keratan-sulfate and Myopia

Many studies have evaluated the association between lumican (LUM) gene polymorphisms and high myopia. However, the results remain controversial. This meta-analysis aims to comprehensively evaluate the relationship between two common LUM polymorphisms (rs3759223 and rs3759222) and the risk of high myopia.. A comprehensive literature search for studies published up until September of 2013 was performed. Data were extracted independently by two investigators, and the weighted Odds Ratios (ORs) and 95% Confidence Intervals (CIs) for the associations were obtained by using a random-effects model.. Eight studies (1425cases and 1271 controls) were identified for the analysis of the association between rs3759223 polymorphism and high myopia. The results indicated that rs3759223 polymorphism was associated with high myopia under a recessive model (OR = 1.71, 95%CI 1.04-2.81). Further subgroup analysis indicated that this polymorphism was associated with high myopia among Chinese people in the additive model (OR = 1.17, 95%CI 1.06-1.29) and a recessive model (OR = 1.75, 95%CI 1.00-3.06) with control group coming from hospital based population. Four studies (1024 cases and 1163 controls) were identified for the analysis of the association between rs3759222 polymorphism and high myopia. The results indicated that rs3759222 polymorphism was not associated with high myopia in all genetic models, even the subgroup analysis couldn't provide relative proof to assure the outcome.. This meta-analysis suggests that LUM polymorphisms are associated with the risk of high myopia. However, well-designed studies with larger sample sizes and more ethnic groups are required to further validate this association.

Topics: Case-Control Studies; Chondroitin Sulfate Proteoglycans; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Keratan Sulfate; Lumican; Myopia; Polymorphism, Single Nucleotide; Publication Bias

Numerous studies have evaluated the association between the single-nucleotide polymorphism (SNP) (rs3759223, C→T) in Lumican gene and high myopia risk in the Chinese population. However, the results have been inconsistent. We therefore here examined whether the rs3759223 polymorphism confers high myopia risk by conducting a meta-analysis.. PubMed, EMBASE, Science Citation Index, and Chinese National Knowledge Infrastructure (up to November 30, 2012) were searched by two investigators independently. Pooled relative ratios (RRs) and 95% confidence interval (CI) were used to assess the strength of the associations between SNP rs3759223 and myopia. Statistical analysis was undertaken using the program STATA 11.0 software (Stata Corporation, College Station, TX).. Five case-control studies involving 923 patients with high myopia and 622 controls were included in this meta-analysis. A significant relationship between SNP rs3759223 and high myopia in the Chinese population was found under the homozygote (RR = 1.47, 95% CI 1.01-2.12, p = 0.04) and recessive (RR = 1.69, 95% CI 1.09-2.62, p = 0.02) genetic models. However, no significant association was found under the heterozygote (RR = 1.01, 95% CI 0.76-1.35, p = 0.93) and dominant (RR = 1.06, 95%CI 0.90-1.26, p = 0.48) genetic models.. This meta-analysis showed the evidence that SNP rs3759223 may affect individual susceptibility to high myopia in the Chinese population. Given the limited sample size, further investigations are needed to validate the association.

Topics: Asian People; Chondroitin Sulfate Proteoglycans; Genetic Predisposition to Disease; Humans; Keratan Sulfate; Lumican; Myopia; Polymorphism, Single Nucleotide

