Identification of a novel mutation in APP gene in a Thai subject with early-onset Alzheimer's disease (original) (raw)
A novel but non-pathogenic mutation in exon 4 of the human amyloid precursor protein (APP) gene
Neuroscience Letters, 1992
Key word~': DNA sequence variant; Familial Alzheimer disease; fl-Amyloid precursor protein gene Mutations in the fl-amyloid precursor protein (APP) gene have been associated with both familial Alzheimer disease (FAD) and with hereditary cerebral haemorrhage. The polymerase chain reaction was used to both amplify and sequence exon 4 of the APP gene from genomic DNA of subjects with FAD and normal control subjects. A novel, rare, conservative DNA sequence variant was discovered at nucleotide 459 of codon 153 (valine) in exon 4 of the APP gene in an affected member of a large FAD pedigree. Segregation studies indicate that this mutation is likely to be non-pathogenic, but must be recognized and discriminated from pathogenic mutations during sequencing studies of the APP gene in patients with FAD.
Journal of Molecular Neuroscience, 2014
In Morocco, Alzheimer's disease (AD) affects almost 30,000 individuals, and this number could increase to 75,000 by 2020. To our knowledge, the genes predisposing individuals to AD and predicting disease incidence remain elusive. In this study, we aimed to evaluate the genetic contribution of mutations in the amyloid precursor protein (APP) gene exons 16 and 17 to familial and sporadic AD cases. Seventeen sporadic cases and eight family cases were seen at the memory clinic of the University of Casablanca Neurology Department. These patients underwent standard somatic neurological examination, cognitive function assessment, brain imaging, and laboratory tests. Direct sequencing of exons 16 and 17 of the APP gene was performed on genomic DNA of AD patients. In this original Moroccan study, we identified seven novel frameshift mutations in exons 16 and 17 of the APP gene. Interestingly, only one novel splice mutation was detected in a family case. There is a strong correlation between clinical symptoms and genetic factors in Moroccan patients with a family history of AD. Therefore, mutations in APP gene exons 16 and 17 may eventually become genetic markers for AD predisposition.
A novel mutation in the ?-protein coding region of the amyloid ?-protein precursor (APP) gene
Human Genetics, 1992
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Brun A. and L.Gustafson (1974): Extent and severity of cerebral lesions related to clinical and regional cerebral blood flow in presenile dementia. In: PPProc of the V11th Intnl Congr of Neuropathology, Akademiai Kiado, Budapest 1974, p44. Gustafson L, D.H.Ingvar and A. Brun (1975): Clinical and neurocirculatory findings in presenile dementia related to neuropathological changes. In proc. of 2nd Intnl congr of CIANS Prague 1975. p. 371 Brun A, L Gustafson, DHI Ingvar (1974/5): Neuropathological findings related to Neuropsychiatric symptoms and regional cerebral blood flow in presenile dementia. Excerpta medica, Amsterdam, Akademiai Kiado, Budapest. Pp 101-5. Brun, A. and Gustafson, L. (1976). Distribution of cerebral degeneration in Alzheimer's disease. A clinico-pathological study. Arch Psychiatr Nervenkr, 223, 15-33. Gustafson L, Brun A and Ingvar D H (1975): Clinical and neurocirculatory findings in presenile dementia related to neuropathological changes. Activ nerv Sub (Praha) 19, 2, 351 -354. Gustafson L, A Brun, DHI Ingvar (1977): Presenile dementia: Clinical symptoms, pathoanatomical findings and cerebral blood flow. Cerebral vascular disease. A Brun, E Englund (1980): degeneration av hjärnans vita substans vid demens. Riksstämman, Hygiea. P 213 Risberg J, Brun A, Johansson M and Gustafson L (1983): Differential diagnosis of dementia by rCBF and psychometric methods. J Cer Blood Flow and Metabolism, 3, 1, Raven Press, New York, 496 -497. + abstr Brun A and Dictor M (1981): Senile plaques and tangles in dialysis dementia. Acta Path. Microbiol Scand Sect A, 89, 193-198. Brun, A. and Englund, E. (1981). Regional pattern of degeneration in Alzheimer's disease: neuronal loss and histopathological grading. Histopathology, 5, 549-564. Englund E and Brun A (1981): Senile