Screening for the β-amyloid precursor protein mutation (APP717: Val → Ile) in extended pedigrees with early onset Alzheimer's disease

Marie Christine Chartier-Harlin; Fiona Crawford; Khalid Hamandi; Mike Mullan; Alison Goate; John Hardy; Hubert Backhovens; Jean Jacques Martin; Christine Van Broeckhoven

doi:10.1016/0304-3940(91)90738-F

Screening for the β-amyloid precursor protein mutation (APP717: Val → Ile) in extended pedigrees with early onset Alzheimer's disease

Marie Christine Chartier-Harlin, Fiona Crawford, Khalid Hamandi, Mike Mullan, Alison Goate, John Hardy, Hubert Backhovens, Jean Jacques Martin, Christine Van Broeckhoven

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63 Scopus citations

Abstract

Screening for the APP717 mutation in 5 further families with early onset Alzheimer's disease failed to reveal further cases with this variant. Screening a further 100 normal individuals for this mutation also failed to reveal further occurrences of this variant in the general population. Sequencing of exons 16 and 17 of the β-amyloid precursor protein gene (the exons which encode the β-amyloid fragment) in pedigree FAD4 revealed them to be of normal sequence. The significance of these observations to the genetics of Alzheimer's disease is discussed.

Original language	English
Pages (from-to)	134-135
Number of pages	2
Journal	Neuroscience Letters
Volume	129
Issue number	1
DOIs	https://doi.org/10.1016/0304-3940(91)90738-F
State	Published - 5 Aug 1991
Externally published	Yes

Keywords

Alzheimer's disease
Chromosome 21
β-Amyloid precursor protein (APP)

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10.1016/0304-3940(91)90738-F

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@article{24f0132cae0a4dd18941aea594137cf2,

title = "Screening for the β-amyloid precursor protein mutation (APP717: Val → Ile) in extended pedigrees with early onset Alzheimer's disease",

abstract = "Screening for the APP717 mutation in 5 further families with early onset Alzheimer's disease failed to reveal further cases with this variant. Screening a further 100 normal individuals for this mutation also failed to reveal further occurrences of this variant in the general population. Sequencing of exons 16 and 17 of the β-amyloid precursor protein gene (the exons which encode the β-amyloid fragment) in pedigree FAD4 revealed them to be of normal sequence. The significance of these observations to the genetics of Alzheimer's disease is discussed.",

keywords = "Alzheimer's disease, Chromosome 21, β-Amyloid precursor protein (APP)",

author = "Chartier-Harlin, {Marie Christine} and Fiona Crawford and Khalid Hamandi and Mike Mullan and Alison Goate and John Hardy and Hubert Backhovens and Martin, {Jean Jacques} and {Van Broeckhoven}, Christine",