To investigate the change of refractive status in transgenic mice with mutant Lumican (bright proteoglycan) gene at different ages.. Experimental Study. Fifty-four 3-week-old with mutant Lumican gene (cDNA 596T > C) mice (27 male and 27 female) were randomly divided into 9 groups (n = 6, half male and half female) by random number table. One group (3-week-old) was randomly chosen and measured the refractive status by retinoscopy after mydriasis. Measurement of other groups were repeated the method above respectively in the fourth, fifth, sixth, eighth, tenth, twelfth, sixteenth, and twentieth week. Differences of diopter between right and left eye and between male and female were compared within each group by paired t test. The differences of mice's diopters in different age were compared by Kruskal-Wallis H test. Pairwise comparisons were acquired by Mann-Whitney U test.. There were no statistic difference of diopters between binoculus: The mice's diopters of right and left eyes were respective measured in the twentieth week (1.50 ± 0.45) D and (1.25 ± 0.42) D (t = -0.889, P > 0.05), The mice's diopters of right and left eyes were respective measured in the third week (-2.50 ± 2.59) D and (-2.50 ± 4.32) D (t = 0.000, P > 0.05); There were no statistic difference of diopters between different genders: The mice's diopters of female and male were respective measured in the third week (-0.5 ± 3.83) D and (-4.17 ± 1.94) D, (t = 2.079, P > 0.05), The mice's diopters of female and male were respective measured in the twelfth week (1.50 ± 0.84) D and (1.50 ± 1.87) D (t = 0.000, P > 0.05); Analysis of binocular diopters revealed significant differences among nine groups (H = 20.910, P < 0.05). Diopters measured in the third week (-2.50 ± 3.40D) and the sixth week (+3.25 ± 2.67) D had statistical difference (Z = -3.259, P < 0.001). There were no statistical significance between other groups (P > 0.001).. Characteristics of diopters gathered from mice with Lumican gene mutation at different weeks are summarized as follows: Myopia could be observed in the third week. And this situation of myopia was gradually transformed into hyperopia with aging. The maximum hyperopic diopter was observed at 6th-week-old mice. From the eighth to twentieth week, the degree of hyperopic diopter gradually decreased and stabilized.

Topics: Age Factors; Animals; Chondroitin Sulfate Proteoglycans; Disease Progression; Female; Hyperopia; Keratan Sulfate; Lumican; Male; Mice; Mice, Transgenic; Myopia; Random Allocation; Refraction, Ocular; Sex Factors

Pathological myopia (PM) is a hereditary ocular disease leading to severe loss of visual acuity and blindness. Lumican gene (LUM) is one of those candidate genes of PM. The purpose of this study was to establish a mutant Lumican transgenic mouse model, and to prepare for the further study of the pathogenesis of PM.. Experimental study. Mutation of LUM gene was created by site-directed mutagenesis. Recombinant DNA techniques were used for the construction of the pRP. EX3d-EF1A>LUM/flag>IRES/hrGFP transgene. The gene fragments were microinjected into the zygote male pronuclei of BDF1 mice, and then the zygote cells alive were transplanted into the oviduct of acceptor pregnant female ICR mice. The F0 generation transgenic mice obtained were named C57-TgN (LUM)CCMU. Genome DNA from mice tail was detected by PCR and Western blotting.. Six of 31 F0 generation mice were positive transgenic mice. The western blotting study showed that the flag-tag was expressed in the mouse tail tissue. Sixty-eight of 128 mice (F1 to F3 generation) were positive transgenic mice, the positive rate is 53.13%.. The mutant Lumican (cDNA 596T>C) transgenic mouse model has been established. This model will provide fundamental conditions for studies of the pathogenesis of PM. Also it will be the basis of further studies about the effect of Lumican mutation on the development of PM and structure and function of the extra cellular matrix.

Topics: Animals; Chondroitin Sulfate Proteoglycans; Disease Models, Animal; Exons; Female; Keratan Sulfate; Lumican; Male; Mice; Mice, Inbred ICR; Mice, Transgenic; Mutagenesis, Site-Directed; Myopia; Plasmids

