Identification and characterization of MTR1, a novel gene with homology to melastatin (MLSN1) and the trp gene family located in the BWS-WT2 critical region on chromosome 11p15.5 and showing allele-specific expression

Abstract

Alterations within human chromosomal region 11p15.5 are associated with the Beckwith-Wiedemann syndrome (BWS) and predisposition to a variety of neoplasias, including Wilms' tumors (WTs), rhabdoid tumors and rhabdomyosarcomas. To identify candidate genes for 11p15. 5-related diseases we compared human genomic sequence with expressed sequence tag and protein databases from different organisms to discover evolutionarily conserved sequences. Herein we describe the identification and characterization of a novel human transcript related to a putative Caenorhabditis elegans protein and the trp (transient receptor potential) gene. The highest homologies are observed with the human TRPC7 and with melastatin 1 ( MLSN1 ), whose transcript is downregulated in metastatic melanomas. Other genes related to and interacting with the trp family include the Grc gene, which codes for a growth factor-regulated channel protein, and PKD1/PKD2, involved in polycystic kidney disease. The novel gene presented here (named MTR1 for MLSN1 - and TRP -related gene 1) resides between TSSC4 and KvLQT1. MTR1 is expressed as a 4.5 kb transcript in a variety of fetal and adult tissues. The putative open reading frame is encoded in 24 exons, one of which is alternatively spliced leading to two possible proteins of 872 or 1165 amino acids with several predicted membrane-spanning domains in both versions. MTR1 transcripts are present in a large proportion of WTs and rhabdomyosarcomas. RT-PCR analysis of somatic cell hybrids harboring a single human chromosome 11 demonstrated exclusive expression of MTR1 in cell lines carrying a paternal chromosome 11, indicating allele-specific inactivation of the maternal copy by genomic imprinting.

Transcriptional regulation and processing increase the functional variability of TRPM channels

“…Similar to TRPM4 it is a Ca 2+ -activated, monovalent selective cation channel (Hofmann et al 2003;Liu and Liman 2003;Prawitt et al 2003) which is involved in taste transduction (Perez et al 2002;Zhang et al 2003b). It has been initially identified in search for genes causal for Beckwith-Wiedemann syndrome (Prawitt et al 2000) but so far it is not clear whether TRPM5 is involved in a disease. 4.5 kb TRPM5 transcripts with a putative open reading frame encoded by 24 exons are expressed in a variety of tissues.…”

A TRP channel contributes to insulin secretion by pancreatic β-cells

“…Interestingly, Two groups now report, surprisingly, that TRPM5 plays a key role in insulin secretion. TRPM5 is a protein of 1,165 amino acids in human 19 and 1,158 amino acids in mouse 20 with highest homology to TRPM4. It is distantly related to other TRPM channels, such as the cold and menthol receptor TRPM8.…”

TRP channels as potential drug targets

“…The reason for this discrepancy is unclear. The TRPM5 (MTR1) gene was originally cloned from a critical region which might be involved in the development of the Beckwidth-Wiedemann syndrome, a predisposition of childhood tumors (Prawitt et al, 2000). Interestingly, in mice TRPM5 has been found as a taste-cell specific protein (Perez et al, 2002) and analysis of TRPM5 -/-mice revealed that reception of sweet, bitter and umami compounds is abolished (Zhang et a l., 2003).…”

“…As mentioned above, there exists an association between the genomic region harboring the TRPM5 locus and a region which might be involved in the development of the BeckwidthWiedemann syndrome, a predisposition of childhood tumors. However, a functional link between TRPM5 and BeckwidthWiedemann syndrome has not been demonstrated (Prawitt et al, 2000). A positional cloning approach led to the identification of TRPM6 as a potential candidate gene in patients with an autosomal-recessive hypomagnesemia disorder (hypomagnesemia with secondary hypocalcemia, HSH).…”