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(Investigative Ophthalmology and Visual Science. 2000;41:3278-3285.)
© 2000 by The Association for Research in Vision and Ophthalmology, Inc.

A New ßA1-Crystallin Splice Junction Mutation in Autosomal Dominant Cataract

J. Bronwyn Bateman1,2,3, David D. Geyer1,3, Pamela Flodman4, Meriam Johannes3, James Sikela5, Nicole Walter5, Ana Teresa Moreira6, Kevin Clancy3 and M. Anne Spence4

1 From the Departments of Ophthalmology and 5 Pharmacology, and 2 The Children’s Hospital, the University of Colorado School of Medicine; the 3 Eleanor Roosevelt Institute, Denver, Colorado; the 4 Department of Pediatrics, University of California, Irvine; and the 6 Department of Ophthalmology, University of Curitiba School of Medicine, Brazil.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. To map the locus for autosomal dominant cataracts (ADCs) in a Brazilian family using candidate gene linkage analyses, describe the clinical variability, and identify potential mutations in the human ßA1-crystallin gene (CRYBA1), a candidate gene identified through linkage studies demonstrating cosegregation with markers on chromosome 17.

METHODS. Members of a Brazilian family with ADC were studied. Clinical examinations and linkage analyses with polymerase chain reaction (PCR) polymorphisms of 22 anonymous markers and 2 within the neurofibromatosis type 1 gene were performed; two-point lod scores were calculated. DNA sequences of all 6 exons and 12 exon–intron boundaries of the ßA1-crystallin gene, a proximal candidate gene mapped to 17q11.1-q12 in one unaffected and two affected individuals, were screened and new variants assessed for cosegregation with the disease.

RESULTS. Affected individuals exhibited variable expressivity of pulverulent opacities in the embryonal nucleus and sutures; star-shaped, shieldlike, or radial opacities in the posterior embryonal nucleus; and/or midcortical opacities. All known loci for ADC in this family on chromosomes 1 and 13 were excluded. A positive lod score on chromosome 17 was calculated. This ADC locus was mapped to two potential regions on the long arm with an intervening recombination. The only known candidate gene in these regions was ßA1-crystallin. Three previously unreported single nucleotide variants were found in this gene, one in the donor splice junction site of intron C. This variant was found in all affected members and is presumed to be the causative mutation.

CONCLUSIONS. An ADC locus was mapped in a Brazilian family with variable expressivity to either 17q23.1-23.2 or 17q11.1-12 based on linkage analyses. Analyses of DNA sequences of the ßA1-crystallin gene in this family revealed three new variants, one of which is within a donor splice junction and cosegregates with affected members.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Pediatric cataracts may be caused by intrauterine embryopathies and single gene defects or may be associated with chromosomal rearrangements. Some cataracts, particularly unilateral, are of unknown cause. The disease is clinically and genetically heterogeneous. The prevalence of congenital cataracts has been estimated to be 2.2 per 10,000 births,1 and the incidence in some countries has been reduced by immunization programs.2 Most autosomal dominant cataract (ADC) forms are congenital and isolated. Phenotypic variability of ADC has been documented among and within families, and some forms are progressive.3 4 5 Generally, the cataracts are bilateral and characterized on the basis of location within the lens, shape, size, color, and the presence or absence of refractivity. Some have been named for the affected family such as the Coppock cataract6 and others for the author reporting the family such as the Marner cataract.7 Despite attempts to clinically categorize hereditary cataracts, there is poor correlation of phenotype with genetic loci.

Previous studies have identified at least 13 loci for ADC based on linkage analyses for which mutations in seven genes have been implicated. Three loci have been identified on chromosome 17, one of which is attributed to a mutation of the ßA18 (formerly ßA3/A1)-crystallin gene (CRYBA1).9 10 We studied a Brazilian family with ADC with variable expressivity of the embryonal, pulverulent variety and mapped the gene using linkage analysis to two potential regions, 17q11.1-12, containing the ßA1-crystallin gene (17qcen-q23)11 12 and a second in a relatively broad region in 17q22-24.1. We identified three new variants within the ßA1-crystallin gene in this family, one of which is within the donor splice junction of intron C (letter nomenclature in common usage as originally designated13 ; intron 3) following exon 3 and is present in all affected family members.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The study adhered to the tenets of the Declaration of Helsinki for research involving human subjects. The family was ascertained through the Ophthalmology Clinic of the University of Curitiba School of Medicine in Curitiba, Brazil. The proband (Fig. 1) underwent cataract extraction. On the basis of the pedigree and male-to-male transmission, autosomal dominant inheritance was demonstrated. Informed consent, with University of Colorado Institutional Review Board approval, was obtained with translation provided by one of the authors (ATM). Nineteen individuals participated. No other diseases aside from age-related disorders were identified by history. Affected status was determined by pupillary dilation and evaluation of lenses at the slit lamp biomicroscope or by a history of cataract extraction (JBB, ATM).



