May 2003
Volume 44, Issue 5
Free
Biochemistry and Molecular Biology  |   May 2003
New Locus for Autosomal Dominant High Myopia Maps to the Long Arm of Chromosome 17
Author Affiliations
  • Prasuna Paluru
    From the Division of Ophthalmology, Children’s Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, Pennsylvania; the
  • Shawn M. Ronan
    Department of Ophthalmology, University of Minnesota, Minneapolis, Minnesota; the
  • Elise Heon
    Department of Ophthalmology and Vision Science Research Program, University Health Network, Toronto, Ontario, Canada; the
  • Marcella Devoto
    Department of Research, Nemours Children’s Clinic, Wilmington, Delaware; the
    Department of Oncology, Biology, and Genetics, University of Genoa, Genoa, Italy; the
  • Scott C. Wildenberg
    Department of Ophthalmology, University of Minnesota, Minneapolis, Minnesota; the
  • Genaro Scavello
    From the Division of Ophthalmology, Children’s Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, Pennsylvania; the
  • Ann Holleschau
    Department of Ophthalmology, University of Minnesota, Minneapolis, Minnesota; the
  • Outi Mäkitie
    Department of Genetics and Orthopedics, Hospital for Sick Children, Toronto, Ontario, Canada; and the
  • William G. Cole
    Department of Genetics and Orthopedics, Hospital for Sick Children, Toronto, Ontario, Canada; and the
  • Richard A. King
    Department of Medicine and Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota.
  • Terri L. Young
    From the Division of Ophthalmology, Children’s Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, Pennsylvania; the
    Department of Ophthalmology, University of Minnesota, Minneapolis, Minnesota; the
Investigative Ophthalmology & Visual Science May 2003, Vol.44, 1830-1836. doi:10.1167/iovs.02-0697
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      Prasuna Paluru, Shawn M. Ronan, Elise Heon, Marcella Devoto, Scott C. Wildenberg, Genaro Scavello, Ann Holleschau, Outi Mäkitie, William G. Cole, Richard A. King, Terri L. Young; New Locus for Autosomal Dominant High Myopia Maps to the Long Arm of Chromosome 17. Invest. Ophthalmol. Vis. Sci. 2003;44(5):1830-1836. doi: 10.1167/iovs.02-0697.

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      © 2016 Association for Research in Vision and Ophthalmology.

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Abstract

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, 12q22-q23, 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.

