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(Investigative Ophthalmology and Visual Science. 2000;41:2665-2670.)
© 2000 by The Association for Research in Vision and Ophthalmology, Inc.

A New Locus for Autosomal Dominant Cataract on Chromosome 12q13

J. Bronwyn Bateman1,3,4,5,7, Meriam Johannes5, Pamela Flodman6, David D. Geyer1,5, Kevin P. Clancy5, Camilla Heinzmann7,9, Tracy Kojis7,9, Rebecca Berry2,5,10, Robert S. Sparkes8 and M. Anne Spence6

1 Departments of Ophthalmology and 2 Pathology, 3 Rocky Mountain Lions Eye Institute, 4 The Children’s Hospital, University of Colorado School of Medicine; 5 Eleanor Roosevelt Institute, Denver, Colorado; 6 Department of Pediatrics, University of California, Irvine; and 7 Jules Stein Eye Institute, 8 Department of Medicine, UCLA School of Medicine, Los Angeles, California. 9 QIAGEN, Santa Clarita, California 1O Genzyme Genetics, Santa Fe, New Mexico


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
PURPOSE. To map the gene for autosomal dominant cataracts (ADC) in an American white family of European descent.

METHODS. Ophthalmic examinations and linkage analyses using a variety of polymorphisms were performed; two-point lod scores calculated.

RESULTS. Affected individuals (14 studied) exhibited variable expressivity of embryonal nuclear opacities based on morphology, location within the lens, and density. This ADC locus to 12q13 was mapped on the basis of statistically significantly positive lod scores and no recombinations ({theta}m = {theta}f = 0) with markers D12S368, D12S270, D12S96, D12S359, D12S1586, D12S312, D12S1632, D12S90, and D12S83; assuming full penetrance, a maximum lod score of 4.73 was calculated between the disease locus and D12S90.

CONCLUSIONS. The disease in this family represents the first ADC locus on chromosome 12; major intrinsic protein of lens fiber (MIP) is a candidate gene.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Cataracts in the pediatric population may be caused by intrauterine embryopathies, single gene defects, and chromosomal rearrangements. Immunization programs have reduced the incidence of rubella, commonly associated with congenital cataracts1 ; some congenital cataracts, particularly unilateral, are of unknown etiology. Hereditary congenital cataracts account for about one third of pediatric visual loss,2 and nonsyndromal autosomal dominant cataracts (ADC) are the most common.

Most ADC are congenital, and progression is common. Phenotypic variability has been documented among and within families.3 4 5 6 7 Generally, the cataracts are bilateral and are characterized on the basis of location, size, color, the presence or absence of refractility, and, most notably, shape.8 9 Despite attempts to clinically categorize hereditary cataracts, there is limited correlation of phenotypes with genetic loci.

ADC is genetically heterogeneous, and 13 loci for ADC have been identified on the basis of linkage analyses and gene mutations; hyperferritinemia, an additional locus, is a systemic disease of autosomal dominant cataracts without other symptoms. Several recent reviews of human cataracts and mouse models are available.10 11 We expanded our clinical study of an American white family of European descent12 with some members affected by ADC of embryonal nuclear and pulverulent cortical forms; expressivity was variable. Using linkage analysis, we mapped the disease to 12q13.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The family (ADC2) of European extraction (Fig. 1) was ascertained at the Ophthalmology Clinic of the Jules Stein Eye Institute, Department of Ophthalmology, UCLA School of Medicine, through the courtesy of Sherwin J. Isenberg, MD; clinical and negative linkage analyses have been reported.12 Informed consent in accordance with the Declaration of Helsinki and with the UCLA Institutional Review Board approval was obtained in all cases. Twenty-seven individuals participated in the study: 14 affected individuals and 13 unaffected individuals of whom 5 were spouses12 ; no other diseases aside from age-related disorders were identified. Affected status was determined by pupillary dilation and evaluation of lenses by slit-lamp biomicroscopy or retroillumination in the field, or by a history of cataract extraction before senility (before 60 years of age; JBB); in this family, all aphakic patients were younger than 20 years of age at the time of venipuncture. In all patients except 1 and 6 (categorized originally as unknown based on an examination in the field), the phenotype was determined before genotyping.



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  		Figure 1. Pedigree of ADC family with haplotypes for the most relevant markers. Only members from whom blood was drawn are included. Solid circles and squares represent affected females and males, respectively; open circles and squares denote unaffected females and males, respectively. The proband is identified by an arrow. The box represents the disease haplotype inherited from the founder.