note = "Funding Information: firmed. Our screeningp rotocolwas as we have pre-viouslyd escribed\[ 2\a] nd makesu seof the fact that the APP717 mutationc reatesa BclI restrictions ite within the PCR productf rom exon 17. A blood derivedF 23 DNA samplew asu seda s a positivec ontroli n all cases. No samplesf rom AD/A, AD/B, FAD1, FAD2 or FAD4 containedth eBclI restrictionsi te,nor did any of the 100n ormali ndidviduals. PCR amplificationo f exon 16 from samplesd erived from FAD4 was carriedo ut using primerso f sequence: (GGA TCC) GGG TAG GCT TTG TCT TAC AG and (GGA TCC) GGC AAG ACA AAC AGT AGT GG. Direct sequencinogf this exon used an internalp rimer of sequenceA: CA AAC AGT AGT GGA AAG AGG TAA ATT AT. Direct sequencinogf exon 17 in samples derivedf rom FAD4 was carried out as we have pre-viouslyd escribed. Exons 16 and 17 in FAD4 had sequenceisdenticatlo thosep ublished\[ 9\]. Thesed atac onfirmt hatthe APP717 variantis rare in the generaCl aucasianp opulation(1 00 normal individuals screenedin this report, 100 in our previousr eport \[1\])I.t s rarity in the generapl opulation(0 /400c hromo-somes)m akesi ts occurrencien two familiesw ith early onset AD more remarkablea nd make the hypothesis that the mutationis pathogenimc orelikely. The data also confirm,h owevert, hatif APP717 is pathogenicit, is a rare causeo f the disease(0 /5 familiesin this report, 2/17 familiesin our previousr eport).D etailede xamina-tion of previousg eneticl inkagep apers,s uggestst hat only in two familiesF, 23 and FAD4 thereis evidencfeo r a geneticlo cuson ch21 (thesea rep edigree2s and 26 re-spectiveloyf ref. 6). There remain 3 possibilitiesto explaint he data con-cerningF AD4. First, that there is anotherp athogenic locus on ch21 causingt hed iseasein this family. Second, that in this pedigreeth e observatioonf non-cosegrega-tion betweenth e AD locus and the APP gened oesnot reflectm eioticr ecombinatiobnu tan error (seea bove)o r reflectsa n intragenirce combinanTt.h ird,it remainsp os-sible that the original observationo f linkage to ch21 markersin this familyr epresentas c hancee vent.F urther genetic linkage analysis of FAD4 and exhaustive sequencingo f the APP locus in samplesf rom patients from this pedigreea rer equiredt o resolveth esep ossibili-ties. This work was supportedb y grants from Research into Ageing, the Mental Health Foundationt,h e Royal Society,t heMedical ResearchC ouncil,the NationalI n-centiveP rogramo n FundamentaRle searchin Life Sci-encest, heF lemishB iotechnologPyr ogramt,h eNational Fund for ScientificR esearcha nd InnogeneticIsn c., Belgium. We thank Marc Bruyland and Jan Gheuensf or help with clinical diagnoseas nd Antoon Vandenberghe and GoedeleD e Winter for genealogsyt udiesT. he samples used in this study were AG06849 and AG07647 (FAD 1), AG08554a ndA G08526( FAD2) and AG08554 and AG08109A (FAD4) from the CorieU Cell repository.",

year = "1991",

month = aug,

day = "5",

doi = "10.1016/0304-3940(91)90738-F",

language = "English",

volume = "129",

pages = "134--135",

journal = "Neuroscience Letters",

issn = "0304-3940",

publisher = "Elsevier Ireland Ltd",

number = "1",

}

TY - JOUR

T1 - Screening for the β-amyloid precursor protein mutation (APP717: Val → Ile) in extended pedigrees with early onset Alzheimer's disease