Myopia affects approximately 25% of the population of the United States between 12 and 54 years, 1 2 3 4 5 and is a significant public health problem, as it is associated with increased risk of visual loss. 1 6 7 8 9 10 Myopic chorioretinal degeneration is the fourth most frequent cause of blindness, leading to registration for visual services and disability, and accounts for 8.8% of all causes. 11 It has been estimated that 5.6% of blindness among school children in the United States is attributable to myopia. 11 Substantial resources are required for optical correction of myopia with spectacles, contact lenses, and, more recently, surgical procedures such as photorefractive keratectomy. The market for optical aids in the United States was estimated to exceed $8 billion in annual sales in 1990. Most dollars were spent for the correction of myopia. 11 12 The development of methods for preventing the onset or limiting the progression of myopia would be of considerable benefit. 
High myopia (refractive spherical dioptric power of −5.00 or higher) is a major cause of legal blindness in many developed countries. 6 7 9 13 14 15 It affects 27% to 33% of all myopic eyes, corresponding to a prevalence of 1.7% to 2% in the general population of the United States. 1 5 High myopia is especially common in Asia. 13 14 16 In Japan, pathologic or high myopia reportedly affects 6% to 18% of myopes and 1% to 2% of the general population. 13 Comparative prevalence rates from different countries show considerable variability, but confirm that myopia affects a significant proportion of the population in many countries. 2 9 13 14 15 16  
Determining the role of genetic factors in the development of nonsyndromic myopia has been hampered by the high prevalence, genetic heterogeneity, and clinical spectrum of this condition. However, substantial efforts have been made in recent years. These efforts include an increased concordance of refractive error and refractive component (axial length, corneal curvature, lens power, anterior chamber depth) in monozygotic twins compared with dizygotic twins. 17 18 19 20 Twin studies estimate a notable heritability value, that is the proportion of the total phenotypic variance that is due to genes, of more than 0.5 to 0.87. 17 18 19 20 Many studies report a positive correlation between parental myopia and myopia in their children, further suggesting a hereditary factor in myopia susceptibility. 21 22 23 24 A segregation analysis of high myopia performed by Naiglin et al. 25 suggested an autosomal dominant (AD) mode of inheritance for their cohort study. 
Despite the impediments inherent in mapping genes for a complex common disorder such as myopia, some progress has been made. An X-linked recessive form of myopia has been mapped and was designated the first myopia locus, MYP1. 26 We have also studied several medium to large multigenerational families with AD high myopia and found significant linkage at 18p11.31 (MYP2) and 12q23.1-24 (MYP3). 27 28 Recently, a novel locus for AD high myopia has been reported on 7q36. 29  
We now report significant linkage of AD high-grade nonsyndromic myopia to a novel autosomal locus on the long arm of chromosome 17 in a single large family, which did not show linkage to the 18p, 12q, or 7q loci. The proband had a severe myopic refractive error of approximately −50.00 D bilaterally, but the spectrum of myopic refractive error in the family was variable. 
Subjects and Methods
A large English/Canadian family (Family MYO-68) consented to participate in the study. This study was approved by the University of Minnesota Hospital and Clinics, the Children’s Hospital of Philadelphia Institutional Review Boards, and the Research Ethics Board of University Health Network and the Hospital for Sick Children, (Toronto, Ontario, Canada). The research project adhered to the tenets of the Declaration of Helsinki. The family was ascertained as part of a larger study of myopia genetics. The criteria for selection included a history of onset of myopia before age 12 years in otherwise healthy affected subjects (parents and offspring), myopia of −5.00 D or higher, and two or more generations affected. The diagnosis of myopia was determined by the refractive error. No participant had known ocular disease or insult that could predispose to myopia, such as a history of retinopathy of prematurity or neonatal problems, or a known genetic disease or connective tissue disorder associated with myopia, such as Stickler or Marfan syndrome. 
A comprehensive ophthalmic examination and blood collection were performed by two of the authors (TLY, EH), as previously described. 27 In most instances, participants declined axial-length measurement of their eyes. Details of the ophthalmic examination are summarized in Table 1
Genotypes for candidate loci were determined, using flanking or intragenic microsatellite markers specific for the following: three previously identified AD high myopia loci on 18p11.31 (markers D18S63, D18S476, and D18S481), 12q22-q23 (markers D12S78, PAH), and 7q36 (markers D7S2423, D7S550, and D7S789). We also optimized flanking and intragenic markers for genes implicated in AD syndromic myopia subtypes that could potentially manifest as mild phenocopies for simple myopia. These phenocopies include Stickler syndrome type 1 (Online Mendelian Inheritance in Man or OMIM accession umber 108300, collagen 2A1 on 12q13.11-q13.2, marker D12S1620), type 2 (OMIM 120290, collagen 11A2 on 6p21.3-p22.3, marker D6S276), and type 2B (OMIM 120280, collagen 11A1 on 1p21, marker D1S535); Marfan syndrome OMIM 154700, fibrillin on 15q15-q21.1, marker D15S648); Ehlers-Danlos syndrome type VIIA (OMIM 120150, collagen 1A1 on 17q21.31-q22, intragenic marker on exon 25); and a juvenile glaucoma locus (OMIM 137750, myocilin on 1q24.3-q25.2, markers D1S218, D1S215, and D1S196). 
DNA analysis was performed as previously described, using multiplexed primer pairs and fluorescence detection techniques initially with an infrared sequencer (model DNA 4000; Li-Cor, Lincoln, NE), 27 and subsequently using an automated DNA sequencer (Prism 377; Applied Biosystems, Inc., Foster City, CA). Polymorphic microsatellite markers from three commercial sets (Weber 4a and 8a; ResGen, Huntsville, AL, and ABI HD-10; Applied Biosystems) and custom-made markers selected from genetic maps available on electronic databases were used. Three to four primer pairs were multiplexed in the amplification reaction. For fine mapping, additional markers were selected from genetic maps of 17q and publicly available maps. 30 31  
Linkage analysis was performed as previously accomplished for the 18p and 12q loci. 27 28 Standard marker databases used for intermarker recombination frequencies and order were Genome Data Base, 32 Gènèthon, 33 the Cooperative Human Linkage Center, and the Marshfield Center for Medical Genetics. See the Appendix for information on databases used in the study. Genetic distances between isolated 17q markers were additionally determined by using the CEPH panel of reference families and the analysis program CRIMAP, 33 as well as by radiation hybrid analysis of chromosome 17 markers, using the automated services for radiation hybrid mapping of the Stanford Institute for Genome Research. 34 Pair-wise linkage analysis was performed with the MLINK and ILINK programs from the FASTLINK 4.0 software package. 35 36 37 Individuals with myopia of −5.00 D or worse were defined as affected, and all others were classified as unaffected. The analysis was run at 90% penetrance, using a myopia gene frequency of 0.0133. Analysis was performed with GeneHunter, a nonparametric multipoint method. 38 A different multipoint linkage analysis was performed using the program VITESSE. 39  
Results
One large multigenerational family with AD high myopia (family MYO-68) was characterized (Fig. 1) . DNA was available from 22 family members (12 affected). The average age of diagnosis of myopia for affected individuals was 8.9 years (range, 2–11), and the average spherical component refractive error for the affected individuals was −13.925 D (range, −5.50 to −50.00 D). Glaucoma, keratoconus, corneal thinning, lenticonus, or dislocated lens were not present in study participants. The representative average axial length of 35.28 mm, measured only in affected individuals 9 and 10, was significantly longer (P = < 0.001, Student’s t-test) compared with the published adult normal length of 24.2 ± 0.85 mm. 20 The average keratometry reading of affected members of 43.97 ± 1.75 D was not significantly steeper (P = 0.1135, Student’s t-test) than the published adult normal value of 43.1 ± 1.62 D. 1  
All candidate loci were excluded in this family. The lod scores at θ = 0.0 were as follows: D18S63, −6.43; D18S476, −11.01; D18S481, −10.45; D12S78, −3.92; PAH, −8.50; D7S2423, −7.94; D7S550, −13.15; D7S789, −4.42; D12S1620, −0.95; D6S276, −10.14; D1S535, −5.34; D15S648, −5.71; exon 25 of Col 1A1, −1.89; D1S218, −2.98; D1S215, −7.36; and D1S196, −3.90. 
A two-point lod score of 1.94, suggestive of linkage, was initially obtained with microsatellite marker D17S1290 after a genome screening (with a lod score range of +0.87 for marker D13S317 and −14.25 for marker D7S3058). Fine mapping of 17q, using additional flanking markers, was undertaken for haplotype analysis. It was noted that two individuals (12 and 20) with moderately high myopic refractive errors shared the same haplotype as their relatives with high myopia. Individual 20 had a refractive error of −4.25+1.25×2 OD, and −4.50+1.00×175 OS at age 17 years when he was initially ascertained. His most recent refraction at 20 years of age was −4.50+1.25×180 OD and −5.50+1.25×175 OS, indicating a pubertal myopic shift. His disease phenotype was then changed from unaffected to affected with this information. The disease phenotype of individual 12 was not changed, because it did not fit the affected criterion (myopia of −5 D or worse). When the analysis was repeated with the additional markers and the new disease phenotype in individual 20, a maximum lod score of 3.17 at θ = 0.0 with marker D17S1604 was obtained. (Table 2) . The refractive error information from all other participants (most were older adults) had not changed during this period. 
