Linkage and mutational analysis of familial alzheimer disease kindreds for the APP gene region

• Published in: American journal of human genetics Vol. 51; no. 5; pp. 998 - 1014
• Main Authors: KAMINO, K, ORR, H. T, SADOVNICK, A. D, BALL, M. J, KAYE, J, WARREN, A, MCINNIS, M, ANTONARAKIS, S. E, KORENBERG, J. R, VIKRAM SHARMA, KUKULL, W, LARSON, E, PAYAMI, H, HESTON, L. L, MARTIN, G. M, BIRD, T. D, SCHELLENBERG, G. D, WIJSMAN, E. M, ALONSO, M. E, PULST, S. M, ANDERSON, L, O'DAHL, S, NEMENS, E, WHITE, J. A
• Format: Journal Article
• Language: English
• Published: Chicago, IL University of Chicago Press 01.11.1992
• Subjects: Adult; Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer's disease; Amino Acid Sequence; Amyloid beta-Protein Precursor - genetics; amyloid precursor protein; Base Sequence; BASIC BIOLOGICAL SCIENCES; Biological and medical sciences; Blotting, Southern; CENTRAL NERVOUS SYSTEM; CHROMOSOMES; Chromosomes, Human, Pair 21; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DISEASES; family studies; Female; GENE MUTATIONS; genes; GENETIC MAPPING; HEREDITARY DISEASES; HUMAN CHROMOSOME 21; HUMAN CHROMOSOMES; HUMAN POPULATIONS; Humans; linkage analysis; Lod Score; Male; man; MAPPING; Medical sciences; Middle Aged; Molecular Sequence Data; mutation; MUTATIONS; NERVOUS SYSTEM; Neurology; Oligodeoxyribonucleotides - genetics; Original; Pedigree; Polymerase Chain Reaction; POPULATIONS 550400 > Genetics; Human; Nervous system diseases; Linkage; Alzheimer disease; Family study; Inheritance; Etiopathogenesis; Exploration; Precursor; Cerebral disorder; Gene; Genetics; Degenerative disease; Amyloid; Mutation; Molecular biology
• ISSN: 0002-9297; 1537-6605

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-->Gly change. This is the same codon as the hereditary cerebral hemorrhage with amyloidosis-Dutch type Glu-->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 unambiguously 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.