Showing papers by "John H. Fingert published in 2006"

Ethnic variation in AMD-associated complement factor H polymorphism p.Tyr402His

Abstract: Age-related macular degeneration (AMD) is the most common cause of irreversible visual loss in the developed world. Previous studies have demonstrated that the c.1204T>C, p.Tyr402His allelic variant in the complement factor H (CFH) gene is associated with an approximately three-fold increased risk for AMD in Caucasians of predominantly European descent. Both the prevalence as well as the phenotypic spectrum of AMD varies widely among persons of different ethnicities. We hypothesized that populations with a lower prevalence of AMD might also have a lower prevalence of the CFH risk allele. In this study we sought to determine the frequency of this sequence variant in control populations of Caucasians, African Americans, Hispanics, Somalis, and Japanese. Normal control populations were assembled for each ethnic group: Caucasian (n=148), Somali (n=128), African American (n=75), Hispanic (n=81), and Japanese (n=82). Individuals were genotyped using a restriction digest assay and the frequency of the C allele at nucleotide position 1204 of the CFH gene was determined. A bioinformatic approach was used to identify SNPs in linkage disequilibrium with rs1061170 (c.1204T>C, p.Tyr402His) from the human haplotype map project database (HapMap) in order to validate the findings. We found widely discordant frequencies of the risk allele between some of the different ethnic groups: Japanese 0.07±0.02, Hispanics 0.17±0.03, African-Americans 0.35±0.04, Caucasians 0.34±0.03, and Somalis 0.34±0.03. Allele frequencies generated by analysis of the HapMap database were consistent with these findings. This study suggests that there are other yet unidentified genetic factors important in the pathogenesis of AMD that may mitigate the effects of c.1204T>C, p.Tyr402His variant. Hum Mutat 27(9), 921–925, 2006. © 2006 Wiley-Liss, Inc.

Case of Stargardt disease caused by uniparental isodisomy.

Abstract: Stargardtdisease is themostcommon form of juvenile macular degeneration, with an incidence of 1 in 10 000 persons.Clinically, it ischaracterized by pisciform flecks at the level of the retinal pigment epithelium and a bull’s-eye maculopathy. A variant of Stargardt disease, fundus flavimaculatus, demonstrates a more peripheral distribution of flecks. In 1997, mutations in the ABCA4 gene on chromosome 1 were associated with bothStargardtdiseaseandfundus flavimaculatus. Stargardt disease is an autosomal recessive condition. Consequently,patientsareexpectedto inherit 1 copy of a mutant ABCA4 gene from each parent. However, we recently identified a patient affected with Stargardt disease who inherited 2 mutant alleles of the ABCA4 gene fromher father throughamechanism known as uniparental disomy. A femalepatientaged15yearswas diagnosedwithStargardtdiseasewith visual acuities of 20/200 OD and 20/150 OS and characteristic retinal findings (Figure1). Goldmann visual fieldsconfirmedbilateral central scotomas, and a standard electroretinogram was normal. The patient was tested for ABCA4 mutations using standard methods and was found to be homozygous for an ABCA4 mutation of proline to leucine at position 1380 (P1380L). Interestingly, only the patient’s father is a carrier of the P1380L mutation. Her mother does notharbor thismutation(Figure2). Maternity and paternity were confirmed by genotyping the family members with genetic markers including X and Y chromosome markers and 3 short tandem repeat polymorphisms locatedonchromosomes 4, 5, and 11. Quantitative polymerase chain reaction experiments confirmed that the patient was truly homozygous for P1380L (data not shown), suggesting that both copies of this mutation were paternally inherited due to uniparental disomy. An error in chromosome sorting (nondisjunction) may lead to offspring inheriting 2 copies of a chromosome from one parent and none from the other parent (uniparental disomy). In uniparental isodisomy, the offspring inherits a pair of identical chromosomes derived from only 1 of a parent’s 2 homologous chromosomes. In uniparental heterodisomy, a portion of the inherited chromosomes is derived from both of a parent’s homologous chromosomes and the other portion is derived from only 1 of the parent’s chromosomes. Nondisjunction during meiotic cell division leads to gametes with abnormal numbers of chromosomes (nullisomy or disomy). When these abnormal gametes form a zygote, either trisomy or monosomy occurs, which may lead to uniparental disomy by loss of the extra chromosome in early mitotic cell division (trisomy rescue) or by duplication of the monosomic chromosome (monosomy rescue). If a nullisomic gamete and a disomic gamete fortuitously combine to form a zygote, no such rescue is necessary to achieve the proper number of chromosomes (gamete complementation). Recessive alleles on the involved chromosome in uniparental disomy may become homozygous in offspring. Consequently, uniparental disomy may result in expression of a recessive disease inherited from only 1 parent. This non-Mendelian mechanism of disease inheritance has been observed in rod monochromacy, retinitis pigmentosa, and Leber congenital amaurosis. We investigated whether the patient inherited both P1380L alleles of the ABCA4 gene from her father by genotyping the patient and her family at 24 short tandem repeat polymorphism genetic markers distributed across chromosome 1 using standard techniques (Figure 3). For all of the 24 markers, the patient was homozygous for a marker allele possessed by her father, and 16 of these markers demonstrated nonmaternal inheritance of chromosome 1 alleles (neither marker allele was of maternal origin). The other 8 marker genotypes, although uninformative, were consistent with nonmaternal inheritance of chromosome 1. The patient’s sister, however, exhibited normal Mendelian inheritance of chromosome 1 alleles from both parents. These data suggest that the patient is homozygous for the P1380L ABCA4 mutation as a consequence of inheriting 2 identical copies of chromosome 1 from her father (uniparental paternal isodisomy). The frequency of uniparental isodisomy in Stargardt disease was assessed by screening a panel of 830 unrelated patients for homozygosity at chromosome 1 markers. Forty of the 830 patients were homozygous at markers closely flanking ABCA4; however, none were homozygous across all of chromosome 1, ruling out the possibility of uniparental isodisomy (data not shown). Therefore, uniparental isodisomy occurs rarely in Stargardt disease at a frequency of less than 0.12% (1/831) of cases. Although unlikely, it remains possible that some of the 40 subjects in this experiment are homozygous for markers near the ABCA4 gene as a consequence of uniparental heterodisomy. Uniparental disomy of chromosome 1 has been inadvertently detected in studies of recessive disease. Estimates of the prevalence Figure 1. Fundus photograph of the patient’s left eye shows macular and extramacular pisciform yellow flecks characteristic of Stargardt macular dystrophy. Wt/P1380L Wt/Wt

The C677T variant in the methylenetetrahydrofolate reductase gene is not associated with disease in cohorts of pseudoexfoliation glaucoma and primary open-angle glaucoma patients from Iowa.

Abstract: Biochemical studies have suggested that elevated serum levels of homocysteine may be associated with primary open-angle glaucoma (POAG)1, 2 and with pseudoexfoliation glaucoma (PEXG).3 More recentl...