Histamine H2 receptor gene variants: lack of association with schizophrenia

Abstract

A role of histaminergic neuronal systems in schizophrenia was suggested by an association with several polymorphisms located in the coding region of the histamine H 2 -receptor (H2R) gene (Orange et al, Mol Psychiatry 1996; 1: 466-469). Using either the reference method of direct sequencing or restriction endonuclease digestion of PCR products amplified from DNA, we could not confirm the existence of these polymorphisms in 53 Swedish controls, 52 French controls and 88 French schizophrenics. In contrast, we detected a G543A transition in the coding region of the gene that was not found in the British population. This allelic variation, which was observed in 15% of the controls with no homozygotes, did not change the amino acid sequence of the receptor. We also analyzed a 1.8-kb nucleotide sequence of the promoter region in which we detected two additional polymorphisms that may modulate the expression of the H2R gene. The first one was a A-592G transition located in the minimal promoter of the gene and found in ෂ10% of controls with no homozygotes. The second one was a G-1018A transition located in an enhancer element of the promoter and was found in ෂ20-30% of controls (with ෂ2-4% homozygotes). DNA analysis of the 88 French schizophrenic subjects revealed that the incidence of the three polymorphisms was not significantly different in this population. In conclusion, the present findings may suggest a surprisingly high variability of the H2R gene polymorphisms in different geographical areas but do not support an association of these allelic variations with schizophrenia. Molecular Psychiatry (2000) 5, 159-164.

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…The multiple transcription initiation sites of the human H 2 receptor gene have been mapped and an 85-bp segment (2610 to 2525 bp) immediately upstream of the initiation site was identified to exhibit a strong promoter activity in the gastric adenocarcinoma, MNK45, expressing the H 2 receptor (Murakami et al, 1999). Several H 2 receptor polymorphisms have been observed with changes, located in the gene promoter or in the coding region, including a nucleotide change leading to an Asn217Asp change (Orange et al, 1996a,b;Ito et al, 2000;Garcia-Martin et al, 2009;Micallef et al, 2013). Currently, no consensus has been obtained on a potential link of the Asn217Asp change to schizophrenia (Orange et al, 1996b;Ito et al, 2000) Currently, there is no direct structural information available for the H 2 receptor.…”

“…Several H 2 receptor polymorphisms have been observed with changes, located in the gene promoter or in the coding region, including a nucleotide change leading to an Asn217Asp change (Orange et al, 1996a,b;Ito et al, 2000;Garcia-Martin et al, 2009;Micallef et al, 2013). Currently, no consensus has been obtained on a potential link of the Asn217Asp change to schizophrenia (Orange et al, 1996b;Ito et al, 2000) Currently, there is no direct structural information available for the H 2 receptor. Yet, the H 2 receptor possesses many of the key prototypical amino acid residues common to the family A aminergic GPCRs, and homology modeling on the basis of the published H 1 receptor X-ray structure and available mutagenesis data leads to reasonable models (Fig.…”

Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer's disease

“…For each of the three promoter regions of the ECE1 gene, B1000 base pairs (bp) of genomic DNA were amplified by polymerase chain reaction (PCR) in 30 healthy individuals, using AmpliTaq Gold (Perkin-Elmer), as described previously (ECE-1a, ECE-1c), 27 or GC-RICH PCR System (Roche Diagnostics), following manufacturer's instructions (ECE-1b-ECE-1d). PCR products were screened for sequence variations by direct sequencing on a Li-Cor 4000L automated DNA sequencer, as described previously.…”

“…PCR products were screened for sequence variations by direct sequencing on a Li-Cor 4000L automated DNA sequencer, as described previously. 27 Wild-type and variant sequences were analyzed for cis-elements using the computer program MatInspector (http://transfac. gbf.de/TRANSFAC).…”

Genetic perspectives of histamine and muscarinic receptors in schizophrenia and clozapine response

“…Studies of the sole polymorphism (543-G/A) identified within the H2 coding region suggest this variant is also not important [Ito et al, 2000;Mancama et al, 2000a], and this is clearly demonstrated upon examination of combined data from existing studies (see Fig. 1).…”