 
Adults in the family reported that the cataracts were present from early in life (Fig. 2) and are presumed to be congenital based on the examinations of the proband and his sister.12 The proband (27) had an embryonal nuclear opacity in each eye with vacuolization; there was mild asymmetry. His affected father (24) had been unaware of his cataracts and had 20/20 vision in each eye. Nystagmus was evident only in those individuals who had undergone cataract surgery early in life and by history had a delay of correction of refractive error.



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  		Figure 2. Photographs of affected members of the family demonstrating phenotypic heterogeneity. Proband (27) had vacuoles in the embryonal nucleus (age, 1 month; A); his father (age, 38 years; 24) has a star-shaped opacity that does not alter vision (B). The proband’s aunt (age, 60 years; no specimen obtained) has a dense cataract in the embryonal nucleus (C).

 
Blood samples (between 7 and 30 ml depending on ease of venipuncture, level of cooperation, and size of the patient) were collected in EDTA, and genomic DNA was extracted.13 Markers were analyzed for linkage with the ADC2 locus several times as methodology evolved; candidate genes/regions were identified on the basis of expression within the lens or linkage with a chromosomal region in another family. Initially, linkage analysis was based on available polymorphic phenotypic blood markers12 ; one individual’s Duffy (FY) genotype was found to be incorrectly coded12 and corrected in the present study. Lod scores for haptoglobin (HP) linked to the CTM locus at 16q22.14 14 15 and FY, linked to the CZP1 locus at 1q21-25 (formerly CAE116 ), were recalculated in the present study. New candidate genes were evaluated using restriction fragment length polymorphisms (RFLPs; methods available on request) and short tandem repeat (STR) microsatellite marker loci. The loci for {alpha}A-crystallin (CRYAA)17 on human chromosome 21q22.3,18 {alpha}B-crystallin(CRYAB)19 on 11q22.3-q23.1,20 ßA1 (formerly ßA3/A1)-crystallin(CRYBA1)21 on 17q11.2-q12,22 23 ßB2-crystallin(CRYBB2)24 on 22q11.2-q12.1,25 26 {gamma}-crystallin cluster(CRYG)27 on 2q33-q35,28 and {zeta}-crystallin (CRYZ)29 on 1p22-p3130 were analyzed for linkage to the ADC2 gene using RFLPs. We screened for new RFLPs for the CRYAB, CRYBA1, and CRYBB2 genes in 10 normal and unaffected individuals. Markers for a mapped ADC locus on 17q31 were studied with STR marker loci.

Once linkage to available candidate genes was excluded, we initiated a genome-wide search using a pooling technique and, thereafter, a systematic approach using the ABI Prism Linkage Mapping Set (version 2; Perkin Elmer–Applied Biosystems, Foster City, CA), with end-labeled fluorescent primers as detailed in the user’s manual. For the pooling method, anonymous markers selected on the basis of predominant alleles in a DNA pool of affected family members compared with an unaffected pool, were amplified using the polymerase chain reaction (PCR).

The marker loci were localized to chromosomal regions based on data from the Marshfield Institute for Molecular Genetics32 and the Genome Database.33 For linkage analyses, pedigree and genotype data were analyzed with LIPED.34 Lod scores were calculated using published allele frequencies.33 35 A gene frequency of 0.0001 and penetrance at 1.0 and 0.9 were assumed for the cataract locus; two-point lod scores were calculated for a full range of {theta}m and {theta}f values.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Two male siblings (1 and 6), initially coded as unknown based on retroillumination in the field, were restudied by slit-lamp biomicroscopy and recategorized as affected. Both had punctate white opacities of the posterior cortical region, the posterior Y suture, and, to a lesser extent, the anterior cortex; individual 6 had small vertical linear opacities in the inferior cortical region.

We identified new RFLPs for the CRYBA1 (PstI; 14.0 and 13.5 kb with frequencies of 0.6 and 0.4, respectively) and CRYBB2 (DraI and PstI in linkage disequilibrium; DraI of 10.5 and 9.6 kb with frequencies of 0.55 and 0.45, respectively and PstI of 11.8 and 6.0/4.5 kb with frequencies of 0.55 and 0.45, respectively). No RFLPs for CRYAB were identified.

