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Biomedical subjects

S H Subramony

Publications and source records attributed to S H Subramony.

At least 19 recordsLinked to original sources
PubMed2006

Tissue transglutaminase crosslinks ataxin-1: possible role in SCA1 pathogenesis.

Transglutaminase type 2 (TG2) has recently been implicated in crosslinking of mutant huntingtin protein into aggregates. Here we show that TG2 also crosslinks spinocerebellar ataxia-1 (SCA1) gene product ataxin-1. HeLa cell lysates expressing GFP tagged ataxin-1 with 2, 30 or 82 glutamines showed covalent crosslinking of ataxin-1 when incubated with exogenously added TG2. This crosslinking was inhibited by TG2 inhibitor cystamine. SCA1 transgenic mice which overexpress the mutant ataxin-1 in cerebellar Purkinje cells showed elevated nuclear TG2 in the absence of ataxin-1 nuclear aggregates. The addition of purified TG2 to the nuclear extracts or addition of SCA1 nuclear TG2 to GFP-Q82 HeLa cell lysates resulted in the formation of insoluble aggregates. These data indicate that ataxin-1 is a substrate of TG2. Further, in SCA1 TG2 may translocate to the nucleus in response to nuclear accumulation of mutant ataxin-1 at early stages of the disease.

Animals↗
PubMed2006

Rational selection of small molecules that increase transcription through the GAA repeats found in Friedreich's ataxia.

Friedreich's ataxia (FRDA) is an autosomal recessive trinucleotide repeat disease with no effective therapy. Expanded GAA repeats in the first intron of the FRDA gene are thought to form unusual non-B DNA conformations that decrease transcription and subsequently reduce levels of the encoded protein, frataxin. Frataxin plays a crucial role in iron metabolism and detoxification. To discover small molecules that increase transcription through the GAA repeat region in FRDA, we have made stable cell lines containing a portion of expanded intron 1 fused to a GFP reporter. Small molecules identified using the competition dialysis method were found to increase FRDA-intron 1-reporter gene expression. One of these compounds, pentamidine, increases frataxin levels in patient cells. Thus our approach can be used to detect small molecules of potential therapeutic value in FRDA.

Antifungal Agents↗
PubMed2006

Measuring Friedreich ataxia: complementary features of examination and performance measures.

OBJECTIVE: To examine the potential validity of performance measures and examination-based scales in Friedreich ataxia (FA) by examining their correlation with disease characteristics. METHODS: The authors assessed the properties of a candidate clinical outcome measure, the Friedreich Ataxia Rating Scale (FARS), and simple performance measures (9-hole peg test, the timed 25-foot walk, PATA test, and low-contrast letter acuity) in 155 patients with FA from six institutions, and correlated the scores with disease duration, functional disability, activity of daily living scores, age, and shorter GAA repeat length to assess whether these measures capture the severity of neurologic dysfunction in FA. RESULTS: Scores for the FARS and performance measures correlated significantly with functional disability, activities of daily living scores, and disease duration, showing that these measures meet essential criteria for construct validity for measuring the progressive nature of FA. In addition, the FARS and transformed performance measures scores were predicted by age and shorter GAA repeat length in linear regression models accounting for sex and testing site. Correlations between performance measures were moderate in magnitude, suggesting that each test captures separate yet related dimensions of neurologic function in FA and that a composite measure might better predict disease status. Composite measures created using cohort means and standard deviations predicted disease status better than or equal to single performance measures or examination-based measures. CONCLUSIONS: The Friedreich Ataxia Rating Scale, performance measures, and performance measure composites provide valid assessments of disease progression in Friedreich ataxia.

Adolescent↗
PubMed2006

Intranasal administration of IGF-I improves behavior and Purkinje cell pathology in SCA1 mice.

