RESUMO
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.
Assuntos
Doença de Alzheimer/genética , Hispânico ou Latino/genética , Proteínas de Membrana/genética , Idade de Início , Idoso , Alanina , Doença de Alzheimer/epidemiologia , Precursor de Proteína beta-Amiloide/genética , Apolipoproteínas E/genética , Região do Caribe/etnologia , Análise Mutacional de DNA , República Dominicana/etnologia , Éxons , Genótipo , Glicina , Haplótipos , Humanos , Repetições de Microssatélites , Pessoa de Meia-Idade , Mutação , Fenótipo , Polimorfismo Genético , Presenilina-1 , Porto Rico/etnologia , Estados Unidos/epidemiologiaRESUMO
We have performed molecular genetic analyses of Hispanic individuals with cystic fibrosis (CF) in the southwestern United States. Of 129 CF chromosomes analyzed, only 46% (59/129) carry delta F508. The G542X mutation was found on 5% (7/129) of CF chromosomes. The 3849 + 10kbC-->T mutation, detected primarily in Ashkenazi Jews, was present on 2% (3/129). R1162X and R334W, mutations identified in Spain and Italy, each occurred on 1.6% (2/129) of CF chromosomes. W1282X and R553X were each detected once. G551D and N1303K were not found. Overall, screening for 22 or more mutations resulted in detection of only 58% of CF transmembrane conductance regulator gene mutations among Hispanic individuals. Analysis of KM19/XV2c haplotypes revealed an unusual distribution. Although the majority of delta F508 mutations are on chromosomes of B haplotypes, the other CF mutations are on A and C haplotypes at higher-than-expected frequencies. These genetic analyses demonstrate significant differences between Hispanic individuals with CF and those of the general North American population. Assessment of carrier/affected risk in Hispanic CF individuals cannot, therefore, be based on the mutation frequencies found through studies of the general population but must be adjusted to better reflect the genetic makeup of this ethnic group. Further studies are necessary to identify the causative mutation(s) in this population and to better delineate genotype/phenotype correlations. These will enable counselors to provide more accurate genetic counseling.
Assuntos
Fibrose Cística/genética , Hispânico ou Latino/genética , Proteínas de Membrana/genética , Mutação Puntual , Sequência de Aminoácidos , California , Cromossomos Humanos , Regulador de Condutância Transmembrana em Fibrose Cística , Genótipo , Haplótipos , Humanos , México/etnologia , Sudoeste dos Estados UnidosRESUMO
To determine whether pulmonary function in infants with asymptomatic cystic fibrosis is related to genotype, we studied 18 infants with cystic fibrosis identified through neonatal screening and 18 healthy control infants. Infants with cystic fibrosis (mean age, 2.0 months; range, 1.0 to 4.6 months) were identified from June 1990 to September 1991 through a statewide screening program based on elevated immunoreactive trypsinogen concentrations. Pulmonary function testing was done before and after inhalation of albuterol. There were no differences in pulmonary function between the cystic fibrosis group and the control infants (mean age, 2.7 months; range, 0.9 to 4.5 months). However, infants homozygous for the delta F508 deletion (n = 10) differed from infants with other genotypic variants of cystic fibrosis and control infants with respect to respiratory system resistance (79.4 +/- 11.5 vs 52.0 +/- 3.8 vs 55.5 +/- 5.0 cm H2O/L per second, respectively; p = 0.04) and specific conductance (0.15 +/- 0.02 vs 0.21 +/- 0.02 vs 0.21 +/- 0.02 cm H2O-1 sec-1, respectively; p = 0.02). Infants homozygous for the delta F508 deletion, but not other infants, responded to albuterol with a decrease in respiratory system resistance. We conclude that infants with asymptomatic cystic fibrosis homozygous for the delta F508 deletion have early evidence of airways obstruction and may need early respiratory treatment.