Two-point lod score(s) were less than -2.00 ({theta}m = {theta}f = 0.001) for crystallins CRYAA, CRYBA1, and CRYBB2 as well as for markers flanking both FY and HP and were less than -1.8 ({theta}m = {theta}f = 0.001) for CRYG flanking markers; multipoint data excluded linkage with flanking markers for CRYZ gene. Using the pooling methods, regions of chromosomes 3, 8, 14, and 19 were excluded. Using the ABI Prism system, markers on chromosomes 1, 12, 13, 17, and 18 were studied and all excluded with the exception of D12S83 and D12S368 (Zmax = 2.33 and 3.76, respectively; {theta}m = {theta}f = 0); additional markers on chromosome 12 (National Jewish Resource Center, Denver, CO or Research Genetics, Huntsville, AL) were tested (Table 1) . Assuming full penetrance, a maximum lod score of 4.73 ({theta}m = {theta}f = 0) was calculated for marker D12S90; lod scores without recombinations extended telomeric from D12S368 to D12S83, a distance of 25 to 31 cM. Lod scores at 0.95 penetrance demonstrated linkage and were similar to those calculated with full penetrance; the maximum score for marker D12S90 was 4.62 ({theta}m = {theta}f = 0).


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  		Table 1. Two-Point Lod Scores between Markers on Chromosome 12 and ADC Loci

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Eight single genes have been implicated as causative for ADC to date each in a single family with the exception of the ßA1-crystallin, gap junction protein {alpha}-3(connexin46), {gamma}D-crystallin, PAX6, and the ß-crystallin gene (CRYBB2) all of which have been reported in two. A chain termination mutation in the ß-crystallin gene (CRYBB2) on chromosome 22,36 37 a missense mutation in the gap junction protein {alpha}-8 gene (connexin50; MP70)38 on 1q21.1,39 and a missense mutation in the human {alpha}A-crystallin gene (CRYAA)40 on chromosome 21 have been shown to cause ADC. Activation of the {gamma}E-crystallin pseudogene (CRYGEP1)41 on 2q33-q35 was reported as the basis of the Coppock-like cataract. Recently, Heon and colleagues42 restudied the family and found that the variation in the pseudogene CRYGEP1, presumed to activate the gene, is a polymorphism and identified a missense mutation in a highly conserved region of exon 2 of the {gamma}C-crystallin (CRYGC). Kannabiran and colleagues43 44 demonstrated a mutation of a donor splice junction (intron C) of the ßA1-crystallin gene on 17q11.2-q12 as the basis for the ADC in an Indian family45 ; we studied a large Brazilian family with ADC of variable morphology and found a new and different mutation at the same ßA1-crystallin splice site (Bateman et al., unpublished data, 2000). Two-point mutations, a missense and a frame-shift, in gap junction protein {alpha}-3 (connexin46) on chromosome 13q11-12 have been reported in two families with granular opacities of the fetal nucleus and juvenile cortex.46 Two families with missense mutations of the {gamma}D crystallin (CRYGD) gene (2q33-q35) and disparate clinical features have been reported.42 47 Although mutations in the homeobox DNA-binding PAX6 gene usually cause aniridia and/or anterior segment dysgenesis, isolated cataracts have been documented.48 49 Hyperferritinemia, an autosomal dominant systemic disease characterized by elevated serum ferritin, congenital cataracts, and abnormal liver biopsy,50 is caused by mutations of the iron responsive element of ferritin L-subunit gene51 and may represent an additional locus.

There is considerable phenotypic variability in the ADC families that have been studied by linkage analyses. Curiously, similar forms of ADC have been mapped to different chromosomal regions, whereas disparate forms have mapped to the same locus. For example, embryonic/fetal and progressive sutural opacities in one family and stationary posterior polar cataracts in another have been mapped to chromosome 1p36.52 53 Recently, affected members of a family with cerulean cataracts were found to have the identical mutation as a family with Coppock-like cataracts.36 37 The cataracts in our family varied considerably among individuals, and correlation with genotype would not be feasible based on morphology.

The locus in family ADC2 is in the 12q13 chromosomal region based on linkage analysis and represents the first ADC locus on chromosome 12. There were no recombinations with 9 markers, and lod scores were over 3.0 with the exception of D12S83; differences are based on the number of informative matings. The region spans 25 to 31 cM,32 33 depending on which map was used (Table 1) .