Because the initial analysis was performed with equal marker allele frequencies and it is known that these may affect the lod scores when there are untyped founders in a pedigree, we also calculated the lod scores for the chromosome 17 markers by using marker allele frequencies estimated on the basis of the pedigree data in the ILINK program of the LINKAGE package 35 36 37 and in PedManager. 38 Both methods implement a maximum-likelihood estimation and both methods provide the same results. 
Maximum lod scores of 3.14 and 3.13 at θ = 0.0 was obtained for markers D17S1604 and D17S1606, respectively. In general, lod scores obtained using estimated marker allele frequencies did not differ by more than ±0.10, on average (range, 0.01–0.28), from those reported in Table 2 , in which equal allele frequencies were used. 
To maximize the linkage information and minimize the effect of unknown marker allele frequencies, we also performed multipoint analysis using the program VITESSE 39 and markers D17S1606, D17S957, D17S1604, and D17S1290. A maximum multipoint lod score of 3.3 was obtained over the whole interval defined by these markers, confirming the positive finding of the two-point analysis. Analysis using GeneHunter did not contribute any additional mapping data. 
Haplotype analysis revealed recombination events that narrowed the critical region containing the gene to 7.71 cM, between markers D17S787 and D17S1811 (Fig. 2) . A centromeric recombinant event was noted between markers D17S790 and D17S787 in the second generation, in that affected individual 4 did not share the same haplotype for markers proximal to D17S787 as her affected siblings 6 and 8. A second centromeric recombination event occurred between markers D17S787 and D17S1606 in affected individual l6. This limit of the critical region is supported by a centromeric recombination event between the same markers in the unaffected individual 25 who shares the affected centromeric haplotype of the left branch of the pedigree. A telomeric recombination event was observed between markers D17S1290 and D17S1811, in the affected individual 6 and her offspring, individuals 16 and 17, defining the distal limit of the critical region. 
Because of noted hyperextensibility of his hand joints and given that during initial haplotype formation the COL1A1 gene appeared to be within the linked region, a skin biopsy of the proband (individual 9) was performed, and fibroblast culture analyses of types I, III, and V collagen production were undertaken. The proteins were biosynthetically labeled with [3H]proline and analyzed by electrophoresis. 40 We were particularly interested in determining whether there were any disulfide-bonded α1 (I) chains. We did not find any anomalies in the type I, III, or V collagen chains (data not shown). 
Discussion
This study identified another novel autosomal locus for high-grade AD myopia. Linkage analysis placed a gene for myopia on the long arm of chromosome 17, region 21-22, within a 7.71-cM interval. This study provides additional evidence for the genetic heterogeneity of AD high myopia. Exclusion of linkage to the candidate gene regions for the Stickler syndromes, juvenile glaucoma, Ehlers-Danlos syndrome, and Marfan syndrome was essential, to ensure that this family did not exhibit a mild phenotypic expression solely of high myopia for any of these AD, early-onset disorders. 
The proband (individual 9) had the highest documented level of myopic refractive error in our clinical experience, which varies between −50 and −60 D. He wore a combination of contact lenses and spectacles for functional vision, and despite these aids he was legally blind (best corrected visual acuity of 20/400 or worse). Both he and his brother (individual 10) had had multiple laser surgeries for retinal holes. His brother had undergone recent cataract surgery for premature cataract, and a −10-D lens was inserted. (Typically, a +20- to 22-D lens is used.) Despite the severe myopia most affected members exhibited, there were two carriers of the putative disease haplotype with more moderate degrees (individuals 12 and 20), reflecting variability in the phenotype and possible modifying factors. The phenotypic variability and somewhat arbitrary assignment of affection status underscores the difficulty in mapping analyses when applying a dichotomous phenotype model to a quantitative trait. 
The sclera, the white tough outer covering of the eye, is connective tissue that provides the structural framework for defining the shape and axial length of the eye. The extracellular matrix of the sclera contains collagen fibrils in close association with proteoglycans and glycoproteins. 41 42 Alterations in any of these extracellular matrix components are likely to lead to changes in scleral shape, which in turn could affect visual acuity, because the axial length of the eye is a major component in determining ocular refraction. Genes responsible for several syndromic forms of myopia have been identified: collagen 2A1 and 11A1 for Stickler syndromes type 1 and 2 respectively, lysyl-protocollagen hydroxylase for type VI Ehlers-Danlos syndrome, collagen 18A1 for Knobloch syndrome, and fibrillin for Marfan syndrome. 43 44 45 46 47 Each of these genes is expressed in the sclera and serves as a model for possible candidate genes for nonsyndromic high myopia. 
Many potential candidate genes in the critical region were identified. The UniGene, Human Gene Map, Celera, and UCSC databases revealed 90 expressed sequence tags and 30 sequences for regulatory or structural genes between markers D17S787 and D17S1811
We initially selected the extracellular matrix proteins COL1A1 and chondroadherin (CHAD) as the most obvious functional candidate genes for high myopia on 17q. Expression of COL1A1 has been noted in skin, tendon, and bone. Mutations in COL1A1 have been described in individuals with type 1 osteogenesis imperfecta, Ehlers-Danlos syndrome type VIIA and VIIB, osteoporosis, and Marfan syndrome, all systemic disorders with scleral thinning and myopia as a clinical component. 48 CHAD is a cell-binding, leucine-rich repeat proteoglycan present in the extracellular matrix of cartilage and has been shown to interact with collagen and influence collagen fibril assembly. 49 50 Direct sequence screening analysis of the coding regions of both genes did not reveal any disease-causing mutations (data not shown). Other candidate genes are under investigation. A refinement of the candidate region may be necessary before a systematic mutation screening of the genes located in the region can be undertaken. 
In summary, we have mapped a new genetic locus for AD high myopia. We continue with our efforts to reduce the 7.71-cM critical region for high myopia through recruitment and analysis of new families before conducting further candidate gene analysis to identify the gene responsible for this myopia phenotype. Mutational characterization of the genes for high myopia will provide additional insight into the molecular mechanisms underlying this most common form of visual impairment and into the regulation of eye growth. 
Appendix 1
Electronic-Database Information
Accession numbers and Internet addresses for databases used in the study are as follows: 
Columbia University Genome Center, Columbia University, New York, NY (for linkage analysis software). ftp://ftp.ebi.ac.uk/pub/software/linkage_and_mapping/linkage_cpmc_columbia/analyze/. 
Cooperative Human Linkage Center, Laboratory for Population Genetics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (for marker and gene loci). http://www.chlc.org/chlcmaps.html/ 
Gènèthon, French Association against Myopathies, Evry, France (for genetic markers and maps). http://ww.genethon.fr/. 
Genome Database, an internation collaboration hosted by The Hospital for Sick Children, Toronto, Ontario Canada (for marker and gene loci). http://gdbwww.gdb.org/. 
Human Genome Mapping Project Resources Center, Cambridge, UK (MLINK and ILINK programs of FASTLINK, ver. 4.0) http:www.hgmp.mrc.ac.uk/. 
Human Gene Nomenclature Committee, Centre for Human Genetics, University College London, London, UK (for abbreviated gene name assignment). http://www.gene.ucl.ac.uk/cgi-bin/nomenclature/search genes.pl/. 
Human Genome Project Working Draft (“Golden Path”), UCSC Genome Bioinformatics, University of California at Santa Cruz, Santa Cruz, CA. http://genome.ucsc.edu/. 
Marshfield Laboratories, Marshfield, WI: (for genetic markers and maps). http://www.marshmed.org/genetics/. 
National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD (for BLAST searches, EST data, the Human Gene Map, and the UniGene and SAGE Collections). http://www.ncbi.nlm.nih.gov/. 
Online Mendelian Inheritance in Man (OMIM), National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD (for accession numbers MYP1 [MIM 310460], MYP2 [MIM 160700], MYP3 [MIM 603221]). http://www.ncbi.nlm.nih.gov/omim/. 
Rockefeller University Statistical Genetics, Rockefeller University, New York, NY (for linkage analysis software GeneHunter). ftp://linkage.rockefeller.edu/. 
Stanford Institute for Genome Research, Stanford University, Stanford, CA. http://www.shgc.stanford.edu/. 
The Whitehead Institute, Massachusetts Institute of Technology, Cambridge, MA (PedManager, pedigree data). http://www.genome.wi.mit.edu/ftp/distribution/software/pedmanager/. 
 
