Spinocerebellar ataxia type 5

Dick, Katherine A.; Ikeda, Yoshio; Day, John W.; Ranum, Laura P.W.

doi:10.1016/b978-0-444-51892-7.00028-0

Cited by 32 publications

(26 citation statements)

References 43 publications

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“…Unlike some of the other degenerative cerebellar ataxias, SCA5 generally does not significantly shorten lifespan, probably since neurodegeneration in SCA5 is restricted to the cerebellum and the brainstem is largely unaffected [38]. First described in an American kindred and subsequently in German and French families, SCA5 was determined to be caused by a mutation in SPTNB2 , which codes for the β-III spectrin protein [39].…”

Section: Altered Intrinsic Purkinje Neuron Pacemaking As a Primary Drmentioning

confidence: 99%

Translating Cerebellar Purkinje Neuron Physiology To Progress In Dominantly Inherited Ataxia

Chopra

Shakkottai

2014

Future Neurol.

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The cerebellum is an important structure for accurate control and timing of movement, and Purkinje neurons in the cerebellar cortex are key players in cerebellar motor control. Cerebellar dysfunction can result in ataxia, a disorder characterized by postural instability, gait disturbances and motor incoordination. Cerebellar ataxia is a symptom of a number of conditions, and the emerging evidence that Purkinje neuron dysfunction, in particular, abnormal Purkinje neuron repetitive firing, is a major driver of motor dysfunction in a subset of dominantly inherited ataxias is dicussed. Abnormalities in Purkinje neuron excitability that are observed in mouse models of each of these disorders, and where appropriate describe studies linking particular ion channels to aberrant excitability are also discussed. Common mechanisms of dysfunction and speculate about potential therapeutic targets, suggesting that Purkinje neuron firing abnormalities are a novel target for improving motor dysfunction in patients with some forms of dominantly inherited ataxia are proposed.

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Section: Altered Intrinsic Purkinje Neuron Pacemaking As a Primary Drmentioning

confidence: 99%

Translating Cerebellar Purkinje Neuron Physiology To Progress In Dominantly Inherited Ataxia

Chopra

Shakkottai

2014

Future Neurol.

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“…We now know that spectrin mutations in other cell types play important roles in pathogenesis of several disease phenotypes, including a number of neurologic disorders. [9][10][11] In the erythrocyte, a-spectrin is an ;280-kDa polypeptide comprising 20 homologous ;106 amino acid "spectrin-type homologous domains" often called "spectrin repeats," an N-terminal partial repeat, an SH3 domain, and a C-terminal EF hand domain. b-Spectrin is an ;246-kDa polypeptide comprising 16 complete repeat units, a partial repeat near the C terminus, an N-terminal actin binding domain, and a nonhomologous phosphorylated C-terminal domain ( Figure 1A).…”

Section: Introductionmentioning

confidence: 99%

The common hereditary elliptocytosis-associated α-spectrin L260P mutation perturbs erythrocyte membranes by stabilizing spectrin in the closed dimer conformation

Harper

Sriswasdi

Tang

et al. 2013

Blood

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• The common HE mutation aL260P reduces spectrin tetramer links between junctional complexes in red cell membranes by favoring closed dimers.• Favoring closed spectrin dimer formation is a new mechanism of red cell membrane destabilization by hereditary anemia mutations.Hereditary elliptocytosis (HE) and hereditary pyropoikilocytosis (HPP) are common disorders of erythrocyte shape primarily because of mutations in spectrin. The most common HE/HPP mutations are located distant from the critical ab-spectrin tetramerization site, yet still interfere with formation of spectrin tetramers and destabilize the membrane by unknown mechanisms. To address this question, we studied the common HE-associated mutation, aL260P, in the context of a fully functional mini-spectrin. The mutation exhibited wild-type tetramer binding in univalent binding assays, but reduced binding affinity in bivalent-binding assays. Biophysical analyses demonstrated the mutation-containing domain was only modestly structurally destabilized and helical content was not significantly changed. Gel filtration analysis of the aL260P mini-spectrin indicated more compact structures for dimers and tetramers compared with wild-type. Chemical crosslinking showed structural changes in the mutant mini-spectrin dimer were primarily restricted to the vicinity of the aL260P mutation and indicated large conformational rearrangements of this region. These data indicate the mutation increased the stability of the closed dimer state, thereby reducing tetramer assembly and resulting in membrane destabilization. These results reveal a novel mechanism of erythrocyte membrane destabilization that could contribute to development of therapeutic interventions for mutations in membrane proteins containing spectrin-type domains associated with inherited disease. (Blood. 2013;122(17): [3045][3046][3047][3048][3049][3050][3051][3052][3053] IntroductionThe hereditary elliptocytosis (HE) syndromes are the most common disorders of erythrocyte shape. In parts of Africa, the incidence of HE approaches that of sickle cell disease, presumably because HE red cells confer some resistance to invasion by malaria parasites. Most cases of HE are due to missense mutations in the erythrocyte membrane skeleton protein spectrin. 1,2 Spectrin is a critical component of the erythrocyte membrane skeleton, a network of proteins on the cytoplasmic face of the membrane that maintains the shape and elasticity of the red cell membrane. 3,4 In the erythrocyte, spectrin exists as an antiparallel ab-heterodimer that self-associates in a head-to-head fashion to form tetramers and higher order oligomers. 5 Studies of spectrin mutations in HE and the related disorder hereditary pyropoikilocytosis (HPP) 6,7 have provided important insights into the structure and function of spectrin in the cell. 8 Furthermore, erythrocyte spectrin has served as the paradigm for our understanding of spectrin proteins in nonerythroid cells. We now know that spectrin mutations in other cell types play important roles in pathogen...