The lumican gene (LUM) encodes a major extracellular component of the fibrous mammalian sclera. Alteration in the expression levels of extracellular matrix components may influence scleral shape, which in turn could affect visual acuity. Single-nucleotide polymorphisms (SNPs) in the LUM gene were determined in an investigation of whether LUM gene polymorphisms correlate with high myopia.. Sequences spanning all three exons, intron-exon boundaries, and promoter regions were determined in 50 normal individuals. Five SNPs were identified, one of which was found to be a newly identified polymorphism. Genomic DNA was prepared from peripheral blood obtained from 201 patients with high myopia and 86 control subjects. Genotypes of the SNPs -1554 T/C (rs3759223), -628 A/-(rs17018757), -59 CC/-(rs3832846), c.601 T/C (rs17853500), and the novel SNP c.1567 C>T were determined by polymerase chain reaction.. Of the five SNPs, one showed a significant difference between patients and control subjects (c.1567 C>T, P = 0.0016). Haplotype analysis revealed a significantly higher presence of polymorphisms in patients with myopia (P < 0.0001). Moreover, the c.1567 T polymorphism was determined to have lower reporter gene activity than that of c.1567 C.. These observations suggest that LUM gene polymorphisms contribute to the development of high myopia.

Topics: 3' Untranslated Regions; Adolescent; Adult; Chondroitin Sulfate Proteoglycans; Exons; Female; Genotype; Haplotypes; Humans; Introns; Keratan Sulfate; Linkage Disequilibrium; Lumican; Male; Myopia; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Young Adult

Lumican (LUM) is one of the major extracellular matrix components of the sclera. Increasing evidence suggests that changes in the structure and composition of the sclera are major factors in regulating scleral integrity and axial elongation of the eye, as in myopia.. Patients (n=182; age range, 17-24 years) were with a myopic spherical equivalent (SE)>6.5 diopters (D) and the control group comprised individuals (n=78; age range, 17-25 years) were with a myopic SE<0.5 D. The DNA fragments were separated by horizontal electrophoresis on 3% agarose gels. The forward primer was labelled with a 5' FAM and the reaction products were detected using a 3100 Genetic Analyzer.. The polymorphisms detected in this study were LUMc.601, LUM-59, LUM-628, and LUM-1554. Moreover, the haplotype distributions of Ht1 (C/A/CC/T), Ht2 (C/A/--/T), Ht3 (T/A/CC/C), Ht4 (T/--/CC/T), Ht5 (T/--/CC/C), and Ht6 (T/--/--/C) of these polymorphisms were compared between the two groups. The haplotype frequencies of Ht1, Ht2, Ht5, and Ht6 differed significantly between the two groups (P=2.08x10(-5), odds ratio (OR): 2.19, 95% confidence interval (CI): 1.52-3.15; P=2.2x10(-5), OR: 0.39, 95% CI: 0.25-0.61; P=2.7x10(-5), OR: 0.36, 95% CI: 0.22-0.59; P=3.7x10(-5), OR: 4.71, 95% CI: 2.12-10.5, respectively).. These observations suggest that the four polymorphisms of the LUM promoter contribute to the pathogenesis of high myopia. Understanding the functions of LUM in myopia helps us design new methods in treating and preventing myopia.

Topics: Adolescent; Adult; Chondroitin Sulfate Proteoglycans; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Keratan Sulfate; Lumican; Male; Myopia; Polymorphism, Single Nucleotide; Sequence Analysis, DNA; Young Adult

Topics: Asian People; Chondroitin Sulfate Proteoglycans; Female; Genotype; Humans; Keratan Sulfate; Lumican; Male; Myopia; Polymorphism, Single Nucleotide; Receptor, Muscarinic M1; Receptors, Muscarinic; Reproducibility of Results; Taiwan

The lumican gene (lum), which encodes one of the major keratan sulfate proteoglycans (KSPGs) in the vertebrate cornea and sclera, has been linked to axial myopia in humans. In this study, we chose zebrafish (Danio rerio) as an animal model to elucidate the role of lumican in the development of axial myopia. The zebrafish lumican gene (zlum) spans approximately 4.6 kb of the zebrafish genome. Like human (hLUM) and mouse (mlum), zlum consists of three exons, two introns, and a TATA box-less promoter at the 5'-flanking region of the transcription initiation site. Sequence analysis of the cDNA predicts that zLum encodes 344 amino acids. zLum shares 51% amino acid sequence identity with human lumican. Similar to hLUM and mlum, zlum mRNA is expressed in the eye and many other tissues, such as brain, muscle, and liver as well. Transgenic zebrafish harboring an enhanced GFP reporter gene construct downstream of a 1.7-kb zlum 5'-flanking region displayed enhanced GFP expression in the cornea and sclera, as well as throughout the body. Down-regulation of zlum expression by antisense zlum morpholinos manifested ocular enlargement resembling axial myopia due to disruption of the collagen fibril arrangement in the sclera and resulted in scleral thinning. Administration of muscarinic receptor antagonists, e.g. atropine and pirenzepine, effectively subdued the ocular enlargement caused by morpholinos in in vivo zebrafish larvae assays. The observation suggests that zebrafish can be used as an in vivo model for screening compounds in treating myopia.