dementia -a structural basis for etiological and therapeutic considerations. Biological Psychiatry. Eds: C Perris and B Jonsson. Elsevier/North Holland Biomed Press 951 -956. Westermark P, Shirahama T, Skinner M, Brun A, Cameron R and Cohen A (1982): Immunohistochemical evidence for the lack of amyloid component in some intracrebral amyloids. Laboratory Investigation 5, 457 -460. Shirhama T, Skinner M, Westermark P, Rubinow A, Cohen A S, Brun A and Kemper T H (1982): Senile cerebral amyloid. Prealbumin as a common constituent in the neuritic plaques, in the neurofibrillary tangle and in the microangiopathic lesion. Am J Pathol 107, 41-50. Brun A (1982): Strukturellt underlag vid organisk senil demens. Symposium Sandoz: Demenstillstånd -synpunkter på etiologi och behandling, 23 -34. Brun A (1982): Alzheimer's disease and its clinical implications. In: Geriatrics. Ed: D Platt. Springer Verlag Heidelberg, NY, 343 -390. Brun A and Englund E (1982): White matter incomplete infarction in dementia. Abstract 9th Internat. Congr. Neuropath. 201. Brun A, L Gusrafson (1983). Down's syndrom -utvecklingsstörning och demens. Läkartidningen 80, 10, pp 936. Risberg J, Brun A, Johansson M and Gustafson L (1983): Differential diagnosis of dementia by rCBF and psychometric methods. J Cer Blood Flow and Metabolism, 3, 1, Raven Press, New York, 496 -497. Gustafson L, Brun A, Hagstadius S, Johansson M and Risberg J (1983): Evaluation of organic dementia and confusional states by rCBF, clinical and psychometric metods. Abstract: 2nd satellite symposium on: Effect of ageing on regulation of cerebral blood flow and metabolism. Eds: Sieshi and C V Loeb. European Neurology, 22, 2. S Karger Medical and Scientific Publishers, Basel. pp. Brun A (1983): Hjärnskada bakom vanliga former av demens. Forskning och Praktik, 15, 7, 103-106. Brun A (1983): An overview of light and electron microscopical changes. In: Alzheimer's disease. Ed: B Reisberg. The Free Press. New York, a division of Mac Millan Inc, 3 -47. Gustafson L, Brun A, Risberg J and Johansson M (1984): Evaluation of organic dementia by regional cerebral blood flow measurements and clinical psychometric methods. Monogr Neural Sci, 11, 111 -117. Karger, Basel. . Gustafson L, Brun A, Hagstadius S, Johansson M and Risberg J (1983): Evaluation of organic dementia and confusional states by rCBF, clinical and psychometric metods. Abstract: 2nd satellite symposium on: Effect of ageing on regulation of cerebral blood flow and metabolism. Eds: Sieshi and C V Loeb. European Neurology, 22, 2. S Karger Medical and Scientific Publishers, Basel. p 23. Brun A (1984): The neuropathological background of clinical signs and symptoms in organic dementia. 2 nd Nordic meeting in Neuropsychology. Lund Sweden. Pp 18-19. Brun A (1985): The structural development of Alzheimer's disease. Danish Medical Bulletin, 32, 1, 25 -27. Friedland R P, A Brun, T F Budinger (1985): Pathological and positron emission tomographic correlations in Alzheimer's disease. The Lancet 8422, vol. I/85, p 228. Brun A and Englund E (1985): Regional variations of cortical degeneration in Alzheimer's disease. Journal of Clinical and Experimental Neuropsychology, 7, 2, 167 Brun A and Englund E (1985): White matter changes in Alzheimer's presenile and senile dementia. In: Normal aging, Alzheimer's disease and senile dementia. Aspects on etiology, pathogenesis, diagnosis and treatment, Ed: C G Gottfries. Editions de lUniversité de Bruxelle's, 47 -50. Gustafson L, Brun A, Holmkvist-Franck A, Risberg J 1985: Regional Cerebral blood flow in degenerative frontal lobe dementia of non-Alzheimer type. Cerebr. Blood Flow Metabol. 5: 141-142. Gustafson L, A Brun, J Risberg (1985): Organic dementia: Clinical picture related to regional cerebral blood flow and neuropathologic al findings. Psychiatry vol. 2. Pp 605-611. Brun A, E Englund (1985): Alzheimer type dementia and white matter changes. Ata neurol. Scand. Vil 71. Pp 87-88. Gustafson L, A Brun, J Risberg (1985): Rating scales for diagnosis of Alzheimer´s disease and frontal lobe dementia of non-Alzheimer type. 26 Englund E, A Brun (1985): A White matter disorder common in Dementia of Alzheimer´s type. Pp 168-169. Englund E, A Brun (1985): demyelination contributes to Alzheimer´s disease. 