A Founder Mutation in Presenilin 1 Causing Early-Onset Alzheimer Disease in Unrelated Caribbean Hispanic Families
- Eleni S. Athan, PhD;
- Jennifer Williamson, MS;
- Alejandra Ciappa, MD;
- Vincent Santana, BBA;
- Stavra N. Romas, MD;
- Joseph H. Lee, DrPh;
- Haydee Rondon, MD;
- Rafael A. Lantigua, MD;
- Martin Medrano, MD;
- Mayobanex Torres, MD;
- Shigeki Arawaka, MD, PhD;
- Ekaterina Rogaeva, PhD;
- You-Qiang Song, PhD;
- Christine Sato, BSc;
- Toshitaka Kawarai, MD, PhD;
- Kimberley C. Fafel, BS;
- Michael A. Boss, PhD;
- William K. Seltzer, PhD, FACMG;
- Yaakov Stern, PhD;
- Peter St George-Hyslop, MD, FRCPC;
- Benjamin Tycko, MD, PhD;
- Richard Mayeux, MD, MSc
- Author Affiliations: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Ms Williamson, Mr Santana, and Drs Romas, Lee, Lantigua, Stern, Tycko, and Mayeux); The Gertrude H. Sergievsky Center (Ms Williamson, Mr Santana, and Drs Romas, Lee, Stern, and Mayeux); Departments of Neurology (Drs Stern and Mayeux); Psychiatry (Drs Stern and Mayeux), Medicine (Dr Lantiqua) and Pathology (Drs Athan, Ciappa, and Tycko), College of Physicians and Surgeons, New York, NY; Division of Epidemiology, School of Public Health, Columbia University, New York, NY (Drs Lee and Mayeux); Universidad Tecnologica de Santiago (Dr Medrano) and Plaza de la Salud Hospital (Drs Rondon and Torres), Dominican Republic; Center for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto and Department of Medicine, Division of Neurology, University Health Network, Toronto, Ontario (Drs Arawaka, Rogaeva, Song, Kawarai, and St George-Hyslop and Ms Sato); and Athena Diagnostics Inc, Worcester, Mass (Drs Boss, Seltzer, and Ms Fafel).
Abstract
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 microsatellite polymorphisms, 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.
