Michèle Vuillaume

Geographical prevalence of two types of Epstein-Barr virus

The Jijoye EBV strain is characterized by a substitution of 1.8 kb in the C-terminal part of the EBNA 2 gene compared to B95-8 or M-ABA virus. This made it possible to construct hybridization probes specific for M-ABA (type A) and Jijoye viruses (type B), which have been used to type the EBV genomes in 38 spontaneously established cell lines. Type A is more prevalent being found in 31 of 38 cases; type B virus was found in five cell lines (Jijoye, LY 67, QIMR-GOR, BL 16, and BL 29); and two cell lines, Daudi and EB-3, contained neither the M-ABA- nor the Jijoye-specific sequences. EBV type B appears to be less ubiquitous, since all type B isolates, including AG 876 virus, originated from Central Africa, La Réunion, and New Guinea. All the other cell lines, carrying EBV type A, were established from patients from Central Africa (4), North Africa (7), New Guinea (1), and Asia (6) and from white individuals (13). The restricted geographical localization of EBV type B in parts of the southern hemisphere and its similarity to herpesvirus papio (T. Dambaugh, K. Hennessy, L. Chamnankit, and E. Kieff (1984) Proc. Natl. Acad. Sci. USA 81, 7632-7636) could suggest that such viruses may have evolved by recombination of EBV with a related Old World monkey virus, alternatively, evolution of virus variants within the human species also being conceivable.

High incidence of cancer in a family segregating a mutation of the ATM gene: possible role of ATM heterozygosity in cancer.

ATM mutations predispose cells to malignancy by promoting chromosomal instability. We have identified a family with multiple cancers that segregates a mutant allele of ATM, IVS61+2insTA, which causes skipping of exon 61 in the mRNA, as well as a previously undescribed polymorphism, IVS61+104C(54):T(46). The mutation was inherited by two sisters, one who developed breast cancer at age 39 and the second at age 44, from their mother, who developed kidney cancer at age 67. Molecular studies were undertaken to determine the role of the ATM gene in the development of cancer in this family. Studies of irradiated lymphocytes from both sisters revealed elevated numbers of chromatid breaks, typical of A‐T heterozygotes. Studies on lymphoblastoid cell lines established from these individuals revealed abnormal p53 induction and apoptosis after DNA damage. Loss of heterozygosity (LOH) in the ATM region of chromosome 11q23.1 showed that the normal ATM allele was lost in the breast tumor of the older sister. LOH was not seen at the BRCA1 or BRCA2 loci. BRCA2 is not likely to be a cancer‐predisposing gene in this family because each sister inherited different chromosomes 13 from each parent. The sisters share their maternal BRCA1 allele, although no mutation in this gene was detected in the family. Our findings suggest that haploinsufficiency at ATM may promote tumorigenesis, even though LOH at the locus supports a more classic two‐hit tumor suppressor gene model. Hum Mutat 14:485–492, 1999.

Expression of the Epstein-Barr Virus (EBV) latent membrane protein is tightly regulated, independently of EB nuclear antigen 2 and of EBV integration or copy number

In vivo, Epstein-Barr virus (EBV) is associated with human tumours and with lymphoproliferations in immunosuppressed patients. In vitro, EBV induces unlimited growth of normal B-lymphocytes, a phenomenon known as immortalization. A limited number of viral genes is expressed during this phenomenon and their relative role concerning the deregulation of cellular proliferation is still unclear. At present, the nuclear antigen EBNA2 and the membrane protein LMP are the two EBV proteins considered to be implicated in the immortalization process. Moreover, many data support the hypothesis that EBNA2 is the major inducer of LMP expression by transactivation; however, in some instances, expression of the two proteins is not correlated, suggesting the existence of complex interactions between EBV and its host-cell that influence viral gene regulation. In an attempt to study thoroughly these EBNA2/LMP interactions, it is important to evaluate whether EBNA2 is or is not a major inducer of LMP expression, and which other parameters can influence LMP expression. By analysing two sets of B-lymphoma lines either infected in vitro with EBV or stably transfected with EBNA2, we have demonstrated that (1) LMP expression can be absolutely independent of EBNA2 expression, (2) the level of LMP expression is very tightly regulated, and is independent of EBV genome status (integrated or episomal) and copy number. Our findings provide compelling evidence that LMP expression has to be related to that of cellular factors that remain to be identified.

Use of 1-Pyrenedecanoic Acid for Demonstrating the Catabolic Block of Cytoplasmic Triacylglycerols in a Lymphoid Cell Line Established from a Patient Affected with Multisystemic Lipid Storage Myopathy (Type 3)

Lipid Storage Myopathies (characterized by a cellular storage of triacylglycerols) are a group of genetic diseases with considerable biochemical and clinical heterogeneity (1). These disorders have been classified by Angelini (1) as follows: type 1 is characterized by a carnitine deficiency (2, 3); type 2 is due to a deficiency of carnitine palmitoyl transferase (4); type 3 is a Multisystemic Lipid Storage Myopathy (MLSM); other mitochondrial myopathies result from defects in the respiratory chain (5, 6) or energy production (7).