There are several eye-related genes in the 12q12-14.1 region. Retinol dehydrogenase 1 (RDH1) expressed in the retinal pigment epithelium54 was assigned to chromosome 12q13-q14.55 Diacylglycerol kinase, alpha (DAGK1) is expressed in the retina56 and involved in the regeneration of phosphatidylinositol during transduction; it has been assigned to 12q13.3.57 However, neither is known to be expressed in the lens. The most promising candidate gene is that for the major intrinsic protein of the lens fiber (MP26; MIP; OMIM 154050),58 the predominant membrane protein59 60 that has been mapped to 12q14 (Fig. 3) .61 MIP accounts for up to 80% of total lens membrane protein62 and is probably lens-specific.63 64 65 The gene is 3.6 kb and contains four exons; Alu repetitive sequences, which may regulate proliferation, differentiation, and transformation, are found in the 5'-flanking region.60 The gene is regulated spatially and temporally, and the 5'-flanking sequence contains an active promoter region for lens expression,66 including Sp1, AP2, and Sp3 binding sites.67 68 It has channel-forming activity69 70 71 72 and may function as an adhesion molecule64 ; MIP probably maintains lens transparency by reducing interfiber space.73 74 The MIP mRNA is expressed in the lens vesicle early in embryogenesis and in the secondary lens fibers.64 65



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  		Figure 3. Ideogram of chromosome 12 with linked markers and MIP. The underlined markers recombined with the ADC locus and identify the interval.32 33

 
There are many candidate genes for ADC based on animal models, gene expression within the lens, and chromosomal localization in humans and other mammals. For example, mutations in the Crybb2(ßBB2)-, Cryge({gamma}E)-, and {zeta}-crystallin genes have been found to cause ADC in the Philly mouse,75 eye lens–obsolescence mouse (ELO),76 and 13/N guinea pig,77 respectively. In the mouse, the homologous region of human chromosome 12q13 (region of our ADC2 locus) is chromosome 1078 and mutations in the Mip (MP26) cause cataracts in the cataract Fraser (CatFr),79 80 lens opacity mutations (Lop),80 and hydropic fibers (Hfi) mice.81 In the CatFr mouse, the most abundant Mip mRNA transcript in the adult lens is truncated and is the result of a transposon-induced splicing defect that substitutes a long terminal repeat sequence for the carboxyl-terminal exon of the gene79 ; in this model, the water channel function is disrupted.72 In the Lop mouse, an amino acid substitution inhibits targeting of Mip to the cell membrane.80 In the Hfi mouse, an exon 2 deletion in the transcript is associated with a cataract.81 MIP is a candidate gene based on its close location to the cataract locus in our ADC2 family and the reported mutations in the mouse.

In conclusion, we have identified a new locus for ADC on chromosome 12q13. Affected members of this American family exhibit variable morphology with some opacities in the embryonal nucleus and others in the cortex. MIP is a candidate gene that we are analyzing in this family.


   Acknowledgements
 
The authors thank Sherwin Isenberg, MD, for referring the proband and his family for genetic counseling and Cindy Jaworski, PhD, Joram Piatigorsky, PhD, Michael Gorin, MD, PhD, Suraj Bhat, PhD, and J. Samuel Zigler, Jr, PhD, for providing the CRYAA, CRYAB, CRYBA1, CRYBB2, CRYGA, and CRYZ clones, respectively.


   Footnotes
 
Supported by National Eye Institute Grant EY 08282 (JBB).

Submitted for publication July 6, 1999; revised October 22, 1999 and February 4, 2000; accepted February 15, 2000.

Commercial relationships policy: N.

Present affiliations: 9QIAGEN, Santa Clarita, California; 10Genzyme Genetics, Santa Fe, New Mexico.

Corresponding author: J. Bronwyn Bateman, Department of Ophthalmology, University of Colorado, Box B204, 4200 East Ninth Avenue, Denver, CO 80262. bronwyn.bateman{at}uchsc.edu


