OMIM_GOF@xiajingbo:104311-24-PSEN1 JSONTXT

Moehlmann et al. (2002) identified a leu166-to-pro (L166P) mutation in the PSEN1 gene in a female proband in whom the onset of familial Alzheimer disease was in adolescence (AD3; 607822). Generalized seizures began at age 15, major depression occurred at age 19, memory was clearly impaired by 24, ataxia and spastic paraplegia were recorded by 27, and moderate stage dementia by 28. Dementia, ataxia, and spasticity progressed until death at age 35. Numerous A-beta-immunopositive neuritic and cotton-wool plaques were seen throughout the cerebral cortex and A-beta-immunopositive amyloid cores were abundant in the cerebellar cortex. This was stated to be 1 of 11 mutations associated with FAD and located in the third transmembrane domain (TM3) of PSEN1. An analysis of other FAD-associated and artificial L166 mutants showed increased A-beta(42) levels in all, suggesting that leucine-166 is critically required for the specificity of gamma-secretase cleavage. However, none of the L166 mutations inhibited gamma-secretase activity.