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Human Molecular Genetics Pages 415-419
A locus for autosomal dominant anterior polar cataract on chromosome 17p
Introduction
Results
Discussion
Materials And Methods
   Genotyping
   Linkage analysis
Abbreviations
References

A locus for autosomal dominant anterior polar cataract on chromosome 17p

A locus for autosomal dominant anterior polar cataract on chromosome 17p Vanita Berry, Alexander C. W. Ionides, Anthony T. Moore1, Catherine Plant1, Shomi S. Bhattacharya and Alan Shiels*

Department of Molecular Genetics, Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK and 1Moorfields Eye Hospital, City Road, London ECIV 2PD, UK

Received November 6, 1995; Revised and Accepted December 18, 1995

Inherited cataract is a clinically and genetically heterogeneous disease. Here we report the identification of a new locus for an autosomal dominant anterior polar cataract on the short arm of chromosome 17. To map this new locus we performed genetic linkage analysis with microsatellite markers in a four-generation pedigree. After exclusion of seven candidate loci for cataract, we obtained significant positive LOD scores for markers D17S849 (Z = 4.01 @ [theta] = 0.05) and D17S796 (Z = 4.17 @ [theta] = 0.05). Multipoint analysis gave a maximum LOD score of 5.2 ([theta] max = 0.06) between these two markers. From haplotype analysis, the cataract locus lies in the 13 cM interval between markers D17S849 and D17S796. This study provides the first genetic mapping of an autosomal dominant anterior polar cataract.

INTRODUCTION

Inherited cataract is a significant cause of visual impairment in childhood and is most often transmitted as a congenital autosomal dominant trait (1 ). Clinical descriptions of inherited cataract are based on the physical appearance and location of opacities within the normally transparent eye lens and, currently, six loci for autosomal dominant cataract phenotypes have been genetically mapped. The Volkmann congenital cataract, with central and zonular opacities in the lens nucleus and Y-suture regions, has been mapped to 1p (2 ). A zonular pulverulent (dustlike) cataract has been linked to the Duffy blood group locus on 1q (3 ); however, the clinically similar Coppock-like pulverulent nuclear cataract has been linked to 2q (4 ) and is associated with activation of the [gamma]E-crystallin pseudogene (5 ). The Marner, nuclear and lamellar, cataract (6 ) and a posterior polar cataract (7 ) have been linked to the haptoglobin locus on 16q, suggesting that clinical heterogeneity may exist at the same cataract locus. Finally, a zonular sutural cataract (8 ) and a cerulean (blue-dot) cataract (9 ) have been mapped to 17q11-12 and 17q24, respectively.

Anterior polar cataract is a clinically well-recognized opacity located at the front of the lens and represents 3-14% of all congenital cataract (reviewed in ref. 10 ). This distinctive cataract phenotype is also associated with certain other genetic eye diseases including aniridia and Peters' anomaly and may present in certain systemic diseases (e.g. Alport syndrome). In addition, congenital anterior polar cataract has been shown to segregate with an unbalanced 3;18 chromosome translocation (11 ) and a balanced reciprocal 2;14 chromosomal translocation (12 ). In the 3;18 translocation, cataract was associated with dysmorphic features presumably resulting from partial trisomy of 3q and partial monosomy of 18p. The 2;14 translocation, however, suggests that a gene for anterior polar cataract lies near the breakpoints at 2p25 or 14q24. In order to gain further insight into the genetic aetiology of anterior polar cataract we performed linkage analysis on a four-generation English family that is solely affected with this type of lens opacity.

