The steps to the gene

In the first years of the 1980s, and particularly after the localization of the "Huntington gene," it became obvious that the future lay in the molecular localization of genes, called "reverse genetics" at the time, and that large extended families, such as family N were the tools for it. I tried to "sell" the family to molecular genetics laboratories urbi etorbi (Foncin and Salmon 1984,1985; Foncin 1985), and we dedicated to it a full paper (Foncin et al. 1985) that concluded, "Detection of genetic markers constitutes a major objective. We think that familial Alzheimer's disease may constitute an interesting model for the understanding of sporadic Alzheimer's disease and senile dementia of the Alzheimer type." Nevertheless, the French molecular genetics community was uninterested. The only French organization to collaborate was the Institut National de Transfusion Sanguine (INTS, Professor Ch. Salmon), which helped in the collection of bloodsamples in France and Italy from family N members and from controls in the same population, and undertook immortalization of lymphocytes and DNA extraction. The interests and possibilities of INTS, however, were in immunology and hematology, and results were negative (Clemenceau et al. 1986; Muller et al. 1986), in spite of the prima facie evidence for a role of immune phenomena in AD (cf., the Fondation Ipsen 1987 meeting, "Immunology and Alzheimer's disease"). An intriguing result (unpublished) was the negative association of family N AD and thalassaemia. We understood it only later, when we found that family N originated in the mountains, whereas thalassaemia was endemic in the plains, due to its protective effect against malaria.

The same year, I participated in still another meeting to "peddle" "my" family (Foncin et al. 1985a). I met a gentleman, Dr. Peter Saint George-Hyslop perceived at once the opportunities provided by family N. He worked in Dr. Gusella's lab in Boston, closely link with NIH, and he organized a wide- ranging collaboration. All came together, as witnessed by the number of co-authors on the resulting publication (St. George- Hyslop et al. 1987a), which proposed a localization on chromosome 21. For a few months, I became sort of a celebrity in the French genetics and Alzheimer microcosms, with the friends who had cut my grant nine years before saying, "Ah! If we only had known." I was further invited to present my work and my ideas at the second Fondation Ipsen "Alzheimer meeting" (Foncin et al. 1988).

In fact, the Science paper raised more questions than it answered. First, it postulated in its title that one genetic defect caused one nosological entity, namely FAD. Second, the "magic" lod score significant for linkage was obtained by adding data from several families, and family N (FAD4 in the paper), which contributed a large fraction of the final lod score, nevertheless showed a recombination between the two "positive" markers. Also, the chromosome 21 "FAD locus" was not linked with the amyloid beta protein gene (Tanzi et al., 1987b) or duplicated (St. George Hyslop et al. 1987b), contrary to what had been predicted from the early Alzheimer manifestations in chromosome 21 trisomics.

The quest for refinement of the localization of "the FAD gene" on chromosome 21 was on. P.St. George-Hyslop, now in Toronto, kept asking for new family N informative subjects; the goal, however, seemed ever further off. Finally (St. George Hyslop et al. 1990), the reason became evident: FAD (not to speak of AD in general) is not a single homogeneous disorder, and groups of subjects identical by descent had to be treated separately. Two years later, overwhelming evidence was found for a FAD locus in the middle of the long arm of chromosome 14 (St. George-Hyslop et al. 1992). Remarkably, family N (FAD4) gave a lod score of 5.21 at 9 = 0.24, strong evidence from this pedigree alone for linkage at this locus, named AD3. The contrast between this result and the major contribution of the same pedigree to the 1987 chromosome 21 AD1 locus result remains unexplained.

In the meantime, Dr. Rainero in Professor Bergamini's department (Torino) had clinically diagnosed FAD in a patient originating in Calabria. He asked Dr. Bruni to investigate the family (Bergamini et al. 1989), which we called "family TO" (Tor1.1 in other papers). She found its cradle in a mountain village about 20 km from the one of family N. The phenotype, including age of manifestation and duration of illness, was identical in both families (identity of the neuropathology was later confirmed). Although we could not identify the common ancestor, who presumably lived before the establishment of church records, we felt confident that FAD patients in both families were identical by descent at the FAD locus (Bruni et al. 1990).

This finding proved important for the ultimate identification and cloning of the gene, mutations of which are causative of early onset FAD in a majority of pedigrees, including family N (Sherrington et al. 1995). To cut a long story short, the S192 gene (later called presenilin 1), mutated in FAD, is situated on a fragment characterized by a haplotype common to the N and TO families. Numerous mutations have been identified on that gene, with families N and TO sharing the M146L mutation. In my opinion, insufficient attention has been given to the correlation between the genotype and phe-notype of patients carrying a presenilin 1 mutation, many reports being content with the mention that "the patients fulfilled so and so criteria for Alzheimer's disease." We reported (El Hachimi et al. 1996) a French family with a A163G presenilin 1 mutation. The corresponding phenotype was clinically evocative of both AD and CreutzfeldtJakob disease; neuropathology (an ultrastructural study and two autopsies) showed plaques and tangles (PHF) but also numerous microspongiosis bubbles. Immunohis-tochemistry revealed separate pA4 and PrPres plaques. I think that this example shows that there is more than the control of pA4 metabolism in the role of presenilin.

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