The human γ-aminobutyric acid A receptor delta (GABRD) gene: molecular characterisation and tissue-specific expression
Introduction
As recent publications have shown, small deletions of the terminal part of 1p36 are a common but often missed cause of developmental and mental retardation with a predicted incidence of about 1 in 5000 (Battaglia et al., 2001, Heilstedt et al., 2001). The 1p36 deletion syndrome is characterised by growth delay, early puberty, orofacial clefting or palate, hearing and vision deficits, heart defects, and dysmorphic features (Reish et al., 1995, Shapira et al., 1997). In addition to moderate to severe psychomotor retardation and epilepsy, a reduced speech development and abusive behaviour are the most obvious neurological features seen in these patients.
Knight-Jones et al. (2000) reported on four patients with terminal sub-microscopic deletions of 1p sharing most of the features known for 1p36 deletion syndrome patients with cytogenetic visible deletions. Besides the mental retardation, seizures were found in the majority of patients of both groups. Although self-abusive behaviour is well known for 1p36 deletion syndrome patients (Shapira et al., 1997), it was not obvious in the microdeletion patients described by Knight-Jones et al. (2000). However, one of them was diagnosed with autistic disorder. Patients with 1p36 deletion syndrome usually have a moderate to severe mental retardation, except those patients with very small terminal deletions (distal to cosmid D1Z2) who only show mild mental retardation but retain the ability for complex speech (Wu et al., 1999).
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be altered by a number of agents like barbiturates, benzodiazepines, steroids or alcohol that bind to the GABA-A receptor. A sub-unit of GABA-A receptors, the γ-aminobutyric acid A receptor delta gene (GABRD; MIM 137,163) has been previously assigned by our group to human chromosomal band 1p36 using radiation hybrid mapping (Emberger et al., 2000). We have confirmed and refined this assignment, mapping the GABRD gene to the critical region of gene loss for the 1p36 deletion syndrome within 1p36.33, flanked by the transcripts for PRKCZ and KIAA1751.
We suggest that GABRD, from its function, expression profile and chromosomal location, can be regarded as a gene that contributes to the neurological and neuropsychiatric anomalies in patients with the 1p36 deletion syndrome.
Section snippets
DNA sequencing
All the DNA sequence analyses were performed using an ABI 310 automatic DNA sequencer, with a BigDye Terminator Cycle Sequencing FS Ready Reaction Kit (Perkin-Elmer).
Rapid amplification of complementary DNA ends (RACE)
The 5′-end fragment of the GABRD cDNA was amplified by 5′-RACE from the human fetal brain Marathon-Ready cDNA library (Clontech). The gene-specific primers were designed based on the corresponding expressed sequence tag (EST) sequences. AP1 primer (Clontech) and GABRD-specific primer 5′-TGTACTCCATGTTGGCCTCTGAGATGT-3′ were used for
Cloning and genomic structure of GABRD
Partial GABRD cDNA sequence from the GenBank database (GenBank accession no. NM_000815) was used as an initial starting point for obtaining full-length cDNA and structure of the GABRD gene. Sequence comparisons using the BLAST software (Altschul et al., 1990; http://www.ncbi.nlm.nih.gov/BLAST/) revealed sequence identity with many additional ESTs from human dbEST. By 5′-RACE and computer assembly of multiple EST sequences, three composite cDNA variants in the 5′-region were identified. 5′-RACE
Discussion
The purpose of this study was to characterise GABRD, a positional and functional candidate of the neurological features seen in 1p36 deletion syndrome. A combination of DNA sequence analysis and 5′-RACE was used to clone the full-length cDNA of GABRD. By sequence comparison with the publicly available genomic sequence, the gene structure was determined and GABRD was mapped to about 1.5 Mb proximal to the telomere in a G-band light region of chromosome 1p. At the 5′-end, three different splicing
Acknowledgements
This work was supported by the ‘Fonds zur Foerderung der wissenschaftlichen Forschung’ (FWF #J1897-GEN)
References (14)
- et al.
Basic local alignment search tool
J. Mol. Biol.
(1990) - et al.
GABA and epileptogenesis: comparing gabrb3 gene-deficient mice with Angelman syndrome in man
Epilepsy Res.
(1999) - et al.
Chromosome 1p36 deletions: the clinical phenotype and molecular characterisation of a common newly delineated syndrome
Am. J. Hum. Genet.
(1997) - et al.
1p deletion syndrome: a common, important and often missed cause of developmental delay/mental retardation
Am. J. Hum. Genet. (Suppl.)
(2001) - et al.
First genetic evidence of GABAA receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene
Nat. Genet.
(2001) - et al.
Deficiency of the beta 3 subunit of the type A gamma-aminobutyric acid receptor causes cleft palate in mice
Nat. Genet.
(1995) - et al.
Assignment of the human GABAA receptor delta-subunit gene (GABRD) to chromosome band 1p36.3 distal to marker NIB1364 by radiation hybrid mapping
Cytogenet. Cell. Genet.
(2000)
Cited by (55)
SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females
2021, American Journal of Human GeneticsCitation Excerpt :Rosenfeld and colleagues suggested that a 174 kb region at 1p36.33 could be linked to some clinical features of del1p36 syndrome.15 Within this region, GABRD (MIM: 137163) has been implicated in the development of DD/neuropsychiatric features and seizures,16,17 PRDM16 (MIM: 605557) in the development of cardiomyopathy,18 MMP23B (MIM: 603321) in delayed fontanel closure,13 KCNAB2 (MIM: 601142) in seizures occurrence,16,19 SKI (MIM: 164780) in orofacial clefting,10 and PRKCZ (MIM: 176982) in cardiovascular malformations and cardiomyopathy.20 The distal critical region also includes a locus for hyperphagia and obesity.21
Gene expression in the epileptic (EL) mouse hippocampus
2021, Neurobiology of DiseaseEnhanced expression of GABRD predicts poor prognosis in patients with colon adenocarcinoma
2020, Translational OncologyCitation Excerpt :In contrast, Jiang et al. reported that GABRP exhibits an immunomodulatory role in pancreatic cancer progression through GABA-independent tuning of KCNN4-mediated Ca2+ signaling [37]. The GABRD gene encodes the δ subunit of the GABAA receptor which is highly expressed in the brain and mediates signaling related to tonic inhibition [38]. The subunit expression is required for synaptic plasticity and neurogenesis [39,40].
Systemic screening identifies GABRD, a subunit gene of GABAA receptor as a prognostic marker in adult IDH wild-type diffuse low-grade glioma
2019, Biomedicine and Pharmacotherapy