RESULTS

Twenty-six family members spanning all four generations of the pedigree (Fig. 2 ) were ophthalmologically examined, including 17 affected with the cataract. The opacities varied in size from <0.5 to >4 mm in diameter and were bilateral in all but one case. The smaller opacities were flat while the larger opacities (Fig. 1 ) were raised and laminated to form a pyramidal cataract protruding from the anterior pole of the lens along the optical axis. The rest of the lens was clear, although in the larger opacities the anterior cortex was minimally affected. Cataract was usually present at birth or developed within the first few months of life but did not progress. Only one patient with small bilateral opacities had normal visual acuity in both eyes. All other affected individuals had amblyopia regardless of the size of the opacity and several had undergone surgery. There was no evidence of anterior lenticonus (symptomatic of Alport syndrome) and no family history of other ocular or systemic abnormalities. A detailed description of the clinical features of affected individuals will be published elsewhere.


Figure 1. Slit-lamp photograph of the right eye of affected female 4-2 from the pedigree (Fig. 2) showing a prominent pyramidal opacification on the anterior pole of the lens.


Figure 2.Abridged pedigree of the anterior polar cataract family used in this study showing the segregation of four chromosome 17 markers (13), D17S849, D17S796, D17S786 and D17S799 listed in descending order from the 17p telomere. Squares and circles symbolize males and females, respectively. Black and white symbols indicate affecteds and unaffecteds, respectively. (--) indicates failed PCR amplification.

Inspection of the pedigree (Fig. 2 ) shows that the cataract is inherited as a fully penetrant autosomal dominant trait. Twenty-eight family members, including 16 affected individuals, eight unaffected individuals and four spouses, were genotyped with microsatellite markers from the Genethon poly-CA map (13 ). We first excluded linkage of the cataract locus in this family with the PAX6 (aniridia) gene on 11p13 and the translocation (2;14)(p25;q24) breakpoints. We then proceeded to a linkage search of 11 known loci for autosomal dominant cataract and crystallin genes, which encode the major soluble proteins of the eye lens, on 22q, 21q, 17q (two loci), 16q, 16p, 11q, 2q, 1q and 1p (two loci) (Human Genome Database, 1995). After exclusion of the [beta] and [alpha]-crystallin genes on 22q and 21q, respectively, we obtained tentatively positive LOD scores (Z) for markers D17S799 (Z = 0.74 @ [theta] = 0.30) and D17S798 (Z = 0.45 @ [theta] = 0.30). These markers flank the zonular sutural cataract locus and the [beta]A3/A1-crystallin gene located near the centromeric end of 17q (8 ). Linkage to these candidate loci was positively excluded, however, using the marker D17S805 (Z =-3.93 @ [theta] = 0.05), which is located between D17S799 and D17S798. We also excluded the cerulean cataract locus on 17q24 using marker D17S802 (Z =-3.27 @ [theta] = 0.05), thereby excluding the known cataract and crystallin loci on the long arm of chromosome 17. Because chromosome 17 is potentially gene-rich (14 ) we decided to exclude the entire chromosome before proceeding to other candidate loci. However, while attempting to exclude linkage with the short arm of chromosome 17, we detected significantly positive LOD scores with markers D17S786 (Z = 3.61 @ [theta] = 0.10), D17S796 (Z = 4.17 @ [theta] = 0.05) and D17S849 (Z = 4.01 @ [theta] = 0.05). The two-point LOD scores of chromosome 17 marker loci are summarized in Table 1 . A maximum LOD score of 4.17 @ [theta]max = 0.05 was obtained with D17S796. Multipoint analysis using markers D17S849, D17S796 and D17S786 yielded a maximum LOD score of 5.2 @ [theta]max = 0.06 (Fig. 3 ), placing the anterior polar cataract locus in the 13 cM interval between markers D17S849 and D17S796 toward the telomeric end of chromosome 17p (Fig. 4 ). Assignment to this genetic interval is also supported by fully informative haplotype analysis (Fig. 2 ), which detected four recombinant individuals (4.2, 4.6, 4.9 and 4.11) with D17S799, two recombinant individuals (4.6 and 4.9) with D17S786 but only one recombinant individual (4.6) with D17S796. Thus, the cataract locus cannot lie centromeric to D17S796.


