Last update 01 Nov 2024

GABRA4

Last update 01 Nov 2024

Basic Info

Synonyms

GABA(A) receptor subunit alpha-4, GABA(A) receptor, alpha 4, GABRA4

+ [3]

Introduction

GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.

Drugs associated with GABRA4

RTI-6305-7

Target

GABRA4 x GABRB3 x GABRD

Mechanism

GABRA4 modulators [+3]

Active Org.-

Originator Org.

Research Triangle Institute

Active Indication-

Inactive Indication

Cocaine-Related Disorders [+1]

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GABRA4

100 Translational Medicine associated with GABRA4

0 Patents (Medical) associated with GABRA4

105

Literatures (Medical) associated with GABRA4

01 Dec 2024·Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms

Machine learning based analysis of single-cell data reveals evidence of subject-specific single-cell gene expression profiles in acute myeloid leukaemia patients and healthy controls

Article

Author: Chrysostomou, Andreas ; Furlan, Cristina ; Saccenti, Edoardo

Acute Myeloid Leukaemia (AML) is characterized by uncontrolled growth of immature myeloid cells, disrupting normal blood production. Treatment typically involves chemotherapy, targeted therapy, and stem cell transplantation but many patients develop chemoresistance, leading to poor outcomes due to the disease's high heterogeneity. In this study, we used publicly available single-cell RNA sequencing data and machine learning to classify AML patients and healthy, monocytes, dendritic and progenitor cells population. We found that gene expression profiles of AML patients and healthy controls can be classified at the individual level with high accuracy (>70 %) when using progenitor cells, suggesting the existence of subject-specific single cell transcriptomics profiles. The analysis also revealed molecular determinants of patient heterogeneity (e.g. TPSD1, CT45A1, and GABRA4) which could support new strategies for patient stratification and personalized treatment in leukaemia.

01 Aug 2024·European Journal of Human Genetics

De novo variants in GABRA4 are associated with a neurological phenotype including developmental delay, behavioral abnormalities and epilepsy

Article

Author: Stockner, Thomas ; Westphal, Dominik S ; Krenn, Martin ; Salyakina, Daria ; Jayakar, Parul ; Ernst, Margot ; William, Nancy ; Kesari, Akanchha ; Bianconi, Simona E ; Heller, Corina ; Cooper, Annina H ; Coffey, Alison J ; Biskup, Saskia ; Vogel, Florian D ; Liu, Shuxi ; Gradisch, Ralph ; Maiwald, Robert ; Soler, Diana ; Sajan, Samin A ; Clarke, Amy ; Jayakar, Anuj ; Benkel-Herrenbrück, Ira ; Leiz, Steffen ; Wagner, Matias

AbstractNine out of 19 genes encoding GABAA receptor subunits have been linked to monogenic syndromes characterized by seizures and developmental disorders. Previously, we reported the de novo variant p.(Thr300Ile) in GABRA4 in a patient with epilepsy and neurodevelopmental abnormalities. However, no new cases have been reported since then. Through an international collaboration, we collected molecular and phenotype data of individuals carrying de novo variants in GABRA4. Patients and their parents were investigated either by exome or genome sequencing, followed by targeted Sanger sequencing in some cases. All variants within the transmembrane domain, including the previously reported p.(Thr300Ile) variant, were characterized in silico and analyzed by molecular dynamics (MD) simulation studies. We identified three novel de novo missense variants in GABRA4 (NM_000809.4): c.797 C > T, p.(Pro266Leu), c.899 C > A, p.(Thr300Asn), and c.634 G > A, p.(Val212Ile). The p.(Thr300Asn) variant impacts the same codon as the previously reported variant p.(Thr300Ile) and likely arose post-zygotically as evidenced by sequencing oral mucosal cells. Overlapping phenotypes among affected individuals included developmental delay (4/4), epileptiform EEG abnormalities (3/4), attention deficits (3/4), seizures (2/4), autistic features (2/4) and structural brain abnormalities (2/4). MD simulations of the three variants within the transmembrane domain of the receptor indicate that sub-microsecond scale dynamics differ between wild-type and mutated subunits. Taken together, our findings further corroborate an association between GABRA4 and a neurological phenotype including variable neurodevelopmental, behavioral and epileptic abnormalities.

01 Jul 2024·Metallomics

Enhanced axon guidance and synaptic markers in rat brains using ferric–tannic nanoparticles

Article

Author: Vachiraarunwong, Arpamas ; Wongpoomchai, Rawiwan ; Pilapong, Chalermchai ; Kittilukkana, Aiyarin ; Intakhad, Jannarong ; Sanit, Jantira

AbstractFerric–tannic nanoparticles (FTs) are now considered to be new pharmaceuticals appropriate for the prevention of brain aging and related diseases. We have previously shown that FTs could activate axon guidance pathways and cellular clearance functioning in neuronal cell lines. Herein, we further investigated whether FTs could activate the two coordinated neuronal functions of axon guidance and synaptic function in rat brains and neuronal cell lines. A single intravenous injection of a safe dose of FTs has been shown to activate a protein expression of axon attractant Netrin-1 and neurotransmitter receptor GABRA4 in the cerebral cortexes of male Wistar rats. According to RNA-seq with targeted analysis, axon guidance and synapses have been enriched and Ephrin membered genes have been identified as coordinating a network of genes for such processes. In vitro, as expected, FTs are also found to activate axon guidance markers and promote neuronal tubes in neuronal cell lines. At the same time, pre-synaptic markers (synaptophysin), post-synaptic markers (synapsin), and GABRA4 neurotransmitter receptors have been found to be activated by FTs. Interestingly, synaptophysin has been found to localize along the promoted neuronal tubes, suggesting that enhanced axon guidance is associated with the formation and transportation of pre-synaptic vesicles. Preliminarily, repeated injection of FTs into adult rats every 3 days for 10 times could enhance an expression of synaptophysin in the cerebral cortex, as compared to control rats. This work demonstrates that FTs can be used for activating brain function associated with axon guidance and synaptic function.

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