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  		Figure 1. Pedigree of the ADC-affected family with haplotypes for the most relevant markers. Two regions, 17q23.1-q23.2 and 17q11.1-q12, are without recombinants. Affected individuals are shaded black; the proband is identified by an arrow. Filled boxes: disease haplotype inherited from founder (number 1); open boxes: all other haplotypes; thick lines connecting filled and open boxes: regions where inheritance cannot be determined.

 
Blood samples were collected in EDTA and leukocyte genomic DNA extracted.14 Sequence-tagged sites (STSs) of the microsatellite variety were amplified using polymerase chain reaction (PCR) with fluorescently labeled primers or by incorporation of fluorescent dUTPs ([F]dUTPs). For [F]dUTP amplification, the protocol recommended by the manufacturer was modified (Perkin–Elmer Applied Biosystems, Foster City, CA) as follows. Twenty-five nanograms of template DNA was used in a 10-µl reaction with 200 µm of dNTPs, 4 picomoles of forward and reverse primers, 0.5 to 2.0 µM [F]dUTP (Perkin–Elmer Applied Biosystems), 0.125 U Taq DNA polymerase in PCR buffer, and 1x Q-Solution (1x PCR buffer: KCl, NH4SO4, and Tris-HCl, [pH 8.7]; Qiagen, Santa Clarita, CA) and 1 to 3 mM MgCl2. Reactions were cycled in a twin-block system cycler (EriComp; San Diego, CA) as follows: an initial 5-minute denaturation at 95°C, then 35 cycles at 1 minute at 94°C, 1 minute at 55°C, and 1 minute at 72°C, finishing with a 7-minute extension cycle at 72°C and a final hold of 4°C. PCR products were mixed with a loading cocktail containing 50% (vol/vol) of deionized formamide and 0.5 µl of internal lane standard (ROX; Perkin–Elmer Applied Biosystems), denatured for 5 minutes at 95°C and immediately placed on ice. The product was loaded onto a 6% sequencing gel (Burst Pak; Owl Scientific, Cambridge, MA) and run on a DNA sequencer (Prism model 373; Perkin–Elmer Applied Biosystems). The data were collected and analyzed by computer (Genescan 672 Collection Software ver. 1.1 and Genescan Analysis Software ver. 2.1; PE Applied Biosystems) For labeled primers (Research Genetics, Huntsville, AL, or Molecular Resource Center, National Jewish Medical and Research Center, Denver, CO), the process was identical except for the use of the following: 250 µM dNTPs, 2.4 picomoles of fluorescently labeled forward and reverse primers, and 2.4 picomoles of TAMRA (Perkin–Elmer Applied Biosystems) as internal lane standards at the same concentration.

Markers were chosen for analysis on the basis of previously reported linkage with an ADC locus or evidence of suggestive linkage in a previous family studied in our laboratory. The following 23 markers were tested initially: D1S1622, D1S1665, D1S2130, D1S1669, D3S2398, D3S2427, D3S2436, D8S592, D8S1119, D8S1128, D8S1132, D8S1179, D13S175, D13S1236, D14S606, D14S610, D14S617, D14S749, D17S796, D19S589, D19S254, D19S601, and ATA43A10. After suggestive linkage with D17S796 (Zmax = 1.82; {theta}m = {theta}f = 0; where Zmax represents maximum lod score, and {theta}m and {theta}f represent male recombination fraction value and female recombination fraction value, respectively), additional markers in the region were tested (Table 1) . The marker loci were localized to chromosomal regions based on data from the Cooperative Human Linkage Center,15 the Genome Database (GDB),16 and the Weizmann Institute17 and Whitehead Institute18 databases.


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  		Table 1. Lod Scores between Chromosome 17 DNA Markers and ADC Loci in a Brazilian Family

 
For linkage analyses, pedigree and genotype data were analyzed with LIPED (freely available from Jurg Ott at http://linkage.rockefeller.edu).19 Lod scores were calculated using published allele frequencies16 or estimates from 30 unrelated individuals outside this family. A gene frequency of 0.0001 and full penetrance were assumed for the cataract locus; two-point lod scores were calculated for a full range of {theta}m and {theta}f values.