Figure 3. Multipoint linkage analysis between the anterior polar cataract phenotype and markers D17S849, D17S796 and D17S786 using the LINKMAP program (22). Genetic distances between the markers (13) are indicated in Figure 4.

Table 1 . Two-point LOD scores (Z) for linkage between the anterior polar cataract locus and chromosome 17 markers
 

 Recombination fraction ([theta])

  

  

  

  

  

  

 Zmax

 [theta]max
Marker

 0.00

 0.01

 0.05

 0.10

 0.20

 0.30

 0.40

  
D17S849

 -[infinity]

 3.68

 4.01

 3.83

 3.10

 2.14

 1.05

 4.01

 0.05
D17S796

 -[infinity]

 3.84

 4.17

 3.99

 3.26

 2.30

 1.17

 4.17

 0.05
D17S786

 -[infinity]

 2.51

 3.52

 3.61

 3.11

 2.24

 1.16

 3.63

 0.08
cen

  

  

  

  

  

  

  

  
D17S799

 -[infinity]

 -3.39

 -0.81

 0.11

 0.71

 0.74

 0.49

 -

 -
D17S805

 -[infinity]

 -8.01

 -3.93

 -2.27

 -0.82

 -0.19

 0.05

 -

 -
D17S798

 -[infinity]

 -2.73

 -0.78

 -0.80

 0.39

 0.45

 0.30

 -

 -
D17S802

 -[infinity]

 -7.19

 -3.27

 -1.83

 -0.73

 -0.28

 -0.04

 -

 -
Maximum LOD scores and corresponding recombination fractions are shown (in bold) only for the 17p markers.

DISCUSSION


Figure 4. Ideogram of chromosome 17 showing the genetic distances (cM) between three Genethon microsatellite markers on 17p (13) and the calculated position of the anterior polar cataract locus. The loci for a zonular sutural cataract (8) and a cerulean cataract (9) on 17q, are also indicated.Using genetic linkage analysis, we have shown that the gene for a non-syndromic autosomal dominant anterior polar cataract is located on the short arm of chromosome 17 within the 13 cM interval between markers D17S849 and D17S796. This new cataract locus is both clinically and genetically distinct from the zonular sutural cataract on 17q11-12 (8 ) and the cerulean (blue-dot) cataract on 17q24 (9 ) and brings the current number of mapped loci for autosomal dominant cataract to seven. In addition, the 17p cataract locus appears to be genetically distinct from the previously reported `syndromic' forms of anterior polar cataract (10 -12 ).

There is no obvious candidate gene for anterior polar cataract currently localized on chromosome 17p (Human Genome Database, 1995) and no cataract mutation has been mapped to the syntenic region of mouse chromosome 11 (Mouse Genome Database, 1995). Certain phenotypic associations of anterior polar cataract with other ocular diseases (10 ), however, may provide clues about likely candidate genes for this type of cataract. First, anterior polar cataract sometimes presents in Alport syndrome, a hereditary disease of basement membranes that primarily affects the kidney glomeruli (nephritis), inner ear (deafness) and lens capsule (anterior lenticonus). Underlying mutations have been identified in collagen genes on Xq (15 ) and 2q (16 ), which in the case of anterior lenticonus may result in the thinning and eventual rupture of the lens capsule perhaps as a consequence of the mechanical stress exerted during growth and accommodation of the lens (17 ). The laminated appearance of the opacity observed in this study is indicative of capsule reduplication, further suggesting that genes for other structural components of the lens capsule could underlie anterior polar cataract. Second, anterior polar cataract is associated with aniridia and Peters' anomaly, which involve mutations in the PAX6 gene on 11p (18 ,19 ). Although PAX6 was excluded in the present study, it is possible that another homeobox-containing gene controlling anterior eye development is involved. Third, although rare, anterior polar cataract can be associated with retinitis pigmentosa and a locus for this retinal degeneration appears to co-localize in the same genetic interval (20 ), raising the intriguing possibility of a related genetic defect. Currently, effort is focused on further characterization of the new anterior polar cataract locus on 17p by fine mapping and positional cloning to identify candidate genes in the region.