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Plotkin, SA, Katz, M, Cordero, JF (1999) The eradication of rubella JAMA 281,561-562[Free Full Text]
  2. Jensen, S, Goldschmidt, E. (1971) Genetic counseling in sporadic cases of congenital cataracts Acta Ophthalmol 49,572-576
  3. Marner, E. (1949) A family with eight generations of hereditary cataract Acta Ophthalmologica Kbh 27,537-551
  4. Marner, E, Rosenberg, T, Eiberg, H. (1989) Autosomal dominant congenital cataract: morphology and genetic mapping Acta Ophthalmologica 67,151-158[Medline][Order article via Infotrieve]
  5. Nettleship, E, Ogilvie, FM (1906) A peculiar form of hereditary cataract Trans Ophthalmol Soc UK 26,191-207
  6. Scott, MH, Hetmancik, JF, Wozencraft, LA, Reuter, LM, Parks, MM, Kaiser–Kupfer, MI (1994) Autosomal dominant congenital cataract: interocular phenotypic variability Ophthalmology 101,866-871[Medline][Order article via Infotrieve]
  7. Mackay, DM, Ionides, ACW, Berry, V, Moore, AT, Bhattacharya, SS, Shiels, A. (1997) Autosomal dominant ‘zonular pulverulent’ cataract linked to human chromosome 13 Am J Hum Genet 60,1474-1478[Medline][Order article via Infotrieve]
  8. Parker, C. (1956) Spear cataract Arch Ophthalmol 55,23-24[Abstract/Free Full Text]
  9. Heon, E, Liu, S, Billingsley, G, et al (1998) Gene localization of aculeiform cataract, on chromosome 2q33-35 Am J Hum Genet 63,921-926[Medline][Order article via Infotrieve]
  10. Hejtmancik, JF (1998) The genetics of cataract: our vision becomes clearer Am J Hum Genet 62,520-525[Medline][Order article via Infotrieve]
  11. Graw, J. (1999) Cataract mutations and lens development Prog Retinal Eye Res 18,235-267[Medline][Order article via Infotrieve]
  12. Bateman, JB, Spence, MA, Marazita, M, Sparkes, RS (1986) Genetic linkage analysis of autosomal dominant congenital cataracts Am J Ophthalmol 101,272-275
  13. Sambrook, J, Fritsch, EF, Maniatis, T. (1989) Molecular Cloning: A Laboratory Manual 2nd ed. Cold Spring Harbor Cold Spring Harbor, NY.
  14. . Richards (sic) J,Maumenee, IH, Rowe, S, Lovrien, EW (1984) Congenital cataract possibly linked to haptoglobin Cytogenet Cell Genet 37,570
  15. Eiberg, H, Marner, E, Rosenberg, T, Mohr, J. (1988) Marner’s cataract (CAM) assigned to chromosome 16: linkage to haptoglobin Clin Genet 34,272-275[Medline][Order article via Infotrieve]
  16. Renwick, JH, Lawler, SD (1963) Probable linkage between a congenital cataract and the Duffy blood group locus Ann Hum Genet 27,67-84[Medline][Order article via Infotrieve]
  17. Jaworski, CJ, Piatigorsky, J. (1989) A pseudo-exon in the functional human {alpha}A-crystallin gene Nature 337,752-754[Medline][Order article via Infotrieve]
  18. Hawkins, JW, van Keuren, ML, Piatigorsky, J, Law, ML, Patterson, D, Kao, FT (1987) Confirmation of assignment of the human {alpha}1-crystallin gene (CRYA1) to human chromosome 21 with regional localization to q22.3 Hum Genet 76,375-380[Medline][Order article via Infotrieve]
  19. Dubin, RA, Ally, AH, Chung, S, Piatigorsky, J. (1990) Human alpha-B-crystallin gene and preferential promoter function in lens Genomics 7,594-601[Medline][Order article via Infotrieve]
  20. Ngo, JT, Klisak, I, Dubin, RA, et al (1989) Assignment of the {alpha}B-crystallin gene to human chromosome 11 Genomics 5,665-669[Medline][Order article via Infotrieve]
  21. Gorin, MB, Horwitz, J. (1984a) Cloning and characterization of a cow beta crystallin cDNA Curr Eye Res 3,939-948[Medline][Order article via Infotrieve]
  22. Sparkes, RS, Mohandas, T, Heinzmann, C, Gorin, MB, Horwitz, J. (1986) Assignment of a human ß-crystallin gene to 17cen-q23 Hum Genet 74,133-136[Medline][Order article via Infotrieve]
  23. van Tuinen, P, Rich, DC, Summers, KM, Ledbetter, DH (1987) Regional mapping panel for human chromosome 17: application to neurofibromatosis type 1 Genomics 1,374-381[Medline][Order article via Infotrieve]
