The Study Of Pedigree And Initial Gene Location For Pathological Myopia

Pathological myopia, defined as a high refractive error inferior to -6 diopters, and characterized with thin posterior sclera, atrophic choroid membrane and degenerative retina due to extreme axial length, is one of the most common human eye disorders and often appears as a familial disease. To understand its genetic mode in Chinese population and to map its locus in human gemone, we conducted a pedigree analysis on 90 Chinese families and a genome-wide screen on 28 families of those.These pedigrees consisted of 401 patients of 1822 individuals from Jiangsu, Zhejiang, Shanghai, Anhui and Henan Provinces. Each pedigree includes at least 3 generations, in whom at least 2 individuals are affected. The major way was to visit their homes to directly identify the family members affected, or to investigate the probands to know the member's state of affection. Altogether 169 nuclear pedigrees were screened, which were divided into two groups according to mating mode, Affected*Normal or Normal*Normal. Simple segregation analysis on A*N and N*N pedigrees was performed repectively. The results showed that A*N pedigrees fit the autosomal dominant inheritance, with segregation ratio 0.6033 and sporadic proportion 13.8%, while N*N pedigrees fit autosomal recessive inheritance, with segregation ratio 0.235245 and sporadic proportion 16.3%, although autosomal dominant inheritance could not be rejected. In complex segregation analysis, SAGE-REGD software was used to fit several genetic model, including Mendelian inheritance (major gene, dominant, recessive, codominant) and non-Mendelian inheritance (non-transmitted, environment, general), and at last all Mendelian inheritances including major gene, dominant, recessive, codominant inheritance were accepted, while codominant inheritance with minimus AIC was best fitted.28 families consented to participate the second part of our study. DNAs were available for 340 individuals from venous blood. 330 pairs of highly heterozygous microsatellite marker primers were selected for a genome-wide screen. We used multi-PCR to amplify these microsatellite markers, then carried out polyacrylamidedel electrophoresis on ABI 377DNA sequencer. Genescan 2.0 and Genetyper 1.1 softwares were used to identify the genotype of every individual. By two-point linkage analysis based on autosomal dominant inheritance model, gene frequency 0.0133 and full penetrance, evidence of significant linkage was found on chromosome 15q in the MP1 family. The maximum LOD score was 1.76 with the markers D15S1010,D15S1007,D15S1042, at a recombination fraction of 0.00. Multipoint linkage analysis strongly supported existence of linkage on this region, with NPL score 5.16. Haplotype analysis by further refined this myopia locus to a 12-cM interval between D15S1019 and D15S146 on 15q12-13. No evidence of linkage was found at known myopia loci such as 18p11.31 and 12q21-23. No evidence of linkage was found in other families. Our study manifests that pathological myopia in Chinese fits autosomal dominant inheritance, but N*N pedigrees may also fit autosomal recessive inheritance with certain sporadic proportion. We find out there is a novel myopia locus on 15q12-13, which is the first myopia locus reported in China to date. 94 confirmed genes locate on this region, so it is necessary to sequence this region to find the virulence gene. This novel locus also demonstrates the high genetic heterogeneity of pathological myopia.