Table 1.
 
Family Participant Clinical Characteristics
Table 1.
 
Family Participant Clinical Characteristics
Subject Gender Myopia Phenotype Refractive Error (OD, OS) Axial Length (mm; OD, OS) Keratometry (D; OD, OS) Ocular History
3 M NA Plano, +1.00 sph NP
4 F A −12.00 + 2.00 × 135, −12.50 + 1.00 × 175 45.50/48.00, 46.00/47.25 Bilateral laser retinopexy surgery for lattice degeneration
5 M NA −3.50 + 2.50 × 178, −4.00 + 2.25 × 5 41.50/44.75, 42.25/45.25
6 F A −0.25 + 1.25 × 110, −2.00 + 1.00 × 86 (postcataract removal OU refractive error; highly myopic OU before cataract removal, by report) 43.25/44.50, 44.00/44.00
8 F A −6.50 + 0.75 × 75, −7.00 + 0.50 × 90 43.75/43.75 (OS only) Cataract surgery age 49 years, bilateral retinal detachments
9 M A −50.00 sph, −50.00 sph 35.85, 35.64 46.00/46.87, 46.37/48.87 Bilateral cataract development at age 45 years, posterior staphylomas, retinal detachments, macular degeneration
10 M A −34.25 sph, −32.50 sph 35.2, 34.43 52.00/37.00, 52.00/38.00 Bilateral lacquer cracks, retinal detachments, cataract surgery at age 46 years
11 F NA −2.00 + 2.75 × 173, −2.00 + 2.50 × 180 41.75/45.50, 41.75/45.50
12 M NA −3.75 sph, −4.00 sph 44.00/44.50, 44.50/44.50
13 M A −6.50 sph, −6.50 + 1.00 × 3 46.00/46.75, 45.25/47.50
14 M A −5.50 sph, −5.50 sph NP
15 F NA +0.50 sph, +1.25 sph 42.50/43.75, 42.25/43.25
16 M A −9.50 + 1.25 × 178, −10.00 + 1.50 × 178 ND
17 M A −7.00 + 1.00 × 12, −5.25 + 1.00 × 160 42.50/43.50, 42.50/44.00
18 M A −6.00 + 0.75 × 84, − 6.50 + 0.25 × 83 43.25/44.00, 43.00/44.00
19 F A −8.00 + 0.50 × 120, −7.50 + 0.50 × 60 43.75/46.50, 44.00/46.00
20 M A −4.50 + 1.25 × 180, −5.50 + 1.25 × 175 42.50/45.75, 42.50/45.75
21 F NA −1.00 sph, −1.50 sph 45.00/46.50, 45.00/46.00
22 F NA −1.25 sph, −1.25 sph 45.50/46.50, 45.50/46.75
23 F NA −1.00 sph, −0.75 sph 44.75/45.50, 45.25/46.00
24 M NA −2.50 + 0.75 × 180, −2.00 + 1.00 × 180 47.50/47.00, 47.25/46.00
25 F NA Plano, Plano 44.50/45.50, 44.50/45.00
Figure 1.
 