  24. Hogg, D, Gorin, M, Heinzmann, C, et al (1987) Nucleotide sequence for the DNA of the bovine ßB2 crystallin and assignment of the orthologous human locus to chromosome 22 Curr Eye Res 6,1335-1342[Medline][Order article via Infotrieve]
  25. Hogg, D, Tsui, LC, Gorin, M, Breitman, M. (1986) Characterization of the human ß-crystallin gene HußA3/A1 reveals ancestral relationships among the ß{gamma}-crystallin superfamily J Biol Chem 261,12420-12427[Abstract/Free Full Text]
  26. Hulsebos, T, Bijlsma, EK, Geurts van Kessel, AHM, Brakenhoff, RH, Westerveld, A. (1991) Direct assignment of the human ßB2 and ßB3 crystallin genes to 22q11.2-q12: markers for neurofibromatosis 2 Cytogenet Cell Genet 56,171-175[Medline][Order article via Infotrieve]
  27. Bhat, SP, Spector, A. (1984) Complete nucleotide sequence of a cDNA derived from calf lens {gamma}-crystallin mRNA: presence of Alu I-like DNA sequences DNA 3,287-295[Medline][Order article via Infotrieve]
  28. Tsui, L–C, Breitman, ML, Meakin, SO, et al (1985) Localization of the human gamma-crystallin gene cluster (CRYG) to the long arm of chromosome 2, region q33–q35 Cytogenet Cell Genet 40,763-764
  29. Gonzalez, P, Rao, PV, Zigler, JS, Jr (1994) Organization of the human zeta-crystallin/quinone reductase gene (CRYZ) Genomics 21,317-324[Medline][Order article via Infotrieve]
  30. Heinzmann, C, Kojis, TL, Gonzalez, P, et al (1994) Assignment of the {zeta}-crystallin gene (CRYZ) to human chromosome 1p21–p31 and identification of restriction fragment length polymorphisms Genomics 23,403-407[Medline][Order article via Infotrieve]
  31. Armitage, MM, Kivlin, JD, Ferrell, RE (1995) A progressive early onset cataract gene maps to human chromosome 17q24 Nat Genet 9,37-40[Medline][Order article via Infotrieve]
  32. The Marshfield Institute for Molecular Genetics. http://www.marshmed.org/genetics/.
  33. The Genome Database (GDB). http://www.gdb.org/.
  34. Ott, J. (1976) A computer program for linkage analysis of general human pedigrees Am J Hum Genet 28,528-529[Medline][Order article via Infotrieve]
  35. The Centre d’Etude du Polymorhisme Humain (CEPH). http://www.cephb.fr/.
  36. Litt, M, Carrero–Valenzuela, R, LaMorticella, DM, et al (1997) Autosomal dominant cerulean cataract is associated with a chain termination mutation in the human ß-crystallin gene CRYBB2 Hum Mol Genet 6,665-668[Abstract/Free Full Text]
  37. Gill, D, Klose, R, Munier, FL, et al (2000) Genetic heterogeneity of the Coppock-like cataract: a mutation in CRYBB2 on chromosome 22q11.2 Invest Ophthalmol Vis Sci 41,159-165[Abstract/Free Full Text]
  38. Shiels, A, Mackay, D, Ionides, A, Berry, V, Moore, A, Bhattacharya, S. (1998) A missense mutation in the human connexin50 gene (GJA8) underlies autosomal dominant ‘zonular pulverulent’ cataract, on chromosome 1q Am J Hum Genet 62,526-532[Medline][Order article via Infotrieve]
  39. Geyer, DD, Church, RL, Steele, EC, Jr, et al (1997) Regional mapping of the human MP70 (Cx50; connexin 50) gene by fluorescence in situ hybridization to1q21.1 Mol Vis 3,13[Medline][Order article via Infotrieve]
  40. Litt, M, Kramer, P, LaMorticella, DM, Murphey, W, Lovrien, EW, Weleber, RG (1998) Autosomal dominant congenital cataract associated with a missense mutation in the human alpha crystallin gene CRYAA Hum Mol Genet 7,471-474[Abstract/Free Full Text]
  41. Brakenhoff, RH, Henskens, HAM, van Rossum, MWPC, Lubsen, NH, Schoenmakers, JGG (1994) Activation of the {gamma}E-crystallin pseudogene in the human hereditary Coppock-like cataract Hum Mol Genet 3,279-283[Abstract/Free Full Text]
  42. Heon, E, Priston, M, Schorderet, DF, et al (1999) The {gamma}-crystallins and human cataracts: a puzzle made clearer Am J Hum Genet 65,1261-1267[Medline][Order article via Infotrieve]
  43. Kannabiran, C, Basti, S, Balasubramanian, D, et al (1998) Autosomal dominant zonular cataract with sutural opacities: Result of a splice site mutation [ARVO Abstract] Invest Ophthalmol Vis Sci 39(4),S418Abstract nr 1953
