Identification of a novel locus on 2q for autosomal dominant high-grade myopia.

PURPOSE. Myopia, or nearsightedness, is a visual disorder of high and growing prevalence in the United States and in other countries. Pathologic high myopia, or myopia of ≤-6.00 D, predisposes individuals to retinal detachment, macular degeneration, cataracts, and glaucoma. Autosomal dominant (AD) nonsyndromic high-grade myopia has been mapped to loci on 18p11.31, 12q21-q23, 17q21-q23, and 7q36. This is the report of significant linkage to a novel locus on the long arm of chromosome 2 in a large, multigenerational family with AD high-grade myopia. METHODS. The family contains 31 participating members (14 affected). The average spherical refractive error for affected individuals was -14.46 D (range, -7.25 to -27.00). Before a genome screening was undertaken, linkage to intragenic or flanking markers for the myopic genetic syndromes of Stickler syndrome types I, II, and III; Marfan syndrome; and juvenile glaucoma were ruled out. In addition, no linkage was found to the known AD high-grade myopia loci listed above. A full genome screen of the family was performed with 382 microsatellite markers with an average intermarker distance of 10 cM. SimWalk2 software was used for multipoint linkage analysis based on an AD model with a penetrance of 90% and a disease allele frequency of 0.01. RESULTS. Fine-point mapping with an additional nine custommade and five commercial markers yielded a maximum two-point lod score of 5.67 at marker D2S2348. Results of multipoint analysis indicate that the 1-unit support intervals for this new locus spans approximately 9.1 cM from (238.7 to 247.8 cM) on the chromosome 2 genetic map at q37.1. CONCLUSIONS. A novel locus for AD high-grade myopia has been determined, providing further evidence of genetic heterogeneity for this disorder

Genetic linkage study of high-grade myopia in a Hutterite population from South Dakota

PURPOSE: Myopia is a common, complex disorder, and severe forms have implications for blindness due to increased risk of premature cataracts, glaucoma, retinal detachment, and macular degeneration. Autosomal dominant (AD) non-syndromic high-grade myopia has been mapped to chromosomes 18p11.31, 12q21-23, 17q21-23, 7q36, 2q37.1, 7p15.3, 15q12-13, 3q26, 4q12, 8p23, 4q22-q27, 1p36, and Xq23-q25. Here, we demonstrate evidence of linkage for AD non-syndromic high-grade myopia in a large Hutterite family to a locus on chromosome 10q21.1. METHODS: After clinical evaluation, genomic DNA was genotyped from 29 members of a Hutterite family from South Dakota (7 affected). The average refractive error of affected individuals was -7.04 diopters. Microsatellite markers were used to exclude linkage to the known AD nonsyndromic high-grade myopia loci as well as to syndromic high-grade myopia loci. A genome screen was then performed using 382 markers with an average inter-marker distance of 10 cM followed by fine-point mapping in all regions of the genome that gave positive LOD scores. SimWalk2 software was used for multipoint linkage based on AD and autosomal recessive (AR) models with a penetrance of 90% and a disease allele frequency of 0.001. RESULTS: A maximum multipoint LOD score of 3.22 was achieved under an AD model at microsatellite marker D10S1643. Fine point mapping and haplotype analysis defined a critical region of 2.67 cM on chromosome 10q21.1. Haplotype analysis demonstrated two distinct haplotypes segregating with high-grade myopia, indicative of two distinct mutations occurring in the same gene. CONCLUSIONS: We have identified a presumptive myopia locus for high-grade myopia based on linkage and haplotype analysis

The negative impact of Wnt signaling on megakaryocyte and primitive erythroid progenitors derived from human embryonic stem cells

AbstractThe Wnt gene family consists of structurally related genes encoding secreted signaling molecules that have been implicated in many developmental processes, including regulation of cell fate and patterning during embryogenesis. Previously, we found that Wnt signaling is required for primitive or yolk sac-derived-erythropoiesis using the murine embryonic stem cell (ESC) system. Here, we examine the effect of Wnt signaling on the formation of early hematopoietic progenitors derived from human ESCs. The first hematopoietic progenitor cells in the human ESC system express the pan-hematopoietic marker CD41 and the erythrocyte marker, glycophorin A or CD235. We have developed a novel serum-free, feeder-free, adherent differentiation system that can efficiently generate large numbers of CD41+CD235+ cells. We demonstrate that this cell population contains progenitors not just for primitive erythroid and megakaryocyte cells but for the myeloid lineage as well and term this population the primitive common myeloid progenitor (CMP). Treatment of mesoderm-specified cells with Wnt3a led to a loss of hematopoietic colony-forming ability while the inhibition of canonical Wnt signaling with DKK1 led to an increase in the number of primitive CMPs. Canonical Wnt signaling also inhibits the expansion and/or survival of primitive erythrocytes and megakaryocytes, but not myeloid cells, derived from this progenitor population. These findings are in contrast to the role of Wnt signaling during mouse ESC differentiation and demonstrate the importance of the human ESC system in studying species-specific differences in development

New locus for autosomal dominant high myopia maps to the long arm of chromosome 17

PURPOSE. To map the gene(s) associated with autosomal dominant (AD) high-grade myopia. METHODS. A multigeneration English/Canadian family with AD severe myopia was ascertained. Myopes were healthy, with no clinical evidence of syndromic disease, anterior segment abnormalities, or glaucoma. The family contained 22 participating members (12 affected). The average age of diagnosis of myopia was 8.9 years (range, birth to 11 years). The average refractive error for affected adults was -13.925 D (range, -5.50 to -50.00). Microsatellite markers for genotyping were used to assess linkage to several candidate loci, including three previously identified AD high-myopia loci on 18p11.31, 12q22q23, and 7q36. Syndromic myopia linkage was excluded by using intragenic or flanking markers for Stickler syndrome types 1, 2, and 2B; Marfan syndrome; Ehlers-Danlos syndrome type 4; and juvenile glaucoma. A full genome screening was performed, with 327 microsatellite markers spaced by 5 to 10 cM. Two-point linkage was analyzed using the FASTLINK program run at 90% penetrance and a myopia gene frequency of 0.0133. RESULTS. Linkage to all candidate loci was excluded. The genome screening yielded a maximum two-point lod score of 3.17 at θ = 0 with microsatellite marker D17S1604. Fine mapping and haplotype analysis defined the critical interval of 7.71 cM at 17q21-22. CONCLUSIONS. A novel putative disease locus for AD high-grade myopia has been identified and provides additional support for genetic heterogeneity for this disorder

Refinement of the X-linked Nonsyndromic High-Grade Myopia Locus MYP1 on Xq28 and Exclusion of 13 Known Positional Candidate Genes by Direct Sequencing

Myopia affects more people worldwide than any other chronic condition, and it is increasing in all populations across the globe. It affects ∼25% of the U.S. general population between the ages of 12 and 54 years. The present study is a genetic investigation of X-linked high-grade myopia that maps to Xq28