DYT-TUBB4A: First Family from India with the Arg2Gly Mutation.
Ontology highlight
ABSTRACT:
SUBMITTER: Garg D
PROVIDER: S-EPMC10171013 | biostudies-literature | 2023 Mar-Apr
REPOSITORIES: biostudies-literature
Publications
DYT-TUBB4A: First Family from India with the Arg2Gly Mutation.
Garg Divyani D Aggarwal Vasundhara V
Annals of Indian Academy of Neurology 20230202 2
Similar Datasets
Project description:ObjectiveTo report 4 novel TUBB4A mutations leading to laryngeal and cervical dystonia with frequent generalization.MethodsWe screened 4 families including a total of 11 definitely affected members with a clinical picture resembling the original description.ResultsFour novel variants in the TUBB4A gene have been identified: D295N, R46M, Q424H, and R121W. In silico modeling showed that all variants have characteristics similar to R2G. The variants segregate with the disease in 3 of the families with evidence of incomplete penetrance in 2 of them. All 4 variants would be classified as likely pathogenic. The clinical picture particularly included laryngeal dystonia (often the site of onset), associated with cervical and upper limb dystonia and frequent generalization. Laryngeal dystonia was extremely prevalent (>90%) both in the original cases and in this case series. The hobby horse gait was evident in only 1 patient in this case series.ConclusionsOur interpretation is that laryngeal involvement is a hallmark feature of DYT-TUBB4A. Nevertheless, TUBB4A mutations remain an exceedingly rare cause of laryngeal or other isolated dystonia.
| S-EPMC8105968 | biostudies-literature
Project description:DYT-5 dystonia usually presents as a dopa-responsive dystonia (DRD) with early or late parkinsonian manifestations and/or dystonic features. Genetically, these patients have been described as having a wide array of independent mutations in the guanosine triphosphate cyclohydrolase 1 gene (GCH1), and these patients may also have a wide array of clinical manifestations. A Colombian family with six affected female members was characterized. Three members, including the index case, revealed mild parkinsonism, whereas three granddaughters of the index case showed severe generalized dystonia. No men were affected. There was anticipation, and a female predominance was uncovered. Treatment with levodopa was generally effective except in a case with severe skeletal deformities and contractions. Detailed genetic analysis in the index case revealed a new mutation in exon 1 of GCH1 (c.159delG). This study revealed a new mutation of GCH1 that resulted in heterogeneous clinical presentations of DRD within a large family.
| S-EPMC3822405 | biostudies-literature
Project description: Not available
| S-EPMC9175436 | biostudies-literature
Project description: Not available
| S-EPMC9978263 | biostudies-literature
Project description:Dystonia is a disabling disease that manifests as prolonged involuntary twisting movements. DYT-THAP1 is an inherited form of isolated dystonia caused by mutations in THAP1 encoding the transcription factor THAP1. The phe81leu (F81L) missense mutation is representative of a category of poorly understood mutations that do not occur on residues critical for DNA binding. Here, we demonstrate that the F81L mutation (THAP1F81L) impairs THAP1 transcriptional activity and disrupts CNS myelination. Strikingly, THAP1F81L exhibits normal DNA binding but causes a significantly reduced DNA binding of YY1, its transcriptional partner that also has an established role in oligodendrocyte lineage progression. Our results suggest a model of molecular pathogenesis whereby THAP1F81L normally binds DNA but is unable to efficiently organize an active transcription complex.
| S-EPMC8976427 | biostudies-literature
Project description:Tubulin beta 4A class IVa (TUBB4A) spectrum disorders include autosomal dominant dystonia type 4 or hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC syndrome). However, in rare cases, only mild hypomyelination in the cortex with no basal ganglia atrophy may be observed. We report a case of a family with TUBB4A mutation and complicated hereditary spasticity paraplegia (HSP). We performed quadro whole-exome sequencing (WES) on the family to identify the causative gene of progressive spastic paraparesis with isolated hypomyelination leukodystrophy. We identified a novel TUBB4A p.F341L mutation, which was present in all three affected patients but absent in the unaffected father. The affected patients presented with adult-onset TUBB4A disorder, predominant spastic paraparesis with/without ataxia, and brain hypomyelination with no cognitive impairment or extrapyramidal symptoms. In the literature, HSP is considered a TUBB4A spectrum disorder.