18. Brun A, L Gustafson, E Englund (1985): Morphology of white matter, subcortical dementia in Alzheimer´s disease. Pp 79 -83. Brun A, Englund E (1986): A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study. Ann Neurol 1986;19:253-262. -Brun A and Gustafson L (1990): Clinico-pathological correlates of dementia: The pathoanatomical substrate of Alzheimer's disease. Excerpta Medica. -Gustafson L, Brun A, Cronqvist S, Dalfelt G, Risberg J, Riesenfeldt W and Rosén I (1990): Regional cerebral blod flow, MRI and BEAM in Alzheimer's disease. J Cer Blood Flow Metab, 9, 1, 543. Brun A, Gustafson L, and Risberg J (1990): A review of 20 years dementia research. Psychiatric Medicine, vol 32k 7, 781 -788. Igakushoin Tokyo Japan. Brun A (1991): Trends in neuropathological enquiry into the dementias: The late life pattern. Workshop on therapeutic and epidemiological aspects. Proc. IPA workshop, Cambridge. Brun A (1991): Dementia of frontal lobe type. Elsevier Science Publishers B V. Biological Psychiatry. Volume 2. G Racagni et al, eds. Pp 126 -127. Pinheiro T, Tapper U A S, Sturesson K, Brun A (1991): Experimental investigation into sample preparation of Alzheimer tissue specimens for nuclear microprobe analysis. Nuclear Instruments and Methods in Physics Research B 54, 186 -190. Brun A (1991): Structural and topographic aspects of degenerative dementia: aspects of degenerative dmentia. Diagnostic considerations. Internat Psychogeriatrics, vol 3, supp. Pp. 75 -83. Englund E, Brun A (1991): Neuropathology of vascular dementia. 5th Congr. Int. Psychogeriatr. Ass. (IP), Rome, Italy, August 18 -23. Brun A (1992): Alzheimer -en demenssjukdom. Vandringar med Böcker. Bibliotekstjänst, Lund. Basun H, O Almquist, K Axelman , A Brun, T A Campbell, J Collinge, C Forsell . S Froelich , L-O Wahlund, L Wetterberg, L Lannfeldt (1997). Clinical characteristics of a family with chromosome 17 -linked rapidly progressive frontotemporal dementia . Arch Neurol, 54 : 539 -544 . Liu X and A Brun (1996): Regional and laminar synaptic pathology in frontal lobe degeneration of non-Alzheimer type. Int. J. Ger. Psych.11, 47-55. Liu X, C Erikson, A Brun (1996). Cortical synaptic changes and gliosis in normal aging, Alzheimer´s disease and frontal lobe degeneration. Dementia 7, 128-134. A 136 Brun A and Passant U (1996): Frontal lobe degeneration of non-Alzheimer type. Structural changes, diagnostic criteria and relation to other fronto-temporal dementias. Acta Neurol.Scand. Suppl 168 28 -30 . A Swedish state of the art document on dementia diseases .Eds L -O Wahlund , B Winblad . Ohlsson Y. A Brun, E Englund (1996): Fundamental pathological lesions in vascular dementia . Acta Neurol Scand Suppl 168, 31-38.A Swedish state of the art document on dementia diseases. ( 1997 ): Misclassification of dementia subtype using the Hachinski ischemic score : results of a meta-analysis of patients with pathologically verified dementias . Annals New York Academy of Sciences. 490 -492....
Alzheimer dementia caused by a novel mutation located in the APP C-terminal intracytosolic fragment
Human Mutation, 2006
Since the first report showing that Alzheimer disease (AD) might be caused by mutations in the amyloid precursor protein gene (APP), 20 different missense mutations have been reported. The majority of early-onset AD mutations alter processing of APP increasing relative levels of Ab42 peptide, either by increasing Ab42 or decreasing Ab40 peptide levels or both. In a diagnostic setting using direct sequence analysis, we identified in one patient with familial early-onset AD a novel mutation in APP (c.2172G4C), predicting a K724N substitution in the intracytosolic fragment. The mutation is located downstream of the e-cleavage site of APP and is the furthermost C-terminal mutation reported to date. In vitro expression of APP K724N cDNA showed an increase in Ab42 and a decrease in Ab40 levels resulting in a near three-fold increase of the Ab42/Ab40 ratio. Further, in vivo amyloid positron emission tomography (PET) imaging revealed significantly increased cortical amyloid deposits, supporting that in human this novel APP mutation is likely causing disease. Hum Mutat 27(9), 888-896, 2006.