Topics: Amino Acid Sequence; Animals; Animals, Genetically Modified; Cattle; Chondroitin Sulfate Proteoglycans; Collagen; Conserved Sequence; Corneal Stroma; Drug Evaluation, Preclinical; Gene Expression Regulation; Gene Knockdown Techniques; Humans; Keratan Sulfate; Larva; Lumican; Mice; Molecular Sequence Data; Muscarinic Antagonists; Myopia; Organ Size; Phylogeny; Promoter Regions, Genetic; Rats; RNA, Messenger; Sclera; Sequence Alignment; Zebrafish

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.

Topics: Amino Acid Sequence; Chondroitin Sulfate Proteoglycans; Conserved Sequence; DNA Mutational Analysis; Extracellular Matrix Proteins; Female; Fibromodulin; Humans; Keratan Sulfate; Leucine; Lumican; Male; Models, Molecular; Molecular Sequence Data; Myopia; Pedigree; Proteoglycans; Sequence Alignment

To better characterize the role of proteoglycans in scleral tissue remodeling during the development of minus lens induced myopia and during recovery in tree shrews.. Competitive reverse-transcription polymerase chain reaction (RT-PCR) was used to quantify the scleral mRNA levels for aggrecan, decorin, biglycan, and lumican in a group of tree shrews following four days of monocular -5 D lens treatment (n=5) and in a group after two days of recovery after 11 days of -5 D lens wear (n=5). Values were compared with age-matched normal animals (n=5). Aggrecan was localized within the sclera using immunohistochemistry.. Four days of -5 D lens wear produced axial (vitreous chamber) elongation and a myopic shift in the treated eyes. Two days of recovery produced significant refractive recovery. Aggrecan mRNA levels showed differential, bidirectional regulation. Levels in the treated eye sclera relative to the control eye were 30.8%+/-2.4% lower after four days of -5 D lens treatment and 51.4%+/-2.4% higher after two days of recovery. Decorin, biglycan, and lumican mRNA levels showed little differential regulation. However, biglycan and lumican along with aggrecan showed binocular regulation (treated and control eye mRNA levels significantly lower than normal eye mRNA levels after 4 days of -5D lens treatment). Immunohistochemical results showed that aggrecan is present in tree shrew sclera and that it is located primarily between the collagen lamella and near the fibroblasts.. These data suggest that the expression of aggrecan is strongly differentially modulated in the sclera during experimentally induced myopia and recovery. The modulation of aggrecan in concert with previously described changes in type I collagen and hyaluronan may play a key functional role in modulating the ability of the lamellae to slip across one another. This may be manifested in the scleral creep rate, which in turn modulates axial elongation rate and refractive state.

Topics: Adaptation, Physiological; Aggrecans; Animals; Biglycan; Chondroitin Sulfate Proteoglycans; Decorin; Extracellular Matrix Proteins; Immunohistochemistry; Keratan Sulfate; Lenses; Lumican; Myopia; Proteoglycans; Recovery of Function; Refraction, Ocular; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sclera; Time Factors; Tupaiidae