PCR primers (Only DNA, Midland, TX) were designed20 (Table 2) to amplify all six exons and intron–exon junctions in the ßA1-crystallin gene (CRYBA1), a candidate gene (GenBank accession M14301-6).13 21 22 PCR products were sequenced from both directions using a dye terminator cycle sequencing kit (Prism FS; Perkin–Elmer Applied Biosystems) and an automated fluorescence sequencer (model 373; Perkin–Elmer Applied Biosystems). For screening, one unaffected (number 16) and two affected (numbers 13 and 14) individuals were compared. Variants of potential biologic significance were assessed in all members of the family. After identification of several variants and a probable mutation, the newly identified sequences were studied in five normal and unrelated Brazilians (10 chromosomes).


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  		Table 2. PCR Primers Used for the Amplification and Sequencing of the ßA1-Crystallin Exons

 

   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Adults in the family reported that cataracts were present from early in life. Historical information was limited, and there were no previous records aside from those of the proband. Most affected individuals who had not undergone cataract extraction had opacities that appeared to be congenital, including clustering of pulverulent opacities in the embryonal nucleus and sutures and star-shaped, shieldlike, or radial opacities in the posterior embryonal nucleus. Midcortical opacities appeared to be postnatal. None of the affected individuals had nystagmus.

Markers on chromosomes 1, 3, 8, 13, 14, and 19 were recombinant with the disease locus, and two-point lod scores did not reveal any regions suggestive of linkage (data not shown). For chromosome 17q loci, scores are summarized (Table 1) and haplotypes depicted (Fig. 1) . Significant lod scores mapped the ADC locus to 17q23.1-q23.2 (markers D17S800 and D17S1299), and suggestive scores mapped the locus to 17q11.1-12 (markers D17S805, D17S1294, and D17S798). Recombination had occurred in individual 7 between the two clusters. The lod scores differed in the two regions due to degrees of informativeness.

By sequencing, three new variants in the ßA1-crystallin gene were identified compared with the original, nearly complete13 and the revised exonic sequences21 (GenBank, accession numbers M14301-622 ). For exon 1, sequences of the affected and unaffected individuals were identical with the original published sequence.13 For exons 2 and 3, sequences in one affected ( number 13) and one unaffected individual were identical with the original published sequence.13 For exon 4, the sequences of all three individuals agreed with the recent sequence revision.21 For exon 5, the sequence of the unaffected individual was normal.13 21 For exon 6, one affected (number 13) family member was normal.13 21

We identified three new and unreported variants. The final nucleotide of the second glycine codon in exon 5 was a G instead of a C13 at position 316 (GenBank accession M1430522 ) in our affected individuals and did not result in an amino acid change. Additionally, there was a C-to-T transition at position 6 before the AG acceptor splice junction at the 3' end of intron E (intron 5; GenBank accession M1430622 ) in both the affected and unaffected individuals. This results in a TAG compared with the published CAG,13 which, as an intronic sequence, would not be expected to alter the protein product. We found a probable mutation at position 474 in the donor splice junction of intron C (intron 3) following exon 3 (GenBank accession M1430322 ). A G-to-C transversion was identified in individuals 13 and 14 (Figs. 2 3) . This variant was found in all 13 affected individuals and was not evident in the 6 unaffected members of the family (numbers 4, 7, 15, 16, 17, and 19). In the five normal Brazilians, no donor splice site mutations were found in the ßA1-crystallin gene. In four of the unrelated Brazilians, position 316 was a C, as originally reported,13 and one individual had a G. Our new variant (TAG) at position 6 before the AG acceptor splice junction of intron E was found in all.



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  		Figure 2. Forward sequence analysis of the donor splice junction of intron C (following exon 3) of ßA1-crystallin (GenBank accession M1430322 ) in our ADC-affected Brazilian family. The unaffected individual (A) was homozygous with a G at position 474 (arbitrarily position 61) and the affected person (B) was heterozygous, with a G-to-C transversion.

