title: Novel mutations in the small leucine-rich repeat protein/proteoglycan (SLRP) genes in high myopia.
abstract: The importance of the genetic component in high myopia has been well established in population and family studies, but only a few candidate genes have been explored to date. The extracellular matrix small leucine-rich repeat proteins/proteoglycans (SLRPs) regulate collagen fibril diameter and spacing. Given their role in extracellular matrix assembly and expression in the eye, they are likely to regulate its shape and size. Analysis of 85 English and 40 Finnish subjects with high myopia (refractive error of -6 diopters [D] or greater) resulted in 23 sequence variations in four SLRP genes, LUM, FMOD, PRELP, and OPTC. We observed higher number of variations in OPTC in English patients than in controls (p=0.042), and a possibly protective variation in LUM (c.893-105G>A) with p-value of 0.0043. Two intronic variations, six nonsynonymous and one synonymous amino acid changes, were not found in any of the nonmyopic controls. Five changes were detected in opticin, Thr177Arg, Arg229His, Arg325Trp, Gly329Ser, and Arg330His, and all but one (Arg229His) were shown to cosegregate with high myopia in families with incomplete penetrance. A homology model for opticin revealed that Arg229His and Arg325Trp are likely to disrupt the protein structure, and PolyPhen analysis suggested that Thr177Arg, Arg325Trp, and Gly329Ser changes may be damaging. A Leu199Pro change in lumican and Gly147Asp and Arg324Thr variations in fibromodulin are located in the highly conserved leucine-rich repeat (LRR) domains. This study provides new insight into the genetics of high myopia, suggesting that sequence variations in the SLRP genes expressed in the eye may be among the genetic risk factors underlying the pathogenesis of high myopia.
authors.affiliation: Collagen Research Unit, Biocenter and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland.
authors.forename: Marja
authors.initials: M
authors.lastname: Majava
authors.forename: Paul N
authors.initials: PN
authors.lastname: Bishop
authors.forename: Pasi
authors.initials: P
authors.lastname: Hägg
authors.forename: Paul G
authors.initials: PG
authors.lastname: Scott
authors.forename: Aine
authors.initials: A
authors.lastname: Rice
authors.forename: Chris
authors.initials: C
authors.lastname: Inglehearn
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hammond
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Leena
authors.initials: L
authors.lastname: Ala-Kokko
authors.forename: Minna
authors.initials: M
authors.lastname: Männikkö
mesh_terms: D000595:Amino Acid Sequence; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D000071235:Fibromodulin; D006801:Humans; D007632:Keratan Sulfate / Q000235:genetics; D007930:Leucine / Q000235:genetics; D000071234:Lumican; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009216:Myopia / Q000235:genetics*; D010375:Pedigree; D011509:Proteoglycans / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D016326:Extracellular Matrix Proteins; C000604330:FMOD protein, human; C000604306:LUM protein, human; D000071234:Lumican; C404108:OPTC protein, human; D011509:Proteoglycans; D000071235:Fibromodulin; D007632:Keratan Sulfate; D007930:Leucine