  44. Kannabiran, C, Rogan, PK, Olmos, L, et al (1998) Autosomal dominant zonular cataract with sutural opacities is associated with a splice mutation in the ßA3/A1-crystallin gene Mol Vis 4,18-23[Medline][Order article via Infotrieve]
  45. Padma, T, Ayyagari, R, Murty, JS, et al (1995) Autosomal dominant zonular cataract with sutural opacities localized to chromosome 17q11–12 Am J Hum Genet 57,840-845[Medline][Order article via Infotrieve]
  46. Mackay, D, Ionides, A, Kibar, Z, et al (1999) Connexin46 mutations in autosomal dominant congenital cataract Am J Hum Genet 64,1357-1364[Medline][Order article via Infotrieve]
  47. Stephan, DA, Gillanders, E, Vanderveen, D, et al (1999) Progressive juvenile-onset punctate cataracts caused by mutation of the gammaD-crystallin gene Proc Natl Acad Sci 96,1008-1012[Abstract/Free Full Text]
  48. Glaser, T, Jepeal, L, Edwards, JG, Young, SR, Favor, J, Maas, RL (1994) PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects Nat Genet 7,463-471[Medline][Order article via Infotrieve]
  49. Azuma, N, Yamaguchi, Y, Handa, H, Hayakawa, M, Kanai, A, Yamada, M. (1999) Missense mutation in the alternative splice region of the PAX6 gene in eye anomalies Am J Hum Genet 65,656-663[Medline][Order article via Infotrieve]
  50. Bonneau, D, Winter–Fuseau, I, Loiseau, M–N, et al (1995) Bilateral cataract and high serum ferritin: a new dominant genetic disorder? J Med Gene 32,778-779
  51. Girelli, D, Corrocher, R, Bisceglia, L, et al (1995) Molecular basis for recently described hereditary hyperferritinemia-cataract syndrome: a mutation in the iron-responsive element of ferritin L-subunit gene Blood 86,4050-4053[Abstract/Free Full Text]
  52. Eiberg, H, Lund, AM, Warburg, M. (1995) Assignment of congenital cataract Volkmann type (CCV) to chromosome 1p36 Hum Genet 96,33-38[Medline][Order article via Infotrieve]
  53. Ionides, ACW, Berry, V, Mackay, D, Moore, AT, Bhattacharya, SS, Shiels, A. (1997) A posterior polar cataract maps to chromosome 1p Hum Mol Genet 6,47-51[Abstract/Free Full Text]
  54. Simon, A, Hellman, U, Wernstedt, C, Eriksson, U. (1995) The retinal pigment epithelial-specific 11-cis retinol dehydrogenase belongs to the family of short chain alcohol dehydrogenases J Biol Chem 270,1107-1112[Abstract/Free Full Text]
  55. Simon, A, Lagercrantz, J, Bajalica–Langercrantz, S, Eriksson, U. (1996) Primary structure of human 11-cis retinol dehydrogenase and organization and chromosomal localization of the corresponding gene Genomics 36,424-430[Medline][Order article via Infotrieve]
  56. Kai, M, Sakane, F, Imai, S, Wada, I, Kanoh, H. (1994) Molecular cloning of a diacylglycerol kinase isozyme predominantly expressed in human retina with a truncated and inactive enzyme expression in most other human cells J Biol Chem 269,18492-18498[Abstract/Free Full Text]
  57. Hart, TC, Zhou, J, Champagne, C, Van Dyke, TE, Rao, PN, Pettenati, MJ (1994) Assignment of the human diacylglycerol kinase gene (DAGK) to 12q13.3 using fluorescence in situ hybridization analysis Genomics 22,246-247[Medline][Order article via Infotrieve]
  58. Online Mendelian Inheritance in Man (OMIM). http://www.ncbi.nlm.nih.gov.
  59. Gorin, MB, Yancey, SB, Cline, J, Revel, JP, Howitz, J. (1984) The major intrinsic protein (MIP) of the bovine lens fiber membrane: characterization and structure based on cDNA cloning Cell 39,49-59[Medline][Order article via Infotrieve]
  60. Pisano, MM, Chepelinsky, AB (1991) Genomic cloning, complete nucleotide sequence, and structure of the human gene encoding the major intrinsic protein (MIP) of the lens Genomics 11,981-990[Medline][Order article via Infotrieve]
  61. Griffin, CS, Shiels, A. (1992) In situ hybridisation localises the gene for the major intrinsic protein of the eye lens fibre cell membranes to human chromosome 12q14 Cytogenet Cell Genet 61,8-9[Medline][Order article via Infotrieve]
  62. Broekhuyse, RM, Kuhlman, ED, Stols, AL (1976) Lens membranes, II: isolation and characterization of the main intrinsic polypeptide (MIP) of bovine lens fiber membranes Exp Eye Res 23,365-371[Medline][Order article via Infotrieve]