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of polyglutamine repeat within ataxin-1 protein. Cerebellar Purkinje cells are the primary targets of SCA1 pathology. These cells synthesize insulin-like growth factor-I (IGF-I) and express its receptors during their entire life. The aim of present study was to determine if intranasally administered IGF-I to SCA1 transgenic mice suppresses toxic effects of ataxin-1. Two-week old SCA1 heterozygous animals were randomly divided into two treatment groups of IGF-I (30 and 60 microg IGF-I/animal) and a vehicle-treated control group. The wildtype animals served as normal controls. IGF-I or vehicle was administered at 48 h intervals for the total of 10 doses. Animals were then subjected to rotarod test, sacrificed, brains removed and processed for immunohistochemical and Western blot analysis. Radiolabeled IGF-I and bioactive TAT peptide accumulated in the brains of SCA1 mice following intranasal administration validating the use of intranasal route. SCA1 mice showed SCA1 pathology with impaired motor function and downregulation of calcium binding proteins as compared to wildtype mice. However, 30 and 60 microg IGF-I-treated animals showed improved performance on the rotarod as compared to vehicle-treated SCA1 mice with significant improvement (p < 0.05) on day 3 in 60 microg IGF-I group. The immunohistochemical data further showed partial recovery in the expression of calbindin D28k and protein kinase C-gamma in Purkinje cells in IGF-I-treated SCA1 animals. Our results indicate that suppression of ataxin-1-mediated adverse effects by intranasal IGF-I treatment may be of a therapeutic value to treat SCA1.

Administration, Intranasal↗
PubMed2005

Interactions between coilin and PIASy partially link Cajal bodies to PML bodies.

The eukaryotic nucleus contains a variety of dynamic structures, yet studies into the functional relationship of one type of subnuclear domain to another have been limited. For example, PML bodies and Cajal bodies associate, but the functional consequence of this association and the mediating factors are unknown. Here we report that an associated PML body/Cajal body can co-localize to an snRNA gene locus, with the Cajal body invariably situated between the PML body and the snRNA locus. Binding studies demonstrate that coilin (a Cajal body protein) directly interacts with PIASy (a PML body protein). Cell biological experiments using coilin and PIASy knockout cell lines demonstrate that interactions between coilin and PIASy account in part for the observed association of Cajal bodies with PML bodies. When the PIASy interaction region on coilin is deleted, the frequency of the association between Cajal bodies and PML bodies is reduced. These studies provide another example of coilin's role in the functional organization of the nucleus.

Chromosomal Proteins, Non-Histone↗
PubMed2005

Measuring Friedreich ataxia: Interrater reliability of a neurologic rating scale.

Measuring the severity of neurologic dysfunction in patients with inherited ataxias, including Friedreich ataxia (FA), is difficult because of the variable rate of progression, the variable age at onset and the variety of neural systems that may be affected. The authors discuss the problems related to rating scales in the ataxias, report a neurologic rating scale for FA, and demonstrate acceptable interrater reliability of the instrument.

Adolescent↗
PubMed2005

CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy.

We tested the efficacy and safety of glutamine (0.6 gm/kg/day) and creatine (5 gm/day) in 50 ambulant boys with Duchenne muscular dystrophy in a 6-month, double-blind, placebo-controlled clinical trial. Drug efficacy was tested by measuring muscle strength manually (34 muscle groups) and quantitatively (10 muscle groups). Timed functional tests, functional parameters, and pulmonary function tests were secondary outcome measures. Although there was no statistically significant effect of either therapy based on manual and quantitative measurements of muscle strength, a disease-modifying effect of creatine in older Duchenne muscular dystrophy and creatine and glutamine in younger Duchenne muscular dystrophy cannot be excluded. Creatine and glutamine were well tolerated.

Child↗
PubMed2004

Tick paralysis.

