Presenilin gene mutations

The y-secretase has been difficult to locate but has been identified as a result of other rare familial forms of Alzheimer disease. These are caused by mutations in genes for proteins known as presenilin-1 (on chromosome 14) and presenilin-2 (on chromosome 1197,1198 Thg presenilins are integral mem-... 

Epidemiological studies have shown that mutations in APP and presenilin genes are linked to rare familial and early-onset forms of AD (2). This observation led to the amyloid cascade hypothesis suggesting that excessive AB production is the primary cause of the disease. 

Two other genes in addition to /SAPP have been implicated in the early onset of autosomal dominant forms of Alzheimer s disease. The other two causative genes are located on chromosomes 14 and 1 and code for transmembrane proteins presenilin 1 (consisting of 467 amino acid residues) and presenilin 2 (consisting of 448 amino acid residues). These proteins are synthesized in neurons but their functions are not known. However, mutations in the presenilin genes lead to excessive production of peptides. 

This type of disease occurs in families and begins unusually at early age (i.e., onset below the age of 60). Approximately 10% of Alzheimer s disease are familial and are inherited in an autosomal dominant manner with high penetrance. Deterministic genes directly cause the disease. Mutations in three different genes encoding for the amyloid precursor protein (APP) and the presenilins 1 and 2 (PS1 and PS2) have been identified to be responsible for early-onset familial Alzheimer s disease. 

Alzheimer s Disease Collaborative Group. (1995) The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD famihes. Nat. Genet., 11, 219-222. 

In the early onset familial form of the disease, affecting approximately 5% of cases, there is a clear autosomal dominant pattern of inheritance. Mutations in three genes have been identified involving the beta amyloid precursor protein, presenilin-1 and presenilin-2. The function of these proteins is described in more detail in the chapter on the dementias (Chapter 14). It has been estimated that mutations in these genes account for approximately 50% of the cases of the early onset disease. 

Perez-Tur J, Froelich S, Prihar G, et al. 1995. A mutation in Alzheimer s disease destroying a splice acceptor site in the presenilin-1 gene. NeuroReport 7 297-301. 

Campion, D., Flaman, J. M., Brice, A., Han-nequin, D., Dubois, B., et al. (1995) Mutations of the presenilin I gene in families with early-onset Alzheimer s disease. Hum Mol Genet2373-2377. 

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