Neurobiology of Aging, 1993
1993.-Alzheimer's disease (AD) is the most common cause of dementia (32). Although the majority of cases of AD are sporadic, the most consistent risk factor detected in several epidemiological studies has been a positive family history of the disease (14,21). In addition, many large pedigrees have been described in which AD appears to be inherited as an autosomal dominant disorder. In one such pedigree (F23) a point mutation within the 13-amyloid precursor protein (APP) gene at codon 717 was identified and hypothesized to be pathogenic (10). The mutation results in a valine to isoleucine change in APP (APP717 Val-,Ile). Subsequent screening has revealed four other pedigrees, detailed in this study, in which this mutation co-segregates with AD (13,26,37). In addition, one other pedigree (Tor3) with this mutation has been described (15) and detailed clinical, neuropsychological, and neuropathological data are reported. Tor3 is discussed below in comparison to the findings in the families in this study. The five families we report with the mutation were identified in Britain (1 family), the United States (1 family), and Japan (3 families). The mutation has not been reported in the general population of any of these countries (3,13,26,33). On this basis alone it seems this mutation is pathogenic. Other APP codon 717 mutations have been identified which co-segregate with the disease (4,25). Also, a double mutation in APP at codons 670/671 has been shown to cosegregate with the disease in two large Swedish pedigrees (22). In all cases, there is complete co-segregation of the APP mutation with early onset AD, providing overwhelming statistical evidence that these mutations are pathogenic. We present the clinical features and limited neuropathology of AD in these families with the APP 717 Val-qle mutation. Human genetics Alzheimer's disease Neuropsychology Chromosome 21 Lewy bodies Dementia Neuropathology
Familial Alzheimer disease associated with A713T mutation in APP
Neuroscience Letters, 2004
Mutations in APP are associated with familial early-onset Alzheimer disease (FAD). Examination of the genomic sequence in one patient with FAD revealed a change located in the axon 17 of the APP gene at position 275329G>A (GenBank accession number: D87675; GI: 2429080); cDNA sequence 2137G>A (GenBank accession number: X06989; GI: 28720). This corresponds to the mutation A713T in APP. AD stage VI of neurofibrillary degeneration and stage C of A-amyloid burden was found at the post-mortem neuropathological examination. Previous studies have suggested that the mutation A713T in APP is a silent mutation or polymorphism. However, we have not found this change in APP in a control population analyzed by the amplification-refractory mutation system (ARMS). It is concluded that A713T in APP is implicated in the pathogenesis of AD. Since the immunohistochemical study indicates that A713T mutation is not likely to relate with A-amyloid processing, the causative role of this rare mutation remains to be warranted.
Neuroscience Letters, 1995
DNA from the probands of seven Australian families with hereditary Alzheimer's disease was screened for the presence of known mutations in the amyloid precursor protein (APP) gene on chromosome 21 using single stranded conformational polymorphism (SSCP) analysis [14]. One subject was found to have a mutation causing a Val + Ile substitution at position 717. This was confirmed by restriction enzyme digestion and sequencing. The mutation has been found in both the other affected family members available for study and in two at-risk relatives. It was not present in the only living unaffected relative who has passed the usual age of onset in this family. There is so far no evidence that apolipoprotein E (APOE) genotype influences age of onset in this family, though numbers are small.
Lack of point mutation of the APP gene in sporadic Alzheimer's disease in Japanese
Acta Neurologica Scandinavica, 2009
We investigated point mutations of the APP gene in 66 patients with sporadic Alzheimer's disease (AD) and 180 normal individuals by use of the PCR (polymerase chain reaction) method. Both the AD patients and the normal individuals were Japanese. We extracted DNA from blood samples using the phenol-chloroform method and amplified exons 16 and 17 of the APP gene by PCR. PCR products were digested by MBO-II (exon 16) and BCL-1(exon 17). Electrophoresis was carried out with 3% agarose gel and the separated fragments were stained with ethidium bromide. In addition we investigated other point mutations of exons 16 and 17 by use of the PCR-SSCP (single stranded conformation polymorphisms) method, and found no fragments that exhibited point mutations in the AD patients and normal individuals. These findings indicate that the presence of point mutation of the APP gene is not a major cause of AD in the Japanese population.
Amyloid Precursor Protein Gene ( APP ) Variation in Late-Onset Alzheimer’s Disease
Journal of Molecular Neuroscience
Mutations in the beta-amyloid precursor protein gene (APP) have been found in familial early-onset Alzheímer’s disease (AD). DNA variants at several genes have been linked to the risk of developing the most common late-onset form of AD (LOAD). A few studies analyzed the contribution of APP variants to LOAD, with negative or conflicting results. We determined the variation in the 18 APP exons and flanking intronic sequences in a total of 350 LOAD patients from Spain. A total of 13 nucleotide changes were found and 6 were new and not found among 340 healthy controls, including the only missense change (D243N). The in silico analysis suggested that none of them would have an effect on pre-mRNA splicing or protein folding (D243N). Patients and controls were also genotyped for three APP promoter polymorphisms, and none of them was significantly associated with LOAD. We concluded that APP variants would not contribute to the risk of developing LOAD in our population.