Tick paralysis results from inoculation of a toxin from tick salivary glands during a blood meal. It is a relatively uncommon neuromuscular disease with a higher prevalence among young girls, although older men who get exposed to ticks may also be affected. It typically presents as an acute ascending paralysis occurring a few days after tick attachment and may result in respiratory failure and death. Patients may report minor sensory symptoms but constitutional signs are usually absent. Deep tendon reflexes are usually hypoactive or absent and ophthalmoplegia and bulbar palsy can occur. Children may be ataxic. Electromyographic studies usually show a variable reduction in the amplitude of compound muscle action potentials but no abnormalities of repetitive nerve stimulation studies. These appear to result from a failure of acetylcholine release at the motor nerve terminal level. There may be subtle abnormalities of motor nerve conduction velocity and sensory action potentials. Removal of the tick results in the very rapid reversal of clinical and physiologic deficits, quicker with North American ticks than with the Ixodes species seen in Australia.

Action Potentials↗
PubMed2003

Novel CACNA1A mutation causes febrile episodic ataxia with interictal cerebellar deficits.

Episodic ataxia type 2 (EA2) is a dominantly inherited disorder, characterized by spells of ataxia, dysarthria, vertigo, and migraines, associated with mutations in the neuronal calcium-channel gene CACNA1A. Ataxic spells lasting minutes to hours are provoked by stress, exercise, or alcohol. Some patients exhibit nystagmus between spells and some develop progressive ataxia later in life. At least 21 distinct CACNA1A mutations have been identified in EA2. The clinical and genetic complexities of EA2 have offered few insights into the underlying pathogenic mechanisms for this disorder. We identified a novel EA2 kindred in which members had ataxic spells induced by fevers or high environmental temperature. We identified a novel CACNA1A mutation (nucleotides 1253+1 G-->A) that was present in all subjects with febrile spells or ataxia. Moreover, we found that, regardless of age or interictal clinical status, all affected subjects had objective evidence of abnormal saccades, ocular fixation, and postural stability. These findings suggest that early cerebellar dysfunction in EA2 results from the intrinsically abnormal properties of the CACNA1A channel rather than a degenerative process.

Adolescent↗
PubMed2003

Dominantly inherited ataxias.

The autosomal dominant ataxias continue to bewilder us as the enormity of their genetic heterogeneity continues to unfold. The Human Genome Organization website now lists 22 such ataxias, not including dentatorubral-pallidoluysian atrophy. The early genetic discoveries in this field included several disorders caused by CAG repeat expansions within coding regions of the respective genes. More recent discoveries have included unstable expansions of nucleotide repeats in noncoding regions of genes as well as point mutations that have formed the basis of progressive dominant ataxias. This article summarizes the clinical and genetic features of the currently identified dominant ataxias.

Genes, Dominant↗
PubMed2002

Tick paralysis in children: electrophysiology and possibility of misdiagnosis.

The authors report six patients with tick paralysis seen over 5 years. Clinical and electrodiagnostic findings failed to adequately distinguish tick paralysis from Guillain-Barré syndrome in these patients. Finding a tick attached to the scalp or the nape of the neck and removing it resulted in rapid clinical improvement.

Child, Preschool↗
PubMed2002

Novel mutations in collagen VI genes: expansion of the Bethlem myopathy phenotype.

OBJECTIVE: To investigate the molecular basis of autosomal dominant limb-girdle muscular dystrophy (AD-LGMD) in three large new families. METHODS AND RESULTS: Genome-wide linkage was performed to show that the causative gene in all three families localized to chromosome 21q22.3 (Zmax = 10.3; theta = 0). This region contained the collagen VI alpha1 and alpha2 genes, which have been previously shown to harbor mutations causing a relatively mild congenital myopathy with contractures (Bethlem myopathy). Screening of the collagen VI alpha1 and alpha2 genes revealed novel, causative mutations in each family (COL6A1-K121R, G341D; COL6A2-D620N); two of these mutations were in novel regions of the proteins not previously associated with disease. Collagen VI is a ubiquitously expressed component of connective tissue; however, both limb-girdle muscular dystrophy and Bethlem myopathy patients show symptoms restricted to skeletal muscle. To address the muscle-specific symptoms resulting from collagen VI mutations, the authors studied three patient muscle biopsies at the molecular level (protein expression). A marked reduction of laminin beta1 protein in the myofiber basal lamina in all biopsies was found, although this protein was expressed normally in the neighboring capillary basal laminae. CONCLUSIONS: The authors' studies widen the clinical spectrum of Bethlem myopathy and suggest collagen VI etiology should be investigated in dominant limb-girdle muscular dystrophy. The authors hypothesize that collagen VI mutations lead to muscle-specific defects of the basal lamina, and may explain the muscle-specific symptoms of Bethlem and limb-girdle muscular dystrophy patients with collagen VI mutations.

