Paragenetic suppressors of suppressor genes--a new class of oncodeterminants.

Impairment or loss of suppressor genes is a common event permitting the oncogene/suppressor gene machinery to develop neoplasia. Following prenatal treatment with X-rays and UV-B, we detected a new class of oncodeterminants that could not be specified as genes. This points to paragenetic elements that suppress suppressorgenes and thus provoke melanoma at earlier ages of onset as expected, with increased severity and increased number of incidences in successive generations, in the absence of further treatment. These elements were isolated from a xiphophorine DNA library by endogenously labeled long terminal repeats (LTR) of a xiphophorine retrovirus, and were characterized as retrotransposons by Southern and Northern blotting and reverse transcription/polymerase chain reaction and transient transfection studies, in situ hybridization, and sequencing. They appear in multiple copies in the telomeric chromosome regions, where they can extend. Three open reading frames (ORF) are flanked by LTR that contain genetically active regulatory elements, and are inducible by UV-B. ORF 3 shows nests of CG dinucleotides and CGG trinucleotides, which are reminiscent of CGG nests predisposing subjects to anticipation of certain human diseases involving tumor generation. Genetic anticipation as defined by Nettleship (1909) or Warren (1996) including an increase of neoplasia might represent an acquired genetic load in preceding generations, which might provide a lead to a molecular understanding of the worldwide increase of incidences of human tumor.

[Presence of alternatively spliced messenger RNA for HLA-A, -B and -C in platelets]. / Untersuchung über das Vorhandensein von alternativ gespleisster Messenger-RNA für HLA-A, -B und -C in Thrombozyten.

Recently we demonstrated that platelets contain specific messenger RNA (mRNA) encoding for the transmembrane HLA class I molecule (44 kDa). In this study we analyzed lymphocytes as well as platelets for the presence of alternatively spliced mRNA with deleted transmembrane domain resulting in soluble HLA class I antigens (39 kDa). PCR amplification of lymphocyte RNA led to a product specific for alternatively spliced cDNA corresponding to the presence of soluble HLA in plasma, while this product could not be obtained from platelet mRNA. These results suggest that platelets in contrast to lymphocytes are unable to synthesize soluble HLA antigens via alternative splicing.

A deletion in the second exon of an HLA-DRB1 allele found in a DR2-negative narcolepsy patient.

In this report, we describe a new allele of the HLA-DRB 1 gene carrying a form of mutation that has not been observed before. It appeared in an HLA-DR2-negative narcolepsy patient who, besides HLA-DR4, revealed a serologic HLA-DR blank segregating with HLA-DQ1. Oligotyping showed that the new allele belongs to the HLA-DR8 group. Restriction analysis and DNA sequencing revealed the deletion of 12 bp as well as the substitution of 9 flanking base pairs between codons 36 and 43. The expression of the mutated gene was demonstrated by the presence of its messenger RNA and a few positive reactions with DR8 sera. Without interrupting the reading frame, the mutation leads to a gene product composed of a modified amino acid sequence. We anticipate that the mutation influences the conformation of the molecule with possible consequences concerning immune response.