AU - Chartier-Harlin, Marie Christine

AU - Crawford, Fiona

AU - Hamandi, Khalid

AU - Mullan, Mike

AU - Goate, Alison

AU - Hardy, John

AU - Backhovens, Hubert

AU - Martin, Jean Jacques

AU - Van Broeckhoven, Christine

N1 - Funding Information: firmed. Our screeningp rotocolwas as we have pre-viouslyd escribed\[ 2\a] nd makesu seof the fact that the APP717 mutationc reatesa BclI restrictions ite within the PCR productf rom exon 17. A blood derivedF 23 DNA samplew asu seda s a positivec ontroli n all cases. No samplesf rom AD/A, AD/B, FAD1, FAD2 or FAD4 containedth eBclI restrictionsi te,nor did any of the 100n ormali ndidviduals. PCR amplificationo f exon 16 from samplesd erived from FAD4 was carriedo ut using primerso f sequence: (GGA TCC) GGG TAG GCT TTG TCT TAC AG and (GGA TCC) GGC AAG ACA AAC AGT AGT GG. Direct sequencinogf this exon used an internalp rimer of sequenceA: CA AAC AGT AGT GGA AAG AGG TAA ATT AT. Direct sequencinogf exon 17 in samples derivedf rom FAD4 was carried out as we have pre-viouslyd escribed. Exons 16 and 17 in FAD4 had sequenceisdenticatlo thosep ublished\[ 9\]. Thesed atac onfirmt hatthe APP717 variantis rare in the generaCl aucasianp opulation(1 00 normal individuals screenedin this report, 100 in our previousr eport \[1\])I.t s rarity in the generapl opulation(0 /400c hromo-somes)m akesi ts occurrencien two familiesw ith early onset AD more remarkablea nd make the hypothesis that the mutationis pathogenimc orelikely. The data also confirm,h owevert, hatif APP717 is pathogenicit, is a rare causeo f the disease(0 /5 familiesin this report, 2/17 familiesin our previousr eport).D etailede xamina-tion of previousg eneticl inkagep apers,s uggestst hat only in two familiesF, 23 and FAD4 thereis evidencfeo r a geneticlo cuson ch21 (thesea rep edigree2s and 26 re-spectiveloyf ref. 6). There remain 3 possibilitiesto explaint he data con-cerningF AD4. First, that there is anotherp athogenic locus on ch21 causingt hed iseasein this family. Second, that in this pedigreeth e observatioonf non-cosegrega-tion betweenth e AD locus and the APP gened oesnot reflectm eioticr ecombinatiobnu tan error (seea bove)o r reflectsa n intragenirce combinanTt.h ird,it remainsp os-sible that the original observationo f linkage to ch21 markersin this familyr epresentas c hancee vent.F urther genetic linkage analysis of FAD4 and exhaustive sequencingo f the APP locus in samplesf rom patients from this pedigreea rer equiredt o resolveth esep ossibili-ties. This work was supportedb y grants from Research into Ageing, the Mental Health Foundationt,h e Royal Society,t heMedical ResearchC ouncil,the NationalI n-centiveP rogramo n FundamentaRle searchin Life Sci-encest, heF lemishB iotechnologPyr ogramt,h eNational Fund for ScientificR esearcha nd InnogeneticIsn c., Belgium. We thank Marc Bruyland and Jan Gheuensf or help with clinical diagnoseas nd Antoon Vandenberghe and GoedeleD e Winter for genealogsyt udiesT. he samples used in this study were AG06849 and AG07647 (FAD 1), AG08554a ndA G08526( FAD2) and AG08554 and AG08109A (FAD4) from the CorieU Cell repository.

PY - 1991/8/5

Y1 - 1991/8/5

N2 - Screening for the APP717 mutation in 5 further families with early onset Alzheimer's disease failed to reveal further cases with this variant. Screening a further 100 normal individuals for this mutation also failed to reveal further occurrences of this variant in the general population. Sequencing of exons 16 and 17 of the β-amyloid precursor protein gene (the exons which encode the β-amyloid fragment) in pedigree FAD4 revealed them to be of normal sequence. The significance of these observations to the genetics of Alzheimer's disease is discussed.

AB - Screening for the APP717 mutation in 5 further families with early onset Alzheimer's disease failed to reveal further cases with this variant. Screening a further 100 normal individuals for this mutation also failed to reveal further occurrences of this variant in the general population. Sequencing of exons 16 and 17 of the β-amyloid precursor protein gene (the exons which encode the β-amyloid fragment) in pedigree FAD4 revealed them to be of normal sequence. The significance of these observations to the genetics of Alzheimer's disease is discussed.

KW - Alzheimer's disease

KW - Chromosome 21

KW - β-Amyloid precursor protein (APP)

UR - http://www.scopus.com/inward/record.url?scp=0025861341&partnerID=8YFLogxK

U2 - 10.1016/0304-3940(91)90738-F

DO - 10.1016/0304-3940(91)90738-F

M3 - Article

C2 - 1922963

AN - SCOPUS:0025861341

SN - 0304-3940

VL - 129

SP - 134

EP - 135

JO - Neuroscience Letters

JF - Neuroscience Letters

IS - 1

ER -

Screening for the β-amyloid precursor protein mutation (APP717: Val → Ile) in extended pedigrees with early onset Alzheimer's disease

Abstract

Keywords

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