PMID- 1671712 OWN - NLM STAT- MEDLINE DCOM- 19910328 LR - 20220330 IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 349 IP - 6311 DP - 1991 Feb 21 TI - Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. PG - 704-6 AB - A locus segregating with familial Alzheimer's disease (AD) has been mapped to chromosome 21, close to the amyloid precursor protein (APP) gene. Recombinants between the APP gene and the AD locus have been reported which seemed to exclude it as the site of the mutation causing familial AD. But recent genetic analysis of a large number of AD families has demonstrated that the disease is heterogeneous. Families with late-onset AD do not show linkage to chromosome 21 markers. Some families with early-onset AD show linkage to chromosome 21 markers, but some do not. This has led to the suggestion that there is non-allelic genetic heterogeneity even within early onset familial AD. To avoid the problems that heterogeneity poses for genetic analysis, we have examined the cosegregation of AD and markers along the long arm of chromosome 21 in a single family with AD confirmed by autopsy. Here we demonstrate that in this kindred, which shows linkage to chromosome 21 markers, there is a point mutation in the APP gene. This mutation causes an amino-acid substitution (Val----Ile) close to the carboxy terminus of the beta-amyloid peptide. Screening other cases of familial AD revealed a second unrelated family in which this variant occurs. This suggests that some cases of AD could be caused by mutations in the APP gene. FAU - Goate, A AU - Goate A AD - Department of Biochemistry, St Mary's Hospital Medical School, London, UK. FAU - Chartier-Harlin, M C AU - Chartier-Harlin MC FAU - Mullan, M AU - Mullan M FAU - Brown, J AU - Brown J FAU - Crawford, F AU - Crawford F FAU - Fidani, L AU - Fidani L FAU - Giuffra, L AU - Giuffra L FAU - Haynes, A AU - Haynes A FAU - Irving, N AU - Irving N FAU - James, L AU - James L AU - et al. LA - eng GR - AG-05128/AG/NIA NIH HHS/United States GR - Wellcome Trust/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (Amyloid beta-Peptides) RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Protein Precursors) SB - IM CIN - Nature. 1991 Feb 21;349(6311):653-4. PMID: 1899915 CIN - Nature. 1991 Apr 18;350(6319):564. PMID: 1901961 GS - APP MH - Alzheimer Disease/*genetics MH - Amino Acid Sequence MH - Amyloid beta-Peptides/*genetics MH - Amyloid beta-Protein Precursor MH - Base Sequence MH - Chromosomes, Human, Pair 21 MH - Exons/genetics MH - Genetic Linkage MH - Genetic Testing MH - Genotype MH - Humans MH - Molecular Sequence Data MH - Mutation MH - Pedigree MH - Polymerase Chain Reaction MH - Polymorphism, Restriction Fragment Length MH - Protein Precursors/*genetics EDAT- 1991/02/21 00:00 MHDA- 1991/02/21 00:01 CRDT- 1991/02/21 00:00 PHST- 1991/02/21 00:00 [pubmed] PHST- 1991/02/21 00:01 [medline] PHST- 1991/02/21 00:00 [entrez] AID - 10.1038/349704a0 [doi] PST - ppublish SO - Nature. 1991 Feb 21;349(6311):704-6. doi: 10.1038/349704a0.