To analyze the amounts and distributions of nonsulfated and sulfated keratan sulfate (KS) and chondroitin/dermatan sulfate (CS/DS) disaccharides in the interface wound of human postmortem LASIK corneas in comparison with normal control corneas.. Corneal stromal tissue samples from central and paracentral hypocellular primitive stromal interface scars of human LASIK corneas and from similar regions of normal control corneas were collected by laser capture microdissection (LCM) and subsequently were digested with specific glycosidase enzymes. Digests were directly analyzed by electrospray ionization tandem mass spectrometry (ESI-MS/MS).. Concentrations of both monosulfated GlcNAc(6S)-beta-1,3-Gal (MSD2) and disulfated Gal (6S)-beta-1,4-GlcNAc(6S) (DSD) KS disaccharides from the LASIK interface scars were significantly lower than in normal control corneal stromas. No significant difference was found for the concentration of nonsulfated (NSD) KS disaccharides in LASIK interface scars compared with normal controls. The concentration of DeltaUA-beta-1,3-GalNAc(6S) (Deltadi-6S) CS/DS disaccharides from the LASIK interface scar was significantly higher than normal corneal stroma, whereas concentrations of DeltaUA-beta-1,3-GalNAc(4S) (Deltadi-4S) and nonsulfated Deltadi-0S CS/DS disaccharides demonstrated no significant differences from normal corneas.. The profiles of KS and CS/DS disaccharides in LASIK interface scars are significantly different from those in normal cornea stromal tissue, as revealed by LCM and ESI-MS/MS.

Topics: Chondroitin Sulfates; Cicatrix; Cornea; Corneal Stroma; Dermatan Sulfate; Humans; Keratan Sulfate; Keratomileusis, Laser In Situ; Middle Aged; Myopia; Spectrometry, Mass, Electrospray Ionization

To study the relationships between single nucleotide polymorphisms (SNPs) of lumican, decorin, and DSPG3 genes and high myopia.. One hundred and twenty adult patients with high myopia (< -10.0 D) and 137 controls were used to study the relationships between the decorin, lumican, and DSPG genes and high myopia. All subjects were free of ocular diseases, other than myopia, as well as of other systemic genetic diseases. Genotyping was performed by direct sequencing after PCR amplification of chromosomal DNA. Allele frequencies were tested for Hardy-Weinberg disequilibrium. The chi(2) or Fisher test was conducted to investigate the genotypic and allelic distribution between the high myopia and control groups.. The genotyping success rate was 100%. Univariate analysis revealed significant differences between patients and control subjects with respect to one of the SNPs (rs3759223, C->T) of the lumican gene, with a p value of 0.000283. There was no significant relationship between other SNPs of lumican, decorin, and DSPG genes and high myopia.. Our results indicate that an SNP (rs3759223), which is located in the promoter region of the lumican gene, may be worth further investigation to determine its association with development of high myopia.

Topics: 5' Flanking Region; Adult; Asian People; Base Sequence; Case-Control Studies; Chondroitin Sulfate Proteoglycans; Decorin; Extracellular Matrix Proteins; Female; Genetic Predisposition to Disease; Genotype; Humans; Keratan Sulfate; Lumican; Male; Middle Aged; Molecular Sequence Data; Myopia; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Proteoglycans; Severity of Illness Index; Small Leucine-Rich Proteoglycans; Taiwan

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.. 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.. 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.. 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.

Topics: Child; Child, Preschool; Chondroitin Sulfate Proteoglycans; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 12; DNA Mutational Analysis; Extracellular Matrix Proteins; Female; Fibromodulin; Genetic Linkage; Genotype; Humans; Infant; Keratan Sulfate; Lod Score; Lumican; Male; Myopia; Pedigree; Polymerase Chain Reaction; Proteoglycans; Sequence Analysis, DNA