Pedigree MYO-068 with familial high myopia. Circles and squares: females and males, respectively; solid symbols: affected individuals. Diagonal lines through symbols: deceased individuals. The alleles for the most informative polymorphic markers are shown for each studied individual. Haplotypes were constructed based on the minimum number of recombinations between these markers. Solid bar: the chromosome assumed to carry the inherited disease allele; open bars: normal haplotypes. Nonparticipating family members are not shown. Only one of the monozygous twins 22 and 23 was used in the linkage analysis. Note that individuals 6, 16, and 17 are recombinant for the telomeric marker D17S1811. Individual 16 was recombinant for the centromeric marker D17S787.
Figure 1.
 
Pedigree MYO-068 with familial high myopia. Circles and squares: females and males, respectively; solid symbols: affected individuals. Diagonal lines through symbols: deceased individuals. The alleles for the most informative polymorphic markers are shown for each studied individual. Haplotypes were constructed based on the minimum number of recombinations between these markers. Solid bar: the chromosome assumed to carry the inherited disease allele; open bars: normal haplotypes. Nonparticipating family members are not shown. Only one of the monozygous twins 22 and 23 was used in the linkage analysis. Note that individuals 6, 16, and 17 are recombinant for the telomeric marker D17S1811. Individual 16 was recombinant for the centromeric marker D17S787.
Table 2.
 
Pairwise LOD Scores for 22 Markers on Chromosome 17
Table 2.
 
Pairwise LOD Scores for 22 Markers on Chromosome 17
MARKER Lod Score at θ θ Zmax
0.0 0.01 0.05 0.1 0.2 0.3 0.4
Centromere
D17S1795 −0.86 0.42 0.84 0.98 0.76 0.36 0.18 1.00
D17S941 −1.68 −0.78 −0.36 −0.04 0.03 0.01 0.31 0.03
D17S1820 −0.27 0.49 0.77 0.87 0.67 0.33 0.17 0.88
D17S788 −2.18 −0.82 −0.29 0.08 0.13 0.06 0.27 0.14
D17S809 −2.22 −0.84 −0.06 0.27 0.47 0.42 0.23 0.22 0.48
D17S790 −3.82 −1.78 −0.97 −0.32 −0.07 −0.00 0.50 0.00
D17S787 −0.74 0.03 0.33 0.47 0.36 0.13 0.19 0.48
D17S1606 3.14 3.11 2.97 2.73 2.13 1.42 0.63 0.00 3.14
D17S957 0.73 0.74 0.74 0.70 0.53 0.31 0.10 0.03 0.74
D17S1604 3.17 3.14 2.99 2.75 2.16 1.44 0.65 0.00 3.17
D17S1290 2.54 2.52 2.41 2.22 1.73 1.13 0.50 0.00 2.54
D17S1811 −0.34 0.99 1.57 1.69 1.51 1.09 0.51 0.11 1.69
D17S948 0.42 1.08 1.58 1.67 1.47 1.03 0.49 0.10 1.67
D17S1855 −0.91 −0.24 0.34 0.54 0.57 0.40 0.15 0.16 0.60
D17S944 −0.64 0.01 0.53 0.69 0.70 0.56 0.32 0.15 0.73
D17S794 0.70 0.68 0.60 0.50 0.30 0.14 0.03 0.00 0.70
D17S807 0.03 0.26 0.68 0.86 0.84 0.63 0.34 0.14 0.89
D17S1816 −2.10 −0.90 −0.20 0.07 0.24 0.20 0.08 0.22 0.24
D17S949 2.08 2.04 1.88 1.67 1.23 0.79 0.37 0.00 2.08
D17S1862 −4.22 −2.20 −1.34 −0.56 −0.21 −0.05 0.50 0.00
D17S1807 −7.96 −1.43 −0.18 0.28 0.52 0.44 0.24 0.21 0.53
Telomere
Figure 2.
 
Ideogram of the long arm of chromosome 17, region 21-23 with the markers within the interval containing the high myopia locus. The first vertical figure shows the informative crossovers seen in affected individuals 16 and 6, which are indicated by their haplotypes, with a solid black bar between them. The distances between markers are given in centimorgans (cM) in the second column.
Figure 2.
 
