Familial Neurodegenerative Diseases and Single Nucleotide Polymorphisms

Familial Neurodegenerative Diseases and Single Nucleotide Polymorphisms 

Genetic disorders produced by a single causal gene, such as our example of dystrophin mutations leading to Duchenne muscular dystrophy, are termed Mendelian disorders, after the Austrian monk Gregor Mendel (1822-1884), who discovered unitary inheritance in pea plants. There are three primary types of Mendelian inheritance. First, dominant genetic variants or alleles produce a trait or disease if one copy of the allele is sufficient to cause the disease (e.g. Huntington disease). Sec- 

Like APP mutations, the PS 1 and PS2 mutations can lead to increased levels of Ap h brain. Whether the presenilins interact directly with APP through their putative y-secretase activity, or act as co-factor for another y-secretase, remains unclear. Furthermore, the relationship betw een identified causal mutations and AD phenotype is not necessarily simple. For example, PS 1 mutations associated with familial early-onset AD have been identified in individuals with frontotemporal dementia who have no evidence of the Ap accumulation characteristic of AD. 

While variants in these three genes (APP, PSl, and PS2) account for between 30% and 50% of early-onset familial AD, overall they account for less than 2% of all cases of AD (Klaver et al., 1998 Finckh et al., 2000 Liddell et al., 1995 Rosenberg et al., 2000). 

Late-Onset Alzheimer s Disease (LOAD) and Susceptibility Genes 

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