  63. Paul, DL, Goodenough, DA (1983) Preparation, characterization, and localization of antisera against bovine MP26, an integral protein from lens fiber plasma membrane J Cell Biol 96,625-632[Abstract/Free Full Text]
  64. Yancey, SB, Koh, K, Chung, J, Revel, JP (1988) Expression of the gene for main intrinsic polypeptide (MIP): separate spatial distributions of MIP and ß-crystallin gene transcripts in rat lens development J Cell Biol 106,705-714[Abstract/Free Full Text]
  65. Watanabe, M, Kobayaski, H, Rutishauser, U, Katar, M, Alcala, J, Maisel, H. (1989) NCAM in the differentiation of embryonic lens tissue Dev Biol 135,414-423[Medline][Order article via Infotrieve]
  66. Wang, XY, Ohtaka–Maruyama, C, Pisano, MM, et al (1995) Isolation and characterization of the 5'-flanking sequence of the human ocular lens MIP gene Gene 167,321-325[Medline][Order article via Infotrieve]
  67. Ohtaka–Maruyama, C, Wang, X, Ge, H, Chepelinsky, AB (1998) Overlapping Sp1 and AP2 binding sites in a promoter element of the lens-specific MIP gene Nucleic Acids Res 26,407-414[Abstract/Free Full Text]
  68. Kim, S, Ge, H, Ohtaka–Maruyama, C, Chepelinsky, AB (1999) The transcription factor Sp3 interacts with promoter elements of the lens specific MIP gene Mol Vis 5,12[Medline][Order article via Infotrieve]
  69. Gooden, M, Rintoul, D, Takehana, M, Takemoto, L. (1985) Major intrinsic polypeptide (MIP26K) from lens membrane: reconstitution into vesicles and inhibition of channel forming activity by peptide antiserum Biochem Biophys Res Commun 128,993-999[Medline][Order article via Infotrieve]
  70. Girsch, SJ, Peracchia, C. (1985) Lens cell-to-cell channel protein, I: self-assembly into liposomes and permeability regulation by calmodulin J Membr Biol 83,217-225[Medline][Order article via Infotrieve]
  71. Ehring, GR, Zampighi, GA, Horwitz, J, Bok, D, Hall, JE (1990) Properties of channels reconstituted from the major intrinsic protein of lens fiber membrane J Gen Physiol 96,631-664[Abstract/Free Full Text]
  72. Varadaraj, K, Kushmerick, C, Baldo, GJ, Bassnett, S, Shiels, A, Mathias, RT (1999) The role of MIP in lens fiber cell membrane transport J Membr Biol 170,191-203[Medline][Order article via Infotrieve]
  73. Mulders, SM, Preston, GM, Deen, PMT, Guggiano, WB, van OS, CH, Agre, P. (1995) Water channel properties of major intrinsic protein of lens J Biol Chem 270,9010-9016[Abstract/Free Full Text]
  74. Kushmerick, C, Rice, SJ, Baldo, GJ, Haspel, HC, Mathias, RT (1995) Ion, water and neutral solute transport in Xenopus oocytes expressing frog lens MIP Exp Eye Res 61,351-362[Medline][Order article via Infotrieve]
  75. Chambers, C, Russell, P. (1991) Deletion mutation in an eye lens ß-crystallin J Biol Chem 266,6742-6746[Abstract/Free Full Text]
  76. Cartier, M, Breitman, ML, Tsui, L–C (1992) A frameshift mutation in the {gamma}E-crystallin gene of the Elo mouse Nat Genet 2,42-45[Medline][Order article via Infotrieve]
  77. Rodriguez, IR, Gonzalez, P, Zigler, JS, Jr, Borras, T. (1992) A guinea-pig hereditary cataract contains a splice-site deletion in a crystallin gene Biochim Biophys Acta 1180,44-52[Medline][Order article via Infotrieve]
  78. The Mouse Genome Database (MGD). http://www.informatics.jax.org/.
  79. Sheils, A, Griffin, CS (1993) Aberrant expression of the gene for lens major intrinsic protein in the CAT mouse Curr Eye Res 12,913-921[Medline][Order article via Infotrieve]
  80. Shiels, A, Bassnett, S. (1996) Mutations in the founder of the MIP gene family underlie cataract development in the mouse Nat Genet 12,212-215[Medline][Order article via Infotrieve]
  81. Chepelinsky AB, Sidjanin DJ, Parker–Wilson DM. Exon 2 deletion in the transcript encoding the lens major intrinsic protein (MIP) results in a mouse genetic cataract [ARVO Abstract]. Invest Ophthalmol Vis Sci. 1997;38(4):S934. Abstract nr 4349.



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