 


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  		Figure 3. Exon 3 and flanking intronic sequences (GenBank accession M1430322 ). Exons are in uppercase, introns in lowercase, and primers for PCR and sequencing underlined; position 474, the first base of the 5' donor splice site junction, is in bold.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Transparency of the lens is predicated on the tertiary structure of the crystallins,25 and any disruption of oligomerization or destabilization could result in cataract formation. With the exception of the iron-responsive element of the L-ferritin gene, mutations in eight genes have been identified as causative of ADC, and most are in crystallins. In the {gamma}-crystallin cluster on 2q33-q35, three alterations in the CRYGD26 27 28 and a missense mutation of CRYGC,26 a chain termination mutation in the ß-crystallin gene (CRYBB2) on chromosome 22 (ßB2-crystallin),29 30 a missense mutation in the connexin50 (gap junction protein {alpha}-8; MP70) gene (GJA8)31 32 on 1q21.1,33 a missense mutation in the human {alpha}A-crystallin gene (CRYAA)34 on chromosome 21, and two mutations,35 one missense and one frame shift, in connexin46 (gap junction protein {alpha}-3; GJA3) on chromosome 13 have been shown to cause ADC. The previously reported activation of a {gamma}E-crystallin pseudogene36 has been found to be an error.26 Although mutations in the homeobox DNA-binding PAX6 gene usually cause aniridia and/or anterior segment dysgenesis, isolated cataracts have been documented.37 38 Hyperferritinemia with congenital cataracts and without other signs and symptoms is inherited as an autosomal dominant disease.39 40 Multiple mutations have been reported since 1995.39 Recently, a mutation was identified by Kannabiran et al.9 10 in a donor splice junction of the ßA1-crystallin gene (position 474 of exon 3 at the 5' donor splice junction) as the basis for ADC in a family41 that has demonstrated linkage with the marker D17S805 on 17q11.2-q12.42

Three loci for ADC43 44 45 (Fig. 4) and numerous retinal degenerations and dystrophies have been localized to chromosome 17.45 46 47 48 49 50 51 52 53 In 1996, Berry et al.43 localized an anterior polar cataract (CTAA2) to 17p with a maximum lod score of 4.17 between marker D17S796 ({theta} = 0.05) and the disease locus. A score of 4.01 ({theta} = 0.05) was calculated with D17S849. Based on current localization,15 16 17 this ADC locus is unchanged at 14 Mb from the pter at 17p13.3-11.2. A second locus, a progressive early-onset cerulean cataract (CCA1) described by Armitage et al.44 maps more distally on the long arm of chromosome 17 than originally reported in 1995. They calculated maximum lod scores with the disease (all at {theta} >0) of 9.46, 5.26, and 7.11 for markers D17S802, D17S836, and AFMa238yb5 (D17S1806), respectively, placing the gene in 17q24. Currently, these markers are 90.29, 91.3, and 91.41 Mb from 17pter, respectively, which localizes this ADC locus to the more distal 17q25.2 region.15 16 17



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  		Figure 4. Ideogram of chromosome 17 with loci of anterior polar (CTAA2),43 cerulean or blue-dot (CCA1),44 and zonular-sutural cataracts (CCZS)9 10 in an Indian family and our Brazilian family.

 
Padma et al.42 mapped a third ADC locus41 to 17q11.2-12 based on a maximum lod score of 3.91 ({theta} = 0) with D17S805; additionally, they found linkage with a neurofibromatosis-1 (NF1) marker (Zmax = 3.85 at {theta} = 0) confirming localization at 17q11.2 (GDB). Kannabiran et al.9 10 found a variant in the ßA1-crystallin gene in affected members of this family,41 42 further confirming the mapping and identifying the presumed mutation. The G-to-A transition in the donor splice junction of the ßA1-crystallin gene cosegregated with the cataract in their Indian family and resulted in interruption of the donor splice junction.

The ßA1-crystallin gene encodes both the ßA3- and ßA1-crystallins, which differ by the addition of 17 amino acids in the ßA3-crystallin terminus.54 An intermediate form of the ßA3-crystallin gene has only nine additional amino acids.55 The ßA1-crystallin aggregates range from dimers to octamers56 and further complexity is related to temporal and spatial regulation of expression as well as posttranslational modifications.57 The first two exons of the ßA1-crystallin gene encode the amino terminal arm, and exons 3 through 6 encode the Greek key motifs.13 Our sequence data of all six exons and six intron–exon boundaries for ßA1-crystallin gene identified three new variants, two of which do not alter the amino acid sequence. The third variant is a G-to-C transversion in the conserved donor splice junction of intron C (following exon 3) at position 474 (GenBank accession M1430322 ) and probably represents a mutation.