Adolescent↗
PubMed2002

Ethnic differences in the expression of neurodegenerative disease: Machado-Joseph disease in Africans and Caucasians.

We describe several families of African origin with SCA3/Machado-Joseph disease gene expansions. In these cases, the phenotype ranges from ataxia with parkinsonian signs to a syndrome clinically almost indistinguishable from idiopathic, L-dopa-responsive Parkinson's disease. In contrast, these parkinsonian phenotypes are rare in those of European descent. Haplotype analysis shows that these African families do not share a common founder, thus a cis-acting element in the promoter is unlikely to be responsible these unusual presentations. We suggest that trans-acting factors are responsible for the variable phenotype and discuss the implications of diseases showing racially different expressivities.

Black or African American↗
PubMed2001

Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome.

Andersen's syndrome is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. We have mapped an Andersen's locus to chromosome 17q23 near the inward rectifying potassium channel gene KCNJ2. A missense mutation in KCNJ2 (encoding D71V) was identified in the linked family. Eight additional mutations were identified in unrelated patients. Expression of two of these mutations in Xenopus oocytes revealed loss of function and a dominant negative effect in Kir2.1 current as assayed by voltage-clamp. We conclude that mutations in Kir2.1 cause Andersen's syndrome. These findings suggest that Kir2.1 plays an important role in developmental signaling in addition to its previously recognized function in controlling cell excitability in skeletal muscle and heart.

Alleles↗
PubMed2001

Sequence variation in GAA repeat expansions may cause differential phenotype display in Friedreich's ataxia.

Friedreich's ataxia, the most common autosomal recessive inherited ataxia, is characterized by progressive gait and limb ataxia. Friedreich's ataxia is known for its occurrence within the first or second decade of life and is associated with hypertrophic cardiomyopathy, and in some cases with diabetes. Genetically, it is identified by the expression of an unstable trinucleotide GAA repeat expansion located in the first intron of the X25 gene on chromosome 9. Two brothers with very late adult-onset ataxia, and their unaffected sister, were examined for the clinical presentation of FA and for the presence of the mutated FA gene. The relationship of the expanded gene sequence to the severity of disease and age of onset were evaluated. Clinical examination revealed that the two brothers had mild ataxia and proprioceptive loss, with age of onset between 60 and 70 years of age. DNA from peripheral blood nucleated cells demonstrated a small homozygous expansion, with approximately 120-130 GAA repeats in the X25 gene in both patients. The expanded repeats were interrupted either with GAAGAG, GAAGGA, or GAAGAAAA sequences. The unaffected sister carried a normal FA genotype with 8-uninterrupted GAA repeat, observed by sequence analysis. In addition, the levels of FA gene transcript in both brothers were relatively lower than that in the unaffected sister. No detectable cardiomyopathy or diabetes was observed. Phenotypic diversity of FA is increasingly expanding. The age of onset and the structure of GAA repeat expansion plays an important role in determining the clinical features and the differential diagnosis of FA. The confirmation of the FA gene mutation in the atypical case, broadens the clinical spectrum of FA, and supports the idea that patients with even a mild form of ataxia of late adult onset should be considered for molecular testing.

Age of Onset↗