Elsevier

Gene

Volume 292, Issues 1–2, 12 June 2002, Pages 25-31
Gene

The human γ-aminobutyric acid A receptor delta (GABRD) gene: molecular characterisation and tissue-specific expression

https://doi.org/10.1016/S0378-1119(02)00649-2Get rights and content

Abstract

Terminal deletions of 1p36 result in a specific and common syndrome characterised by the following: growth delay, distinctive facial anomalies, hearing and visual deficits, heart defects, body asymmetry, moderate to severe psychomotor retardation, epilepsy, and self-abusive behaviour. The human gamma-aminobutyric acid A receptor delta-subunit gene (GABRD) encodes for one of at least 15 ligand-gated chloride channels for gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian brain. Recently we have mapped this gene by radiation hybrid mapping to the critical region of gene loss of the 1p36 deletion syndrome within 1p36.33. The complete complementary DNA (cDNA) sequence of GABRD was generated using assembled sequence of cDNA fragments already available, and 5′-rapid amplification of cDNA ends products. Fine physical mapping of the GABRD gene within this genomic interval was performed by screening bacterial artificial chromosome contigs spanning the critical region of the 1p36 deletion syndrome. The GABRD gene maps immediately proximal to the PRKCZ gene that is located between marker D1S243 and cosmid D1Z2 – a region thought to be critical for cognition and speech development. The GABRD gene is expressed most abundantly in brain and has three alternative exons (1A–C) with alternative start codons at the 5′-end. Genomic localisation, function, and expression would suggest that the GABRD gene represents a good candidate for the neurodevelopmental and neuropsychiatric anomalies seen in the 1p36 deletion syndrome.

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)

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