MATERIALS AND METHODS

Genotyping

Genomic DNA was extracted from EDTA-sequestered blood samples using the Nucleon II DNA extraction kit (Scotlab Bioscience). Genethon microsatellite markers (13 ) were amplified using the polymerase chain reaction (PCR). The forward PCR primer was 5'-end labelled using [[gamma]-32P]dATP (~110 TBq/mmol) and T4 polynucleotide kinase prior to amplification. The standard PCR mix (10 µl) contained 200 ng DNA, 2.5 pmol of each primer, 50 mM KCl, 10 mM Tris-HCl (pH 9.0), 0.15% Triton-X-100, 1.5 mM MgCl2, 250 µM of each dNTP and 0.6 U of Taq DNA polymerase. Standard PCR conditions were: 1 cycle at 94oC for 3 min, followed by 30 cycles at 94oC for 1 min, 50 or 55oC for 1 min, 72oC for 1 min, then one cycle at 72oC for 5 min. Radiolabelled PCR products were separated on denaturing 6% polyacrylamide sequencing gels and detected by autoradiography.

Linkage analysis

Data were collated using the LINKSYS (version 3.1) data management package (21 ). Two-point LOD scores were calculated using the MLINK and ILINK sub-programs of the LINKAGE (version 5.1) package (22 ). Allele frequencies calculated from the spouses in the family were similar to those quoted by Genethon (13 ). Multipoint analysis was computed using LINKMAP (22 ) run on the computing facilities of UK Human Genome Mapping Project Resource Centre computing facilities. A full penetrance and a gene frequency of 0.0001 were assumed for the disease locus.

ACKNOWLEDGEMENTS

We thank the family for their cooperation in this study, Neil Ebenezer and Mai Al-Maghtheh for help with computing LOD scores and the UK Human Genome Mapping Resource Centre (Cambridge, UK) for microsatellite primer synthesis and use of computing facilities. This work is supported by a grant from The Wellcome Trust (043073/Z/94/Z). AI is supported by a grant from the Friends of Moorfields Eye Hospital.

ABBREVIATIONS

PAX6, paired-box 6 gene.

REFERENCES

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2 Eiberg,H., Lund,A.M., Warburg,M. and Rosenberg,T. (1995) Assignment of congenital cataract Volkmann type (CCV) to chromosome 1p36. Hum. Genet., 96, 33-38. MEDLINE Abstract

3 Renwick,J.H. and Lawler,S.D. (1963) Probable linkage between a congenital cataract locus and the Duffy blood group locus. Ann. Hum. Genet., 27, 67-84.

4 Lubsen,N.H., Renwick,J.H., Tsui,L-C., Breitman,M.L. and Schoenmakers,J.G.G. (1987) A locus for a human hereditary cataract is closely linked to the [gamma]-crystallin gene family. Proc. Natl Acad. Sci. USA, 84, 489-492. MEDLINE Abstract

5 Brakenhoff,R.H., Henskens,H.A.M., van Rossum,M.W.P.C., Lubsen,N.H. and Schoenmakers,J.G.G. (1994) Activation of the [gamma]E-crystallin pseudogene in the human hereditary Coppock-like cataract. Hum. Mol. Genet., 3, 279-283. MEDLINE Abstract

6 Marner,E., Rosenberg,T. and Eibergh,H. (1989) Autosomal dominant congenital cataract: morphology and genetic mapping. Acta Ophthalmol., 67, 151-158.

7 Maumenee,I.H. (1979) Classification of hereditary cataracts in children by linkage analysis. Ophthalmol., 86, 1554-1558.