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“…Spinocerebellar ataxia 5 (SCA5) is an autosomal dominant neurodegenerative disorder that targets the cerebellum 1 . SCA5 has a worldwide prevalence of <1% and is rare among dominant ataxias 2, 3 .…”

Section: Introductionmentioning

confidence: 99%

“…SCA5 has a worldwide prevalence of <1% and is rare among dominant ataxias 2, 3 . SCA5 patients primarily exhibit limb and gait ataxia (>90%), but truncal ataxia, sensory deficits, abnormal eye movements, dysarthria, and hyperactive deep tendon reflexes are also prevalent (25-90%) 1 . Individuals generally struggle with fine motor coordination but rarely require a wheelchair until late in the disease course 1 .…”

Section: Introductionmentioning

confidence: 99%

“…Onset typically occurs in the early 30s and is progressive throughout life. It is known that mutations in the SPTBN2 gene on chromosome 11 cause SCA5 1, 4 . SPTBN2 , primarily expressed in the brain, encodes the beta-III spectrin protein consisting of 2390 amino acids comprising 2 calponin homology domains, 10 SPEC domains (consisting of 17 triple helical spectrin repeats), and a pleckstrin homology domain 1, 4 .…”

Section: Introductionmentioning

confidence: 99%

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A Family with Spinocerebellar Ataxia Type 5 Found to Have a Novel Missense Mutation within a SPTBN2 Spectrin Repeat

Cho¹,

Fogel²

2012

Cerebellum

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OBJECTIVE Identification of a novel missense mutation in the SPTBN2 gene of a family with a clinical diagnosis of spinocerebellar ataxia type 5 (SCA5). METHODS A family with late-onset autosomal dominant pure cerebellar ataxia, consistent with SCA5 but lacking previously reported SPTBN2 mutations, was identified. DNA was collected from seven individuals across two generations and the SPTBN2 gene on chromosome 11 was sequenced. RESULTS A nonsynonymous heterozygous substitution in exon 12 was detected in individuals diagnosed with SCA5 while unaffected family members did not possess this variant. The identified c.1415C>T variant results in a p.T472M substitution in the second SPEC domain of the beta-III spectrin protein. The threonine at position 472 is not in close proximity to the characteristic residues that define the SPEC domain and is variable across diverse SPEC domains, yet is highly conserved in SPTBN2. Consistent with these observations, bioinformatic analysis of the p.T472M variant suggests it to be pathological. CONCLUSION Two deletions within the SPTBN2 SPEC domains (E532_M544del and L629_R634delinsW) have been previously reported to cause SCA5, but this is the first missense mutation in this region of the protein shown to likely be pathogenic.

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Spinocerebellar ataxia type 5

Cited by 32 publications

References 43 publications

Translating Cerebellar Purkinje Neuron Physiology To Progress In Dominantly Inherited Ataxia

Translating Cerebellar Purkinje Neuron Physiology To Progress In Dominantly Inherited Ataxia

The common hereditary elliptocytosis-associated α-spectrin L260P mutation perturbs erythrocyte membranes by stabilizing spectrin in the closed dimer conformation

A Family with Spinocerebellar Ataxia Type 5 Found to Have a Novel Missense Mutation within a SPTBN2 Spectrin Repeat

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