Ideogram of the long arm of chromosome 17, region 21-23 with the markers within the interval containing the high myopia locus. The first vertical figure shows the informative crossovers seen in affected individuals 16 and 6, which are indicated by their haplotypes, with a solid black bar between them. The distances between markers are given in centimorgans (cM) in the second column.
The authors thank the family members of this kindred for their enthusiastic participation in the project, Catherine Armstrong and Karen Bebchuk for technical assistance, and Beverly Emanuel for helpful discussions and comments on the manuscript. 
Curtin, BJ. (1985) Basic Science and clinical management The Myopias ,237-245 Harper and Row New York.
Sperduto, RD, Siegel, D, Roberts, J, Rowland, M. (1983) Prevalence of myopia in the United States Arch Ophthalmol 101,405-407 [CrossRef] [PubMed]
Wang, Q, Klein, BEK, Klein, R, et al (1994) Refractive status in the Beaver Dam Eye study Invest Ophthalmol Vis Sci 35,4344-4347 [PubMed]
Sperduto, RD, Siegel, D, Roberts, J, Rowland, M. (1983) Prevalence of myopia in the United States Arch Ophthalmol 101,405-407 [CrossRef] [PubMed]
Angle, J, Wissmann, DA. (1980) The epidemiology of myopia Am J Epidemiol 111,220-228 [PubMed]
Leibowtiz, HM, Krueger, DE, Maunder, LR. (1980) The Framingham eye study monograph Surv Ophthalmol 24,472-479 [CrossRef]
Katz, J, Tielsch, JM, Sommer, A. (1997) Prevalence and risk factors for refractive errors in an adult inner city population Invest Ophthalmol Vis Sci 38,334-340 [PubMed]
Burton, TC. (1990) The influence of refractive error and lattice degeneration on the incidence of RD Trans Am Ophthalmol Soc 87,143-155
Curtin, BJ. (1970) Myopia: A review of its etiology, pathogenesis, and treatment Surv Ophthalmol 15,1-17
Ghafour, IM, Allan, D, Foulds, WS. (1983) Common causes of blindness and visual handicap in the west of Scotland Br J Ophthalmol 67,209-213 [CrossRef] [PubMed]
. National Advisory Eye Council, Strabismus, Amblyopia and Visual Processing Panel (1999–2003) Vision Research: A National Plan National Institutes of Health Washington, DC. NIH Publication 98-4120
Javitt, JC, Chiang, Y-P. (1994) The socioeconomic aspects of laser refractive surgery Arch Ophthalmol 112,1526-1530 [CrossRef] [PubMed]
Tokoro, T Sato, A eds. Results of Investigation of Pathologic Myopia in Japan: Report of Myopic Chorioretinal Atrophy 1982,32-35 Ministry of Health and Welfare Tokyo.
Lin, LL, Chen, CJ, Hung, PT, et al (1988) Nation-wide survey of myopia among schoolchildren in Taiwan Acta Ophthalmol 66,29-33
Fledelius, HC. (1988) Myopia prevalence in Scandinavia: a survey, with emphasis on factors of relevance for epidemiological refraction studies in general Acta Ophthalmol 185,44-50
Wilson, A, Woo, G. (1989) A review of the prevalence and causes of myopia Singapore Med J 30,479-484 [PubMed]
Teikara, JM, O’Donnell, J, Kaprio, J, Kosenvuo, M. (1991) Impact of heredity in myopia Hum Hered 41,151-156 [CrossRef] [PubMed]
Teikari, JM, Kaprio, J, Koskenvuo, M, O’Donnell, J. (1992) Heritability of defects of far vision in young adults: a twin study Scand J Soc Med 20,73-78 [PubMed]
Sorsby, A, Leary, GA, Richards, MJ. (1962) Correlation ametropia and component ametropia Vision Res 2,309-313 [CrossRef]
Sorsby, A, Sheriden, M, Leary, GA. (1962) Refraction and its components in twins Medical Research Council Special Reports HMSO London. Series 303
. The Framingham Offspring Eye Study Group (1996) Familial aggregation and prevalence of myopia in the Framingham offspring eye study Arch Ophthalmol 114,326-332 [CrossRef] [PubMed]
Goss, DA, Jackson, TW. (1996) Clinical findings before the onset of myopia in youth: parental history of myopia Optom Vis Sci 73,279-282 [CrossRef] [PubMed]
Pacella, R, McLellan, J, Grice, K, Del Bono, EA, Wiggs, JL, Gwiazda, JE. (1999) Role of genetic factors in the etiology of juvenile-onset myopia based on a longitudinal study of refractive error Optom Vis Sci 76,381-386 [CrossRef] [PubMed]
Zadnik, K, Satariano, WA, Mutti, DO, Sholtz, RI, Adams, AJ. (1994) The effect of parental history of myopia on children’s eye size JAMA 271,1323-1327 [CrossRef] [PubMed]
Naiglin, L, Clayton, J, Gazagne, C, Dallongeville, F, Malecaze, F, Calvas, P. (1999) Familial high myopia: evidence of an autosomal dominant mode of inheritance and genetic heterogeneity Ann Genet 42,140-146 [PubMed]
Schwartz, M, Haim, M, Skarsholm, D. (1990) X-linked myopia: Bornholm eye disease—linkage to DNA markers on the distal part of Xq Clin Genet 38,281-286 [PubMed]
Young, TL, Ronan, SM, Drahozal, LA, et al (1998) Evidence that a locus for familial high myopia maps to chromosome 18p Am J Hum Genet 63,109-119 [CrossRef] [PubMed]
Young, TL, Ronan, SM, Alvear, A, et al (1998b) A second locus for familial high myopia maps to chromosome 12q Am J Hum Genet 63,1419-1424 [CrossRef]
Naiglin, L, Gazagne, Ch, Dallongeville, F, et al (2002) A genome wide scan for familial high myopia suggests a novel locus on chromosome 7q36 J Med Genet 39,118-124 [CrossRef] [PubMed]
Gyapay, G, Morissette, J, Vignal, A, et al (1994) The 1993–94 Gènèthon human genetic linkage map Nat Genet 7,246-339 [CrossRef] [PubMed]
Dib, C, Faure, S, Fizames, C, et al (1996) A comprehensive genetic map of the human genome based on 5264 microsatellites Nature 380,152-154 [CrossRef] [PubMed]
Fasman, KH, Cuticchia, AJ, Kingsbury, DT. (1994) The GDB human genome database anno 1994 Nucleic Acids Res 22,3462-3469 [CrossRef] [PubMed]
Lander, E, Green, P. (1987) Construction of multilocus genetic linkage maps in humans Proc Natl Acad Sci USA 84,2363-2367 [CrossRef] [PubMed]
Stewart, EA, McKusick, KB, Aggarwal, A, et al (1997) An STS-based radiation hybrid map of the human genome Genome Res 7,422-433 [PubMed]
Lathrop, GM, Lalouel, JM. (1984) Easy calculation of LOD scores and genetic risks on small computers Am J Hum Genet 36,460-465 [PubMed]
Cottingham, RW, Jr, Idury, RM, Schaffer, AA. (1993) Faster sequential genetic linkage computations Am J Hum Genet 53,252-263 [PubMed]
Schaffer, AA, Gupta, SK, Shriram, K, Cottingham, RW. (1994) Avoiding recomputation in linkage analysis Hum Hered 44,225-237 [CrossRef] [PubMed]
Kruglyak, L, Daly, MJ, Reeve-Daly, MP, Lander, ES. (1996) Parametric and non-parametric linkage analysis: a unified multipoint approach Am J Hum Genet 58,1347-1363 [PubMed]
O’Connell, JR, Weeks, DE. (1995) The VITESSE algorithm for rapid exact multi-locus linkage analysis via genotype set-recoding and fuzzy inheritance Nat Genet 11,402-408 [CrossRef] [PubMed]
Steinmann, B, Nicholls, A, Pope, FM. (1986) Clinical variability of osteogenesis imperfecta reflecting molecular heterogeneity: cysteine substitutions in the alpha 1(I) collagen chain producing lethal and mild forms Biol Chem 261,8958-8964
Muir, H. (1982) Proteoglycans as organizers of the intercellular matrix Biochem Soc Trans Seventeenth CIBA Med Lect 11,613-622
Hassell, JR, Blochberger, TC, Rada, JA, Chakravarti, S, Noonan, D. (1993) Proteoglycan gene families Bittar, EE Kleinman, HK eds. Advances in Molecular and Cell Biology 6,69-113 JAI Press Greenwich, CT. Extracellular Matrix, vol 6
Knowlton, RG, Weaver, EJ, Struyk, AF, et al (1989) Genetic linkage analysis of hereditary arthro-ophthalmopathy (Stickler syndrome) and the type II procollagen gene Am J Hum Genet 45,681-688 [PubMed]
Richards, AJ, Yates, JRW, Williams, R, et al (1996) A family with Stickler syndrome type 2 has a mutation in the COL11A1 gene resulting in the substitution of glycine 97 by valine in alpha-1 (XI) collagen Hum Mol Genet 5,1339-1343 [CrossRef] [PubMed]
Pousi, B, Hautala, T, Heikkinen, J, Pajunen, L, Kivirikko, KI, Myllyla, R. (1994) Alu-alu recombination results in a duplication of seven exons in the lysyl hydroxylase gene in a patient with the type VI variant of Ehlers-Danlos syndrome Am J Hum Genet 55,899-906 [PubMed]
Sertie, AL, Sossi, V, Camargo, AA, Zatz, M, Brahe, C, Passos-Bueno, MR. (2000) Collagen XVIII, containing an endogenous inhibitor of angiogenesis and tumor growth, plays a critical role in the maintenance of retinal structure and in neural tube closure (Knobloch syndrome) Hum Mol Genet 9,2051-2058 [CrossRef] [PubMed]
Nijbroek, G, Sood, S, McIntosh, I, et al (1995) Fifteen novel FBN1 mutations causing Marfan syndrome detected by heteroduplex analysis of genomic amplicons Am J Hum Genet 57,8-21 [PubMed]
Dalgleish, R. (1997) The human type 1 collagen mutation database Nucleic Acids Res 25,181-187 [CrossRef] [PubMed]
Mansson, B, Wenglen, C, Morgelin,, Saxnel, T, Heinegard, D. (2001) Association of chondroadherin with collagen type II J Biol Chem 276,32883-32888 [CrossRef] [PubMed]
Hedbom, E, Heinegard, D. (1989) Interaction of a 59kDa connective tissue matrix protein with collagen I and collagen II J Biol Chem 264,6898-6905 [PubMed]
Figure 1.
 
