Kwok, J.B.J. et al. Two novel (M233T and R278T) presenilin 1 mutations in early onset Alzheimer's disease and preliminary evidence for association of presenilin 1 mutations with a novel phenotype. NeuroReport 8, 1537−1542

Garvan Institute of Medical Research, Sydney, NSW, Australia.
Neuroreport (Impact Factor: 1.52). 05/1997; 8(6):1537-42.
Source: PubMed


Eleven early-onset dementia families, all with affected individuals who have either presented clinical symptoms of early onset familial Alzheimer's disease (EOFAD) or have been confirmed to have EOFAD by autopsy, and two early onset cases with biopsy-confirmed AD pathology, were screened for missense mutations in the entire coding region of presenilin-1 (PS-1) and -2 (PS-2) genes. Missense mutations were detected by direct sequence analysis of PCR products amplified from genomic DNA templates of affected individuals. Three pedigrees were attributable to known mutations in the PS-1 gene: P264L, E280A and the splice acceptor site (G to T) mutation, which results in the deletion of residues 290-319 of PS-1 (PS-1 delta 290-319). In a fourth pedigree, a novel PS-1 mutation was identified in exon 7 (M233T), which is homologous to a pathogenic PS-2 mutation (M239V), and is characterized by a very early average age of onset (before the age of 35). In one early onset case, another novel PS-1 mutation was identified in exon 8 (R278T). Of the five remaining families and the other early onset case, none have missense mutations in the PS-1 or PS-2 genes, or in exon 16 and 17 of the APP gene. Moreover, two of the PS-1 mutations, PS-1 delta 290-319 and R278T, are associated with the co-presentation of familial spastic paraparesis (FSP) in some of the affected family members. Our data raise the possibility that the phenotypic spectrum associated with PS-1 mutations may extend beyond typical FAD to include FSP, a disease heretofore unsuspected to bear any relationship to FAD. In addition, our data suggest that other novel EOFAD loci, in addition to APP and the presenilin genes, are involved in the aetiology of up to 50% of EOFAD cases.

4 Reads
  • Source
    • "CWP are large, non-cored and diffuse amyloid plaques, which are composed primarily of Aβ42 without surrounding neuritic dystrophy and glial activation in Alzheimer cases [167]. CWP is often associated with spastic paraparesis (SP) [168], both of which were reported in a subset of PS1 mutants like PS1M233T, PS1R278T and PS1ΔE9[169,170]. The mechanism underlying these unique clinical and pathological phenotypes is unknown. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Presenilins (PSs) are the catalytic core of gamma-secretase complex. However, the mechanism of FAD-associated PS mutations in AD pathogenesis still remains elusive. Here we review the general biology and mechanism of gamma-secretase and focus on the catalytic components -- presenilins and their biological functions and contributions to the AD pathogenesis. The functions of presenilins are divided into gamma-secretase dependent and gamma-secretase independent ones. The gamma-secretase dependent functions of presenilins are exemplified by the sequential cleavages in the processing of APP and Notch; the gamma-secretase independent functions of presenilins include stabilizing beta-catenin in Wnt signaling pathway, regulating calcium homeostasis and their interaction with synaptic transmission.
    Translational Neurodegeneration 07/2013; 2(1):15. DOI:10.1186/2047-9158-2-15
  • Source
    • "Colombian kindred 28 Onset 49.01 (6.08) – – 1997 [27] PS1 E280A genealogy in Australia 1 Onset 47 – – 1997 [25] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Presenilin 1 (PS1) mutations are the most common cause of early-onset familial Alzheimer's disease (EOFAD). They show a common phenotypic profile characterized by early age of onset, severe dementia and distinct neurodegeneration. The largest population of EOFAD carries the E280A mutation in PS1 and resides in Antioquia, Colombia, currently comprising around 5,000 individuals. Carriers start showing memory impairment in the third decade of life, followed by progressive impairment of language and other cognitive processes. They reach mild cognitive impairment around 45 and dementia around 50 years of age. There is some phenotypic variability among the carriers of this single PS1 mutation. Some patients present with epilepsy, verbal impairment, and cerebellar ataxia. Neuropathologically, PS1 E280A cases show pronounced brain atrophy, severe amyloid-β pathology, distinct hyperphosphorylated tau-related pathology, and cerebellar damage. The earliest event identified by functional magnetic imaging resonance is hyperactivation within the right anterior hippocampus around 33 years of age. This well-studied population with a clear pre-clinical profile and wide phenotypic variability in age of onset and clinical presentation is ideally suited for clinical trials and to study molecular mechanisms of Alzheimer's disease.
    Journal of Alzheimer's disease: JAD 07/2012; 32(1):1-12. DOI:10.3233/JAD-2012-120907 · 4.15 Impact Factor
  • Source
    • "The G206S mutation in the PSEN1 gene has been reported in two families (17, 18), and their age of onset was 30 to 35 yr, which is similar to that in our patients. The M233T mutation was previously identified in French and Australian families with 3-5 affected individuals in each family and the mean age of onset of 35 yr (10, 17, 19). And, it is of note that our patient showed rapidly progressive course by worsening the Korean Mini-Mental State Examination (K-MMSE) score from 20 at 2 yr after the first symptom into 4 at 2 yr later, which might be due to the presence of the APOE ε4 allele. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although mutations in three genes, amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2), have been identified as genetic causes of early-onset Alzheimer s disease (EOAD), there has been a single report on a PSEN1 mutation in Koreans. In the present study, we performed a genetic analysis of six Korean patients with EOAD. Direct sequencing analysis of the APP, PSEN1 and PSEN2 genes revealed two different mutations of the PSEN1 gene (G206S and M233T) and one mutation of the APP gene (V715M) in three patients with age-at-onset of 34, 35, and 42 yr, respectively. In addition, two patients with age-at-onset of 55 and 62 yr, respectively, were homozygous for APOE epsilon 4 allele. One woman had no genetic alterations. These findings suggest that PSEN1 and APP gene mutations may not be uncommon in Korean patients with EOAD and that genetic analysis should be provided to EOAD patients not only for the identification of their genetic causes but also for the appropriate genetic counseling.
    Journal of Korean Medical Science 05/2008; 23(2):213-7. DOI:10.3346/jkms.2008.23.2.213 · 1.27 Impact Factor
Show more