8 Padma,T., Ayyagari,R. Murty,J.S., Basti,S., Fletcher,T., Rao,G.N., Kaiser-Kupfer,M. and Hejtmancik,JF. (1995) Autosomal dominant zonular cataract with sutural opacities localized to chromosome 17q11-12. Am. J. Hum. Genet., 57, 840-845. MEDLINE Abstract

9 Armitage,M.M., Kivlin,J.D. and Ferell,R.E. (1995) A progressive early onset cataract gene maps to human chromosome 17q24. Nature Genet., 9, 37-40. MEDLINE Abstract

10 Jaafar,M.S. and Robb, R.M. (1984) Congenital anterior polar cataract: a review of 63 cases. Ophthalmology, 91, 249-254. MEDLINE Abstract

11 Rubin,S.E., Nelson,L.B. and Pletcher,B.A. (1994) Anterior polar cataract in two sisters with an unbalanced 3;18 chromosomal translocation. Am. J. Opthalmol., 117, 512-515. MEDLINE Abstract

12 Moross,T., Vaithilingam,S.S., Styles,S. and Garder,H.A. (1984) Autosomal dominant anterior polar cataracts associated with a familial 2;14 translocation. J. Med. Genet., 21, 52-53. MEDLINE Abstract

13 Gyapay,G., Morissette,J., Vignal,A., Dib,C., Fizames,C., Millasseau,P., Marc,S., Bernardi,G., Lathrop,M. and Weissenbach,J. (1994) The 1993-1994 Genethon human genetic linkage map. Nature Genet., 7, 246-339. MEDLINE Abstract

14 Antonarakis,S.E. (1994) Genome linkage scanning: systematic or intelligent? Nature Genet., 8, 211-212. MEDLINE Abstract

15 Barker,D.F., Hostikka,S.L.,Zhou,J.,Chow,L.T., Oliphant,A.R., Gerken,S.C., Gregory,M.C., Skolnick,M.H., Atkin,C.L. and Tryggvason,K. (1990) Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science, 248, 1224-1226. MEDLINE Abstract

16 Mochizuki,T., Lemmink,H.H., Mariyama,M., Antignac,C., Gubler,M-C., Pirson,Y., Verellen-Dumoulin,C., Chan,B., Schroder,C.H., Smeets,H.J. and Reeders,S.T. (1994) Identification of mutations in the [alpha]3(IV) and [alpha]4(IV) collagen genes in autosomal recessive Alport syndrome. Nature Genet., 8, 77-82. MEDLINE Abstract

17 Streeten,B.W., Robinson,M.R., Wallace,R. and Jones,M.D. (1987) Lens capsule abnormalities in Alport's syndrome. Arch. Ophthalmol., 105, 1693-1697. MEDLINE Abstract

18 Hanson,I.M., Fletcher,J.M., Jordan,T., Brown,A., Taylor,D., Adams,R.J., Punnett,H. and van Heyningen,V. (1994) Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters' anomaly. Nature Genet., 6, 168-173. MEDLINE Abstract

19 Glaser,T., Jepeal,L., Edwards,J.G., Young,S.R., Favor,J. and Maas,R.L. (1994) PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects. Nature Genet., 7, 463-471. MEDLINE Abstract

20 Greenberg,J., Goliath,R., Beighton,P. and Ramesar,R. (1994) A new locus for autosomal dominant retinitis pigmentosa on the short arm of chromosome 17. Hum. Mol. Genet., 3, 915-918. MEDLINE Abstract

21 Attwood,J.and Bryant,S.A. (1988) A computer program to make analysis with LIPED and LINKAGE easier to perform and less prone to input errors. Am. J. Hum. Genet., 52, 259.

22 Lathrop,G.M., Lalouel,J.M., Julier,C. and Ott,J. (1984) Strategies for multipoint linkage analysis in humans. Proc. Natl Acad. Sci. USA, 81, 3443-3446. MEDLINE Abstract

*To whom correspondence should be addressed

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