| S-EPMC10846974 | biostudies-literature
Project description:DYT-PRKRA (dystonia 16 or DYT-PRKRA) is caused by mutations in the PRKRA gene that encodes PACT, the protein activator of interferon (IFN)-induced double-stranded (ds) RNA-activated protein kinase (PKR). PACT participates in several cellular pathways, of which its role as a PKR activator protein during integrated stress response (ISR) is the best characterized. Previously, we have established that the DYT-PRKRA mutations cause enhanced activation of PKR during ISR to sensitize DYT-PRKRA cells to apoptosis. In this study, we evaluate if the most prevalent substitution mutation reported in DYT-PRKRA patients alters PACT's functional role in induction of type I IFNs via the retinoic acid-inducible gene I (RIG-I) signaling. Our results indicate that the P222L mutation augments PACT's ability to induce IFN β in response to dsRNA and the basal expression of IFN β and IFN-stimulated genes (ISGs) is higher in DYT-PRKRA patient cells compared to cells from the unaffected controls. Additionally, IFN β and ISGs are also induced at higher levels in DYT-PRKRA cells in response to dsRNA. These results offer a new avenue for investigations directed towards understanding the underlying molecular pathomechanisms in DYT-PRKRA.
| S-EPMC9138762 | biostudies-literature
Project description:IntroductionX-linked spondyloepiphyseal dysplasia tarda(SEDT) is a type of shorttrunk skeletal dysplasia, occurring in males due to mutation in TRAPPC2 gene.Case reportWe describe a large Indian family with multiple males affected with X-linked SEDT. The affected individuals presented with disproportionate short stature, short trunk, and barrel-shaped chest. Elder sibs aged 26 years and 31 years had back and hip pain. Premature osteoarthritis was seen requiring hip replacement surgery in one sib. The known pathogenic nonsense mutation c.209G>A (p.W70X) was identified in TRAPPC2 gene. This is the first mutation proven Indian kindred with X-linked SEDT.ConclusionKnowledge of molecular basis is essential to provide definitive diagnosis, accurate counseling, and prenatal diagnosis or early postnatal diagnosis for this rare condition.
| S-EPMC7476708 | biostudies-literature
Project description:Variants in the PRKRA gene, which encodes PACT, cause the early-onset primary dystonia DYT-PRKRA, a movement disorder associated with disruption of coordinated muscle movements. PACT and its murine homolog RAX activate protein kinase R (PKR; also known as EIF2AK2) by a direct interaction in response to cellular stressors to mediate phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α). Mice homozygous for a naturally arisen, recessively inherited frameshift mutation, Prkralear-5J, exhibit progressive dystonia. In the present study, we investigated the biochemical and developmental consequences of the Prkralear-5J mutation. Our results indicated that the truncated PACT/RAX protein retains its ability to interact with PKR but inhibits PKR activation. Mice homozygous for the mutation showed abnormalities in cerebellar development as well as a severe lack of dendritic arborization of Purkinje neurons. Additionally, reduced eIF2α phosphorylation was noted in the cerebellum and Purkinje neurons of the homozygous Prkralear-5J mice. These findings indicate that PACT/RAX-mediated regulation of PKR activity and eIF2α phosphorylation plays a role in cerebellar development and contributes to the dystonia phenotype resulting from the Prkralear-5J mutation.
| S-EPMC11625895 | biostudies-literature
Project description:The tubulin beta-4A gene (TUBB4A) is associated with two different clinical conditions, dystonia type 4 (DYT4) and hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). We identified a novel TUBB4A mutation, c.286G>A (p.G96R), in an adult male patient who suffered neurological symptoms beyond adolescence. This patient shows intermediate clinical features between DYT4 and H-ABC, suggesting that the TUBB4A disorder would constitute a spectrum disorder.
| S-EPMC5540734 | biostudies-literature