Pedigree MYO-068 with familial high myopia. Circles and squares: females and males, respectively; solid symbols: affected individuals. Diagonal lines through symbols: deceased individuals. The alleles for the most informative polymorphic markers are shown for each studied individual. Haplotypes were constructed based on the minimum number of recombinations between these markers. Solid bar: the chromosome assumed to carry the inherited disease allele; open bars: normal haplotypes. Nonparticipating family members are not shown. Only one of the monozygous twins 22 and 23 was used in the linkage analysis. Note that individuals 6, 16, and 17 are recombinant for the telomeric marker D17S1811. Individual 16 was recombinant for the centromeric marker D17S787.
Figure 1.
 
Pedigree MYO-068 with familial high myopia. Circles and squares: females and males, respectively; solid symbols: affected individuals. Diagonal lines through symbols: deceased individuals. The alleles for the most informative polymorphic markers are shown for each studied individual. Haplotypes were constructed based on the minimum number of recombinations between these markers. Solid bar: the chromosome assumed to carry the inherited disease allele; open bars: normal haplotypes. Nonparticipating family members are not shown. Only one of the monozygous twins 22 and 23 was used in the linkage analysis. Note that individuals 6, 16, and 17 are recombinant for the telomeric marker D17S1811. Individual 16 was recombinant for the centromeric marker D17S787.
Figure 2.
 
Ideogram of the long arm of chromosome 17, region 21-23 with the markers within the interval containing the high myopia locus. The first vertical figure shows the informative crossovers seen in affected individuals 16 and 6, which are indicated by their haplotypes, with a solid black bar between them. The distances between markers are given in centimorgans (cM) in the second column.
Figure 2.
 
