th Street North
    Sioux Falls SD 57104
    Phone: 605-312-6423
    Email: sanfordresearch@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 14: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar
PRKCG19q13​.42Protein kinase C gamma typePRKCGPRKCG

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Spinocerebellar Ataxia Type 14 (View All in OMIM)

176980PROTEIN KINASE C, GAMMA; PRKCG
605361SPINOCEREBELLAR ATAXIA 14; SCA14

Molecular Genetic Pathogenesis

Mutated PKCγ aggregates in the cytoplasm of cultured cells transfected with mutated PKCγ expression vectors [Lin & Takemoto 2007, Seki et al 2007, Doran et al 2008], but the role of these aggregates in the pathogenesis of SCA14 is not known. When treated with an inducer of autophagy, cultured SH-SY5Y cells transfected with mutated PKCγ demonstrated accelerated clearance of aggregates, indicating that autophagy contributes to the degradation of mutated PKCγ [Yamamoto et al 2010]. In primary cultures of Purkinje cells transfected with mutated PKCγ, abnormal dendritic development occurred independent of aggregation [Seki et al 2009], translocation of mutated PKCγ in PC dendrites was prominently reduced, and both pruning of climbing fiber synapses from developing PCs and long-term depression expression were impaired [Seki et al 2011, Shuvaev et al 2011].

PKCγ is a serine-threonine kinase. Studies of the effect of SCA14-related pathogenic variants on kinase activity have not been consistent across groups, but a dominant negative effect has not been documented [Seki et al 2005, Verbeek et al 2005a, Lin et al 2007, Seki et al 2007, Verbeek et al 2008, Asai et al 2009].

Aprataxin (APTX), the gene associated with autosomal recessive ataxia with oculomotor apraxia type 1 (AOA1) [Moreira et al 2001], was found to be a preferential substrate of mutated PKCγ [Asai et al 2009]. This observation suggests that the pathogenesis of SCA14 may involve altered phosphorylation-dependent pathways.

Cells expressing mutated PKCγ exhibit increased oxidative stress-induced DNA damage and cell death [Seki et al 2007, Doran et al 2008, Asai et al 2009]. The ubiquitin-proteasome pathway has been implicated in this process [Seki et al 2007].

The observation that mutated PKCγ fails to phosphorylate TRPC channels, resulting in sustained Ca2+ entry into the cell, supports a role for abnormal Ca2+-mediated signaling in neurodegeneration [Adachi et al 2008].

A transgenic mouse model with ubiquitous expression of human mutated cDNA p.His101Tyr-PKCγ manifests loss of Purkinje cells at age four weeks and stereotypic clasping responses in the hind limbs [Zhang et al 2009].

Gene structure. PRKCG has 18 exons encompassing 25 kb of genomic DNA.

Benign variants. Multiple silent variants have been identified.

The variant c.285C>T was reported as a possible splice site variant [Chen et al 2005], but later was found to be a polymorphism in individuals of North African descent [Klebe et al 2005].

Note: A nucleotide change resulting in an amino acid substitution (p.Arg659Ser) reported in families with RP11 [Al-Maghtheh et al 1998] is likely a benign variant because a pathogenic variant in another gene (PRPF31) was later found to be causative in these families [Vithana et al 2001].

Pathogenic variants. Twenty-three pathogenic missense variants, one in-frame deletion, and a 102-bp deletion from the last coding nucleotide (codon 697) have been described (Table 2). The majority of pathogenic variants in PRKCG described to date are in exon 4 (13/25, or 52%); this exon appears to be a relative mutational hot spot (for more information, see Table 2). Other reported pathogenic variants are located in exons 1, 2, 3, 5, 7, 10, and 18.

Normal gene product. The 3-kb mRNA encodes 697 amino acids. PKC is a multifunctional family of closely related serine/threonine protein kinases that function in a wide variety of cellular processes, such as membrane-receptor signal transduction and control of gene expression [Zeidman et al 1999, Newton 2001]. They are organized into three subgroups on the basis of diacylglycerol/phorbol ester binding and Ca++ dependence [Nishizuka 2001, Amadio et al 2006]. PKCγ is a member of the conventional or typical subgroup because it is calcium activated and phospholipid dependent. It comprises [Newton 2001]:

  • An amino-terminal regulatory domain containing a calcium-binding region and two cysteine-rich regions; and
  • A carboxyl-terminal catalytic domain containing ATP-binding and substrate recognition sites.

