A Founder Mutation in Presenilin 1 Causing Early-Onset Alzheimer Disease in Unrelated Caribbean Hispanic Families

• Published in: JAMA : the journal of the American Medical Association Vol. 286; no. 18; pp. 2257 - 2263
• Main Authors: Athan, Eleni S, Williamson, Jennifer, Ciappa, Alejandra, Santana, Vincent, Romas, Stavra N, Lee, Joseph H, Rondon, Haydee, Lantigua, Rafael A, Medrano, Martin, Torres, Mayobanex, Arawaka, Shigeki, Rogaeva, Ekaterina, Song, You-Qiang, Sato, Christine, Kawarai, Toshitaka, Fafel, Kimberley C, Boss, Michael A, Seltzer, William K, Stern, Yaakov, St George-Hyslop, Peter, Tycko, Benjamin, Mayeux, Richard
• Format: Journal Article
• Language: English
• Published: Chicago, IL American Medical Association 14-11-2001
• Subjects: Age of Onset; Aged; Alanine; Alzheimer Disease - epidemiology; Alzheimer Disease - genetics; Alzheimer's disease; Amyloid beta-Protein Precursor - genetics; Apolipoproteins E - genetics; Biological and medical sciences; Caribbean Region - ethnology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA Mutational Analysis; Dominican Republic - ethnology; Exons; Genetics; Genotype; Glycine; Haplotypes; Hispanic Americans - genetics; Hispanic people; Humans; Medical research; Medical sciences; Membrane Proteins - genetics; Microsatellite Repeats; Middle Aged; Mutation; Neurology; Phenotype; Polymorphism, Genetic; Presenilin-1; Puerto Rico - ethnology; United States - epidemiology; Caribbean Sea; United States; North America; America; Dominican Republic; Puerto Rico; Caribbean Region; Human; Nervous system diseases; Alzheimer disease; Family study; Presenilin; Genetic determinism; Ethnic group; Cerebral disorder; Age of onset; Gene; Central nervous system disease; Predisposition; Genetics; Adult; Early; Degenerative disease; Mutation
• ISSN: 0098-7484; 1538-3598
• DOI: 10.1001/jama.286.18.2257

CONTEXT Genetic determinants of Alzheimer disease (AD) have not been comprehensively
examined in Caribbean Hispanics, a population in the United States in whom
the frequency of AD is higher compared with non-Hispanic whites. OBJECTIVE To identify variant
alleles in
genes related to familial early-onset
AD among Caribbean Hispanics. DESIGN AND SETTING Family-based case series conducted in 1998-2001 at an AD research center
in New York, NY, and clinics in the Dominican Republic. PATIENTS Among 206 Caribbean Hispanic families with 2 or more living members
with AD who were identified, 19 (9.2%) had at least 1 individual with onset
of AD before the age of 55 years. MAIN OUTCOME MEASURE The entire coding region of the presenilin 1 gene and
exons 16 and 17
of the amyloid precursor protein gene were sequenced in probands from the
19 families and their living relatives. RESULTS A G-to-C
nucleotide change resulting in a glycine–alanine
amino acid substitution at
codon 206 (Gly206Ala) in exon 7 of presenilin 1 was observed
in 23 individuals from 8 (42%) of the 19 families. A Caribbean Hispanic individual
with the Gly206Ala
mutation and early-onset familial disease was also found
by sequencing the corresponding genes of 319 unrelated individuals in New
York City. The Gly206Ala mutation was not found in public genetic databases
but was reported in 5 individuals from 4 Hispanic families with AD referred
for genetic testing. None of the members of these families were related to
one another, yet all carriers of the Gly206Ala mutation tested shared a variant
allele at 2 nearby
microsatellitepolymorphisms, indicating a common ancestor.
No mutations were found in the amyloid precursor protein gene. CONCLUSIONS The Gly206Ala mutation was found in 8 of 19 unrelated Caribbean Hispanic
families with early-onset familial AD. This genetic change may be a prevalent
cause of early-onset familial AD in the Caribbean Hispanic population.