Position 474 is the first nucleotide in the invariant GT dinucleotide of the 5' splice junction consensus sequence. Krawczak et al.58 reviewed the literature and found that 15% of all point mutations alter pre-mRNA and 60% of the 5' splice mutations involve this dinucleotide. This variant is at the identical site that Kannabiran et al.9 10 found in affected members of their Indian family with ADC; however, their variant was a G-to-A transition and cosegregated with the disease. There are multiple reports of mutations at this site in human disease.58 59 Because the variants, although different, cosegregate with the disease in both the Indian family9 10 and our Brazilian family and occur in a conserved region of the donor splice junction, we believe that it represents the causative mutation.

We expect that all forms of the ßA3- and the ßA1-crystallins would be disrupted by the mutation. Kannabiran et al.9 10 speculated that the effect would be a skipping of the donor splice junction or the recruitment of a cryptic splice site. They postulated an alteration of the reading frame if splicing of exon 2 to exon 4 occurred; after addition of four amino acids to the 32 amino acids of exon 2, a premature termination would be encountered. If splicing of exons 3 to 5 occurred, the coding frame would be maintained and a truncated protein predicted. Splicing to exon 6 would result in a frame shift with preservation of the amino terminal arm followed by 18 additional amino acids. Using a WALKER representation (a graphical method to display how binding proteins interact with DNA or RNA sequences), they identified an upstream potential splice site at position 460 with a low information content (Ri 4.5 bits) that would result in transcription of the first 35 amino acids of exon 3, followed by addition of the same 4 additional amino acids and then premature termination. They postulated that all possibilities would result in improper folding of the first Greek key motif, an unstable protein, and subsequent cataract formation.

There is considerable phenotypic variability in the cataracts that have been studied by linkage analyses. Curiously, there are disparate forms mapped to the same locus or region and, conversely, similar forms to different regions. For example, embryonic-fetal and progressive sutural opacities in one family and stationary posterior polar cataracts in another have been mapped to chromosome 1p36.60 61 Loci in a different family with a posterior polar cataract62 63 and the Marner cataract family with progressive pulverulent opacities in the embryonic nucleus3 7 64 have been mapped to marker haptoglobin on 16q22.1. The zonular pulverulent cataract caused by a connexin50 (MP70) mutation30 32 is on 1q21-25,65 and the similar Coppock-like cataract has been mapped to both chromosome 135 and the {gamma}-crystallin gene cluster on 2q33-q35.29 66 67 A polymorphic congenital cataract also has been linked to the {gamma}-crystallin gene cluster.68 A cerulean cataract in one family is caused by a mutation of the ß-crystallin gene CRYBB2 on chromosome 2230 69 70 and a progressive form in another has been mapped to 17q25.2 (formerly 17q24).44 Explanations for this variability are speculative and probably relate to expression patterns and tertiary structure of the crystallins.

The clinical characteristics were varied among the affected members of this Brazilian family. The affected individuals who were examined had pulverulent opacities in the embryonal nucleus and sutures; star-shaped, shieldlike, or radial opacities in the posterior embryonal nucleus, and/or midcortical opacities that appeared to be postnatal. None of the affected individuals had nystagmus. Such clinical variability of ADC within families has been documented previously.3 5 6 41 The clinical features in our family are similar to those in the family with a mutation of the ßA1-crystallin described by Padma et al.42 The marked variability of the cataract in members of our Brazilian family appears to be greater than the family described by Basti et al.41 and may be related to the alternative effects of the mutation at the protein product level, skipping of the donor splice junction, or recruitment of several cryptic splice sites.

Thus, based on previous reports of mutations at this donor splice site causing human disease and the identification of ADC in the Indian family reported by Kannabiran et al.,9 10 we believe that we have identified the basis of ADC in our Brazilian family. Although the specific mutation, a G-to-C transversion, found in the affected members our family is different from the G-to-A variant found in the Indian family,9 10 the donor splice junction locus is identical. Because the clinical features of the cataract in our family were highly variable, the type of the gene defect would not be suggested by the phenotype.


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

Submitted for publication February 28, 2000; accepted April 11, 2000.

Commercial relationships policy: N.

Corresponding author: J. Bronwyn Bateman, Department of Ophthalmology, University of Colorado School of Medicine, 4200 East Ninth Avenue, Box B204, Denver, CO 80264. bronwyn.bateman{at}uchsc.edu


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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