To describe histopathological and immunohistochemical findings in human corneas after myopic laser in situ keratomileusis (LASIK) followed by iatrogenic keratectasia and after hyperopic LASIK.. Department of Ophthalmology, University of Innsbruck, Innsbruck, Austria.. Clinical, histological, and immunohistochemical investigations were performed of 1 human cornea with iatrogenic keratectasia following myopic LASIK and 1 human cornea with irregular astigmatism and central scar formation after hyperopic LASIK. Corneal buttons were obtained during penetrating keratoplasty in both patients.. Histopathological examination showed thinning of the central stroma with a posterior residual thickness of 190 microm in the patient with iatrogenic keratectasia after myopic LASIK and significant midperipheral thinning in the patient who had hyperopic LASIK. However, this characteristic ablation profile of the stroma after hyperopic LASIK was partially mitigated and compensated by the epithelium, which was significantly thinned in the center and markedly thickened in the midperiphery. Traces of wound healing with minimal scar tissue were present at the flap margin after myopic and hyperopic LASIK. In a few sections of the cornea with keratectasia after myopia LASIK, only a few collagen lamellae were visible crossing between the posterior residual stroma and the superficial flap. Immunohistochemical examination revealed minimally increased staining of dermatan sulfate proteoglycan within the stroma adjacent to the interface of the microkeratome incision. Increased staining of hepatocyte growth factor was found on keratocytes/fibroblasts at the flap margin in both corneas.. The wound-healing response is generally poor after LASIK, which may result in significant weakening of the tensile strength of the cornea after myopic LASIK, probably due to biomechanically ineffective superficial lamella. After LASIK in patients with high hyperopia, compensatory epithelial thickening in the annular midperipheral ablation zone might be partly responsible for regression.

Topics: Adult; Chondroitin Sulfate Proteoglycans; Collagen; Cornea; Corneal Diseases; Dermatan Sulfate; Dilatation, Pathologic; Female; Hepatocyte Growth Factor; Humans; Hyperopia; Iatrogenic Disease; Immunoenzyme Techniques; Keratan Sulfate; Keratomileusis, Laser In Situ; Keratoplasty, Penetrating; Male; Middle Aged; Myopia; Platelet-Derived Growth Factor; Transforming Growth Factor beta

To elucidate the role of leucine-rich proteoglycans lumican and fibromodulin in the sclera.. Lumican- and fibromodulin-null heterozygous mice were intercrossed to obtain wild-type (Lum(+/+)Fmod(+/+)), lumican-null (Lum(-/-)Fmod(+/+)), fibromodulin-null (Lum(+/+)Fmod(-/-)), and double-null (Lum(-/-)Fmod(-/-)) littermates. Axial length was measured on enucleated whole eyes, and ocular structural changes were examined by histology. The morphology of collagen fibrils in the sclera was examined by transmission electron microscopy (TEM).. Compared with the ocular axial length in wild type mice, the axial length was increased by 10% in Lum(-/-)Fmod(-/-) (P = 0.02) mice. Retinal detachment was frequent in the double-null and rare in the lumican-null animals. Compared with the wild-type sclera, the sclera in all null mutants was significantly thinner with fewer lamellae (P < 0.05). The double-null sclera contained abnormally large-diameter (120-160 nm) and small-diameter (30-60 nm) collagen fibrils, whereas the fibromodulin-null sclera was enriched for the small-diameter fibrils. The collagen fibril diameter distribution in the lumican-null sclera was similar to that of the wild-type.. An increase in small-diameter fibrils in the fibromodulin-null sclera suggests a key role for fibromodulin in the maturation and assembly of scleral collagen fibrils. That fibril diameter distribution in the lumican-null sclera was comparable to that in the wild type, but severely disrupted in the double null, suggests a role for lumican that is crucial in the absence of fibromodulin. The eyes of Lum(-/-)Fmod(-/-) mice show certain features of high myopia: increased axial length, thin sclera, and retinal detachment. Mutations or altered expression of these proteoglycans may contribute to myopia in humans.

Topics: Animals; Blotting, Western; Carrier Proteins; Chondroitin Sulfate Proteoglycans; Extracellular Matrix Proteins; Female; Fibrillar Collagens; Fibromodulin; Gene Targeting; Keratan Sulfate; Lumican; Male; Mice; Mice, Knockout; Myopia; Proteoglycans; Retinal Detachment; Sclera; Scleral Diseases