Alternative splicing variants of the human DBL (MCF-2) proto-oncogene.

The DBL (MCF-2) proto-oncogene is a prototype guanine nucleotide exchange factor (GEF) that modulates the Rho family of GTPases. In this communication we describe the isolation of three novel splicing variants of Dbl. The prototype Dbl gene (designated var.1 here) contains 25 exons, while splicing variant 2 (var.2) lacks exons 23 and 24. Var.3 contains additional 3 exons from 5(')-UTR in place of exon 1, while var.4, var.2, and var.3 contain a 48bp insertion between exons 10 and 11, resulting in the insertion of 16 amino acids. We found that var.1 was expressed only in brain, whereas var.3 was expressed in heart, kidney, spleen, liver, and testis, and var.4 in brain, heart, kidney, testis, placenta, stomach, and peripheral blood. The Dbl protein was detectable in brain, heart, kidney, intestine, muscle, lung, and testis. An assay for GEF activity revealed that the var.2 exhibits decreased GEF activity towards Cdc42, var.3 exhibits a weak but significant activity toward Rac1 and Cdc42, var.4 exhibits significant activity toward RhoA and Cdc42, while var.1 exhibits no activity toward RhoA, Rac1, or Cdc42. In summary, we describe 4 splicing variants of the human DBL proto-oncogene that show different tissue distributions and GEF specificities.

[The molecular genetics of rheumatoid arthritis disease gene].

Rheumatoid arthritis(RA) is a chronic polyarthritis of unknown etiology affecting approximately 1% of the population worldwide. Previous studies have shown that the ratio of the risk for siblings of patients with the disease versus the prevalence of that disease in the general population (lambda s) is much greater in RA, suggesting that genetic factors may be involved in familial clustering. Using microsatellite marker analysis and sib-pair linkage study, we have identified three chromosome regions D1S214/253, D8S556 and DXS1232/984 as candidate loci for RA disease genes. In this article, we review the molecular genetic findings on the RA disease genes located respectively at each of the above chromosome regions. We show that the death receptor 3(DR3) gene, a Fas family member, containing nucleotide polymorphism is the candidate disease gene located at D1S214/253. We also identify the mutant forms of angiopoietin-1(Ang-1) and Dbl proto-oncogenes respectively as the candidate genes located at D8S556 and DXS1232/984. We surmise that these mutations are responsible for the impairment of apoptosis induction, angiogenesis and leukocyte function in the patients, which may predispose to autoimmunity.