The genomic structure of the DMBT1 gene: evidence for a region with susceptibility to genomic instability

Increasing evidence has accumulated for an involvement of the inactivation of tumour suppressor genes at chromosome 10q in the carcinogenesis of brain tumours, melanomas, and carcinomas of the lung, the prostate, the pancreas , and the endometrium. The gene DMBT1 (Deleted in Malignant Brain Tumours 1 ) is located at chromosome 10q25.3-q26.1, within one of the putative interv als for tumour suppressor genes. DMBT1 is a member of the scavenger-recepto r cysteine-rich (SRCR) superfamily and displays homozygous deletions or lac k of expression in glioblastoma multiforme, medulloblastoma, and in gastroi ntestinal and lung cancers. Based on these properties, DMBT1 has been propo sed to be a candidate tumour suppressor gene. We have determined the genomi c sequence of DMBT1 to allow analyses of mutations. The gene has at least 5 4 exons that span a genomic region of about 80 kb, We have identified a put ative exon with coding potential for a transmembrane domain. Our data furth er suggest that alternative splicing gives rise to isoforms of DMBT1 with a differential utilization of SRCR domains and SRCR interspersed domains. Th e major part of the gene harbours locus specific repeats. These repeats may point to the DMBT1 locus as a region susceptible to chromosomal instabilit y.