Ideogram of the long arm of chromosome 17, region 21-23 with the markers within the interval containing the high myopia locus. The first vertical figure shows the informative crossovers seen in affected individuals 16 and 6, which are indicated by their haplotypes, with a solid black bar between them. The distances between markers are given in centimorgans (cM) in the second column.
Table 1.
 
Family Participant Clinical Characteristics
Table 1.
 
Family Participant Clinical Characteristics
Subject Gender Myopia Phenotype Refractive Error (OD, OS) Axial Length (mm; OD, OS) Keratometry (D; OD, OS) Ocular History
3 M NA Plano, +1.00 sph NP
4 F A −12.00 + 2.00 × 135, −12.50 + 1.00 × 175 45.50/48.00, 46.00/47.25 Bilateral laser retinopexy surgery for lattice degeneration
5 M NA −3.50 + 2.50 × 178, −4.00 + 2.25 × 5 41.50/44.75, 42.25/45.25
6 F A −0.25 + 1.25 × 110, −2.00 + 1.00 × 86 (postcataract removal OU refractive error; highly myopic OU before cataract removal, by report) 43.25/44.50, 44.00/44.00
8 F A −6.50 + 0.75 × 75, −7.00 + 0.50 × 90 43.75/43.75 (OS only) Cataract surgery age 49 years, bilateral retinal detachments
9 M A −50.00 sph, −50.00 sph 35.85, 35.64 46.00/46.87, 46.37/48.87 Bilateral cataract development at age 45 years, posterior staphylomas, retinal detachments, macular degeneration
10 M A −34.25 sph, −32.50 sph 35.2, 34.43 52.00/37.00, 52.00/38.00 Bilateral lacquer cracks, retinal detachments, cataract surgery at age 46 years
11 F NA −2.00 + 2.75 × 173, −2.00 + 2.50 × 180 41.75/45.50, 41.75/45.50
12 M NA −3.75 sph, −4.00 sph 44.00/44.50, 44.50/44.50
13 M A −6.50 sph, −6.50 + 1.00 × 3 46.00/46.75, 45.25/47.50
14 M A −5.50 sph, −5.50 sph NP
15 F NA +0.50 sph, +1.25 sph 42.50/43.75, 42.25/43.25
16 M A −9.50 + 1.25 × 178, −10.00 + 1.50 × 178 ND
17 M A −7.00 + 1.00 × 12, −5.25 + 1.00 × 160 42.50/43.50, 42.50/44.00
18 M A −6.00 + 0.75 × 84, − 6.50 + 0.25 × 83 43.25/44.00, 43.00/44.00
19 F A −8.00 + 0.50 × 120, −7.50 + 0.50 × 60 43.75/46.50, 44.00/46.00
20 M A −4.50 + 1.25 × 180, −5.50 + 1.25 × 175 42.50/45.75, 42.50/45.75
21 F NA −1.00 sph, −1.50 sph 45.00/46.50, 45.00/46.00
22 F NA −1.25 sph, −1.25 sph 45.50/46.50, 45.50/46.75
23 F NA −1.00 sph, −0.75 sph 44.75/45.50, 45.25/46.00
24 M NA −2.50 + 0.75 × 180, −2.00 + 1.00 × 180 47.50/47.00, 47.25/46.00
25 F NA Plano, Plano 44.50/45.50, 44.50/45.00
Table 2.
 
Pairwise LOD Scores for 22 Markers on Chromosome 17
Table 2.
 
Pairwise LOD Scores for 22 Markers on Chromosome 17
MARKER Lod Score at θ θ Zmax
0.0 0.01 0.05 0.1 0.2 0.3 0.4
Centromere
D17S1795 −0.86 0.42 0.84 0.98 0.76 0.36 0.18 1.00
D17S941 −1.68 −0.78 −0.36 −0.04 0.03 0.01 0.31 0.03
D17S1820 −0.27 0.49 0.77 0.87 0.67 0.33 0.17 0.88
D17S788 −2.18 −0.82 −0.29 0.08 0.13 0.06 0.27 0.14
D17S809 −2.22 −0.84 −0.06 0.27 0.47 0.42 0.23 0.22 0.48
D17S790 −3.82 −1.78 −0.97 −0.32 −0.07 −0.00 0.50 0.00
D17S787 −0.74 0.03 0.33 0.47 0.36 0.13 0.19 0.48
D17S1606 3.14 3.11 2.97 2.73 2.13 1.42 0.63 0.00 3.14
D17S957 0.73 0.74 0.74 0.70 0.53 0.31 0.10 0.03 0.74
D17S1604 3.17 3.14 2.99 2.75 2.16 1.44 0.65 0.00 3.17
D17S1290 2.54 2.52 2.41 2.22 1.73 1.13 0.50 0.00 2.54
D17S1811 −0.34 0.99 1.57 1.69 1.51 1.09 0.51 0.11 1.69
D17S948 0.42 1.08 1.58 1.67 1.47 1.03 0.49 0.10 1.67
D17S1855 −0.91 −0.24 0.34 0.54 0.57 0.40 0.15 0.16 0.60
D17S944 −0.64 0.01 0.53 0.69 0.70 0.56 0.32 0.15 0.73
D17S794 0.70 0.68 0.60 0.50 0.30 0.14 0.03 0.00 0.70
D17S807 0.03 0.26 0.68 0.86 0.84 0.63 0.34 0.14 0.89
D17S1816 −2.10 −0.90 −0.20 0.07 0.24 0.20 0.08 0.22 0.24
D17S949 2.08 2.04 1.88 1.67 1.23 0.79 0.37 0.00 2.08
D17S1862 −4.22 −2.20 −1.34 −0.56 −0.21 −0.05 0.50 0.00
D17S1807 −7.96 −1.43 −0.18 0.28 0.52 0.44 0.24 0.21 0.53
Telomere
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