Neurogenetics
John W. Scadding, Nicholas A. Losseff in Clinical Neurology, 2011
There are a number of disorders that have a similar clinical phenotype to HD but do not harbour the CAG repeat mutation. These disorders have been termed HD phenocopies. Huntington’s disease-like 2 (HDL2) is caused by CTG/CAG triplet repeats in the junctophilin 3 gene and have only been described in patients of African ancestry. The most common HD phenocopy is SCA17 (HDL4), which is caused by a CAG repeat in the TBP gene. DRPLA (dentatorubropallidoluysian atrophy) is caused by a CAG repeat in the atrophin-1 gene. Familial prion disease, neuroacanthocytosis, neuroferritinopathy and PKAN may also mimic the HD phenotype.
New discoveries in progressive myoclonus epilepsies: a clinical outlook
Published in Expert Review of Neurotherapeutics, 2018
Shweta Bhat, Subramaniam Ganesh
The pathological hallmark of DRPLA is characteristic degeneration of the dentatorubral and pallido-luysian systems [115]. The molecular process behind this degeneration is said to be the nuclear accumulation of the ATN1 and its C-terminal fragments with expanded polyQ. The mutated form of ATN1 is reported to impair ubiquitin-proteasome system and is degraded slowly. The ubiquitinated undigested protein and its fragments accumulate in neurons, and glial cells in the striatum, pontine, inferior olive, cerebellar cortex, and dentate nucleus and are highly toxic to cells [116]. Neuronal intranuclear aggregates show the presence of several transcription factors, such as TBP, TAF, CREB, and CBP, indicating that transcriptional processes may be affected in DRPLA [117]. ATN1 is also a known substrate of caspases and also interacts with enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) [118]. Recently, using RNA sequencing it was found that ATN1 act as transcriptional co-regulator of 15 target genes and specifically, a gene causative for epilepsy was found to be down-regulated in cells expressing mutant ATN1 [119]
Strict network analysis of evolutionary conserved and brain-expressed genes reveals new putative candidates implicated in Intellectual Disability and in Global Development Delay
Published in The World Journal of Biological Psychiatry, 2021
Rafael Mina Piergiorge, Ana Tereza Ribeiro de Vasconcelos, Márcia Mattos Gonçalves Pimentel, Cíntia Barros Santos-Rebouças
Despite the identification of 1625 proteins with high-reliability interactions and 172 coding genes involved in conserved interactions with evidence of expression in the cortex and cerebellum, our data are computational predictions. Thus, the findings should be supported by future experimental approaches involving whole exome/genome sequencing and transcriptome data. It is worth mentioning that during this study other versions of the HPO were published. Comparison of our ID/GDD candidate genes list with the most recent HPO version (June 2020 release) recovered 31 new genes, from which eight are specific to ID (ADCY3, CDK8, CSNK2B, DLG4, KIF5A, MC2R, REEP6, and WASF1), 15 are specific to GDD (ABL1, ALB, ATN1, CACNA2D2, CNOT1, GP1BA, ITGA2B, ITGB3, KMT2E, MED13, NPM1, PPP2CA, SALL4, TOP3A, and TRHR) and eight are shared by both conditions (DYNC1I2, LAMA1, MYSM1, PCGF2, RAD51, SIK1, STAG2, and SUZ12). Altogether, these findings reinforce the power of our methodology in identifying new ID, GDD, and ID/GDD candidate genes.
Related Knowledge Centers
- Corepressor
- Mutation
- Nervous Tissue
- Protein
- Gene
- DNA-Binding Protein
- Nuclear Export Signal
- Trinucleotide Repeat Disorder
- Dentatorubral–Pallidoluysian Atrophy
- Neurodegenerative Disease