Exclusion of lumican and fibromodulin as candidate genes in MYP3 linked high grade myopia.
OBJECTIVE
The proteoglycans lumican and fibromodulin regulate collagen fibril assembly and show expression in ocular tissues. A recent mouse knockout study implicates lumican and fibromodulin as functional candidate genes for high myopia. Lumican maps within the chromosome 12q21-q23 autosomal dominant high grade myopia-3 (MYP3) interval, and fibromodulin maps to chromosome 1q32. We screened individuals for lumican and fibromodulin sequence alterations from the original MYP3 family, and from a second high grade myopia pedigree that showed suggestive linkage to both the MYP3 interval and to chromosome 1q32.


METHODS
A total of 10 affected (average spherical refractive error was -16.13 D) and 5 unaffected individuals from the 2 families were screened by direct DNA sequencing. Six primer pairs spanning intron-exon boundaries and coding regions were designed for the 3-exon 1804 base pair (bp) lumican gene. Two primer pairs for the 2-exon 2863 bp fibromodulin gene were designed. Polymerase chain reaction products were sequenced and analyzed using standard fluorescent methods. Sequences were quality scored and aligned for polymorphic analysis.


RESULTS
Direct DNA sequencing of lumican amplicons yielded the expected sequence with no evidence of polymorphism or pathologic mutation. Sequencing of fibromodulin amplicons revealed 6 polymorphisms, 1 of which was novel. One polymorphism was a silent mutation, and five were in the 3' untranslated region. No polymorphism segregated with high myopia.


CONCLUSIONS
Although null and double null Lum and Fmod mouse models have been developed for high myopia, our human cohort did not show affected status association with these genes. Sequencing of the human lumican and fibromodulin genes has excluded them as candidate genes for MYP3 associated high grade myopia.
Paluru
Prasuna C
PC
Division of Ophthalmology, Children's Hospital of Philadelphia, University of Pennsylvania Medical School, Philadelphia, PA 19104, USA.
Scavello
Genaro S
GS
Ganter
William R
WR
Young
Terri L
TL
D002648:Child; D002675:Child, Preschool; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D000071235:Fibromodulin; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D007223:Infant; D007632:Keratan Sulfate / Q000235:genetics*; D008126:Lod Score; D000071234:Lumican; D008297:Male; D009216:Myopia / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011509:Proteoglycans / Q000235:genetics*; D017422:Sequence Analysis, DNA
D011508:Chondroitin Sulfate Proteoglycans; D016326:Extracellular Matrix Proteins; C000604330:FMOD protein, human; C000604332:Fmod protein, mouse; C000604306:LUM protein, human; C000604307:Lum protein, mouse; D000071234:Lumican; D011509:Proteoglycans; D000071235:Fibromodulin; D007632:Keratan Sulfate