The Clinical phenotype of two missense mutations in the presenilin I gene in Japanese patients

Abstract

We report the clinical and neuropathologic phenotypes associated with two different missense mutations in the presenilin 1 (PS-1) gene in Japanese patients with early-onset familial Alzheimer's disease (FAD). In the AM/JPN1 pedigree a missense mutation (C-->T) was found at nucleotide 1102, which is predicted to cause an alanine-to-valine missense substitution at codon 260. In this family, the disease had a mean age of onset of 40.3 years and an indolent course (range, 8-19 years). Neuropathologic studies in 3 members of this pedigree showed widespread senile plaques, neurofibrillary tangles, and neuronal loss, as well as abundant perivascular subpial amyloid deposits in the Virchow-Robin spaces and the presence of Pick-like intraneuronal inclusions in the dentate gyrus. In the second pedigree, transmitting a C-->T nucleotide substitution at position 1027, leading to the missense mutation of alanine to valine at codon 285, the disease had a later onset (mean, 51 years) but a more rapid course. Comparison of the disease phenotypes associated with other missense mutations in exon 9 of PS-1 reveals no clinical or pathological phenotype, which uniquely distinguishes Alzheimer's disease associated with PS-1 mutations from other forms of early-onset FAD, implying that direct mutation screening is required to identify these cases.

Tau is central in the genetic Alzheimer–frontotemporal dementia spectrum

“…Interestingly, neuropathological examination in a patient with PS1 G183V revealed tauopathy in the form of Pick bodies and complete absence of amyloid plaque pathology [57]. Consistent with the idea that PS mutations can produce Pick bodies [57], co-existent AD and Pick body pathology was observed in patients with PS1 M146L and A260V mutations [58,59].…”

Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene

“…The KG family mutation (P264L) has been observed in two other families (Campion et al, 1995;Wasco et al, 1995) and in each case, the onset ages cluster tightly around 45 years. The AM family mutation (A260V) also has been observed in another Japanese family ; cosegregation of this mutation with AD in this family has been described elsewhere (Ikeda et al, 1996). The SNW family mutation C410Y (see also Sherrington et al, 1995) has been observed in two other FAD families (Campion et al, 1995;Sherrington et al, 1995) with onset ages ranging from 40-60 years.…”

“…Clinical features of the L, V, AM, and SNW families have been described previously (Cook et al, 1979;Bird et al, 1989;Lampe et al, 1994;Ikeda et al, 1996. the HRX-III family, a nonconservative amino acid change (A426P) is found in both affected subjects and in three at-risk individuals below the age of 51. The V family mutation is a conservative amino acid change (E120D) that is found in all four affected individuals and in one at-risk individual in the pedigree under the age of 50 years.…”

“…The known mutations are scattered throughout the coding sequence in exons 4-9 and 11. Analysis of the amino acid sequences of these proteins suggests that 10 hydrophilic domains are potential transmembrane domains (TMDs), and, depending on the method of analysis, these proteins may span the membrane between 7 ( Kyte and Doolittle, 1982;Levy-Lahad et al, 1995;Sherrington et al, 1996) and 10 (Jones et al, 1994) times. Recent work on the topology of PS-1 (Doan et al, 1996) and sel-12 (Li and Greenwald, 1996), the Caenohabditis elegans homologue of PS-1 and PS-2, suggests that eight of these 10 hydrophobic domains are TMDs.…”

“…Cosegregation of these mutations with AD in each family and the absence of these variants in controls clearly demonstrate that the mutations are pathogenic. The clinical and neuropathologic phenotype of these families has been extensively described (Bird et al, 1989;Lampe et al, 1994;Ikeda et al, 1996;Mann et al, 1996;Murphy et al, 1996). Also, work on the molecular phenotype of AD in these families has demonstrated that these mutations result in the overproduction of the form of the Aβ ending in amino acid 42 (Mann et al, 1996;Scheuner et al, 1996).…”