PKCγ is highly expressed in brain and spinal cord, with particularly high expression in Purkinje cells of the cerebellar cortex during dendritic development. It is thought to be a negative regulator of dendritic growth and branching [Schrenk et al 2002]. PKCγ also localizes in lens epithelial cells and the hippocampus and amygdala, regions of the brain associated with anxiety and memory.

Abnormal gene product. The pathogenic variants identified to date result in amino acid substitutions, deletion of two residues, or deletion involving the termination codon that results in extension of the protein by 13 amino acids. In silico and in vitro investigations of some effects of these pathogenic variants on the function of the protein have been performed. Computer simulation studies on three pathogenic missense variants [Chen et al 2003] suggested that mutated gene products may be less stable than the normal protein. In vitro experiments on multiple pathogenic missense variants demonstrated protein aggregation [Lin & Takemoto 2007, Seki et al 2007, Doran et al 2008], altered kinase activity [Seki et al 2005, Verbeek et al 2005a, Lin et al 2007, Asai et al 2009], and altered substrate specificity [Asai et al 2009]. It is speculated that the SCA14 phenotype results from gain of function rather than haploinsufficiency because no chain-terminating pathogenic variants have been found, heterozygous PKCγ-null animals are neurologically normal, and mutated PKCγ showed a different substrate preference from wild type [Asai et al 2009].

References

Literature Cited

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  • Al-Maghtheh M, Vithana EN, Inglehearn CF, Moore T, Bird AC, Bhattacharya SS. Segregation of a PRKCG mutation in two RP11 families. Am J Hum Genet. 1998;62:1248–52. [PMC free article: PMC1377077] [PubMed: 9545390]
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  • Asai H, Hirano M, Shimada K, Kiriyama T, Furiya Y, Ikeda M, Iwamoto T, Mori T, Nishinaka K, Konishi N, Udaka F, Ueno S. Protein kinase C gamma, a protein causative for dominant ataxia, negatively regulates nuclear import of recessive-ataxia-related aprataxin. Hum Mol Genet. 2009;18:3533–43. [PubMed: 19561170]
  • Basri R, Yabe I, Soma H, Sasaki H. Spectrum and prevalence of autosomal dominant spinocerebellar ataxia in Hokkaido, the northern island of Japan: a study of 113 Japanese families. J Hum Genet. 2007;52:848–55. [PubMed: 17805477]
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  • Brkanac Z, Bylenok L, Fernandez M, Matsushita M, Lipe H, Wolff J, Nochlin D, Raskind WH, Bird TD. A new dominant spinocerebellar ataxia linked to chromosome 19q13.4-qter. Arch Neurol. 2002;59:1291–5. [PubMed: 12164726]
  • Chen DH, Brkanac Z, Verlinde CL, Tan XJ, Bylenok L, Nochlin D, Matsushita M, Lipe H, Wolff J, Fernandez M, Cimino PJ, Bird TD, Raskind WH. Missense mutations in the regulatory domain of PKC gamma: a new mechanism for dominant nonepisodic cerebellar ataxia. Am J Hum Genet. 2003;72:839–49. [PMC free article: PMC1180348] [PubMed: 12644968]
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  • Dalski A, Mitulla B, Burk K, Schattenfroh C, Schwinger E, Zuhlke C. Mutation of the highly conserved cysteine residue 131 of the SCA14 associated PRKCG gene in a family with slow progressive cerebellar ataxia. J Neurol. 2006;253:1111–2. [PubMed: 16649092]
  • Doran G, Davies KE, Talbot K. Activation of mutant protein kinase Cgamma leads to aberrant sequestration and impairment of its cellular function. Biochem Biophys Res Commun. 2008;372:447–53. [PubMed: 18503760]
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Chapter Notes

Author Notes

Supported by funds from the NORD, the NINDS, and the Department of Veterans Affairs

Revision History

  • 18 April 2013 (me) Comprehensive update posted live
  • 23 March 2010 (me) Comprehensive update posted live
  • 8 February 2007 (me) Comprehensive update posted to live Web site
  • 21 December 2005 (dhc) Revision: prenatal diagnosis available
  • 28 January 2005 (me) Review posted to live Web site
  • 23 September 2004 (dhc) Original submission
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