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Title: Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region

Abstract

A large number of familial Alzheimer disease (FAD) kindreds were examined to determine whether mutations in the amyloid precursor protein (APP) gene could be responsible for the disease. Previous studies have identified three mutations at APP codon 717 which are pathogenic for Alzheimer disease (AD). Samples from affected subjects were examined for mutations in exons 16 and 17 of the APP gene. A combination of direct sequencing and single-strand conformational polymorphism analysis was used. Sporadic AD and normal controls were also examined by the same methods. Five sequence variants were identified. One variant at APP codon 693 resulted in a Glu[yields]Gly change. This is the same codon as the hereditary cerebral hemorrhage with amyloidosis-Dutch type Glu[yields]Gln mutation. Another single-base change at APP codon 708 did not alter the amino acid encoded at this site. Two point mutations and a 6-bp deletion were identified in the intronic sequences surrounding exon 17. None of the variants could be unambigously determined to be responsible for FAD. The larger families were also analyzed by testing for linkage of FAD to a highly polymorphic short tandem repeat marker (D21S210) that is tightly linked to APP. Highly negative LOD scores were obtained for the family groupsmore » tested, and linkage was formally excluded beyond [theta] = .10 for the Volga German kindreds, [theta] = .20 for early-onset non-Volga Germans, and [theta] = .10 for late-onset families. LOD scores for linkage of FAD to markers centromeric to APP (D21S1/S11, D21S13, and D21S215) were also negative in the three family groups. These studies show that APP mutations account for AD in only a small fraction of FAD kindreds. 49 refs., 6 figs., 4 tabs.« less

Authors:
; ; ; ; ; ; ; ;  [1];  [2]
  1. Univ. of Washington, Seattle, WA (United States)
  2. and others
Publication Date:
OSTI Identifier:
6974799
Resource Type:
Journal Article
Journal Name:
American Journal of Human Genetics; (United States)
Additional Journal Information:
Journal Volume: 51:5; Journal ID: ISSN 0002-9297
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; CENTRAL NERVOUS SYSTEM; GENE MUTATIONS; HEREDITARY DISEASES; HUMAN CHROMOSOME 21; GENETIC MAPPING; HUMAN POPULATIONS; CHROMOSOMES; DISEASES; HUMAN CHROMOSOMES; MAPPING; MUTATIONS; NERVOUS SYSTEM; POPULATIONS; 550400* - Genetics

Citation Formats

Kamino, K, Anderson, L, O'dahl, S, Nemens, E, Bird, T D, Schellenberg, G D, Wijsman, E M, Kukall, W, Larson, E, and Heston, L L. Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region. United States: N. p., 1992. Web.
Kamino, K, Anderson, L, O'dahl, S, Nemens, E, Bird, T D, Schellenberg, G D, Wijsman, E M, Kukall, W, Larson, E, & Heston, L L. Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region. United States.
Kamino, K, Anderson, L, O'dahl, S, Nemens, E, Bird, T D, Schellenberg, G D, Wijsman, E M, Kukall, W, Larson, E, and Heston, L L. 1992. "Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region". United States.
@article{osti_6974799,
title = {Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region},
author = {Kamino, K and Anderson, L and O'dahl, S and Nemens, E and Bird, T D and Schellenberg, G D and Wijsman, E M and Kukall, W and Larson, E and Heston, L L},
abstractNote = {A large number of familial Alzheimer disease (FAD) kindreds were examined to determine whether mutations in the amyloid precursor protein (APP) gene could be responsible for the disease. Previous studies have identified three mutations at APP codon 717 which are pathogenic for Alzheimer disease (AD). Samples from affected subjects were examined for mutations in exons 16 and 17 of the APP gene. A combination of direct sequencing and single-strand conformational polymorphism analysis was used. Sporadic AD and normal controls were also examined by the same methods. Five sequence variants were identified. One variant at APP codon 693 resulted in a Glu[yields]Gly change. This is the same codon as the hereditary cerebral hemorrhage with amyloidosis-Dutch type Glu[yields]Gln mutation. Another single-base change at APP codon 708 did not alter the amino acid encoded at this site. Two point mutations and a 6-bp deletion were identified in the intronic sequences surrounding exon 17. None of the variants could be unambigously determined to be responsible for FAD. The larger families were also analyzed by testing for linkage of FAD to a highly polymorphic short tandem repeat marker (D21S210) that is tightly linked to APP. Highly negative LOD scores were obtained for the family groups tested, and linkage was formally excluded beyond [theta] = .10 for the Volga German kindreds, [theta] = .20 for early-onset non-Volga Germans, and [theta] = .10 for late-onset families. LOD scores for linkage of FAD to markers centromeric to APP (D21S1/S11, D21S13, and D21S215) were also negative in the three family groups. These studies show that APP mutations account for AD in only a small fraction of FAD kindreds. 49 refs., 6 figs., 4 tabs.},
doi = {},
url = {https://www.osti.gov/biblio/6974799}, journal = {American Journal of Human Genetics; (United States)},
issn = {0002-9297},
number = ,
volume = 51:5,
place = {United States},
year = {Sun Nov 01 00:00:00 EST 1992},
month = {Sun Nov 01 00:00:00 EST 1992}
}