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(Investigative Ophthalmology and Visual Science. 2002;43:236-240.)
© 2002 by The Association for Research in Vision and Ophthalmology, Inc.

A 6-bp Deletion in the Crygc Gene Leading to a Nuclear and Radial Cataract in the Mouse

Jochen Graw, Angelika Neuhäuser-Klaus, Jana Löster and Jack Favor

From the National Research Center for Environment and Health (Forschungszentrum für Umwelt und Gesundheit), Institute of Mammalian Genetics, Neuherberg, Germany.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Discussion
 References
 
PURPOSE. A mouse mutant expressing a bilateral nuclear and radial cataract was found after paternal treatment with chlorambucil. The purpose of this study was to establish the linkage of the mutation to a particular chromosome to allow molecular characterization. Moreover, the mutants were examined morphologically.

METHODS. Isolated lenses were photographed and histologic sections of the eye were analyzed according to standard procedures. The mutation was localized to chromosome 1 by allelism testing with the Crygenz mutation. Candidate genes were amplified by PCR from cDNA or genomic DNA and sequenced.

RESULTS. A novel mouse cataract was characterized by a nuclear and radial opacification of the lens. The lenses of the mutants are smaller than those of the wild type. The histologic analysis demonstrated degeneration of lens fibers in the lens core. Abnormal remnants of cell nuclei are present throughout the entire lens. Genetic analysis revealed allelism to the Cat2 group of dominant cataracts on mouse chromosome 1; therefore, the cluster of the Cryg genes and the closely linked Cryba2 gene were tested as candidates. A 6-bp deletion in exon 3 of the {gamma}C-crystallin encoding gene (Crygc) is causative for the cataract phenotype; the mutation is therefore designated CrygcChl3. The deletion of the bases 420 to 425 leads to a loss of two amino acids, Gly and Arg, in the fourth Greek-key motif.

CONCLUSIONS. The CrygcChl3 is the first mutation in the mouse affecting the Crygc gene. Dominant mutations for five of the six Cryg genes on mouse chromosome 1 have now been characterized, demonstrating the importance of this gene cluster for lens transparency.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Discussion
 References
 
The ß- and {gamma}-crystallins were biochemically characterized as major lens proteins more than 100 years ago.1 They belong to a superfamily of proteins that were considered for a long time to be present only in the eye and mainly in the ocular lens. However, the expression of the ßB2-crystallin–encoding gene was reported recently also in brain and testis.2 3

The common characteristic of all ß- and {gamma}-crystallins is the Greek-key motif. Crystallography has shown that each of the ß- and {gamma}-crystallins is composed of two domains, each built up by two Greek-key motifs. It is widely accepted that ß- and {gamma}-crystallins evolved in two duplication steps from an ancestral gene. The Cryg genes in all mammals consist of three exons: The first one codes for only three amino acids, and the subsequent two are responsible for two Greek-key motifs each. Biochemically, the {gamma}-crystallins are characterized as monomers with a molecular mass of 21 kDa.4 5 6

The family of Cryg genes is mainly located in a cluster of six highly related genes (Cryga->Crygf) on mouse chromosome 1 or human chromosome 2q33-35. The seventh Cryg gene (Crygs) is on mouse chromosome 16 or human chromosome 3. Several mutations in the Cryg genes leading to cataracts have been identified. Thus, the mutation ENU-436 affects the Cryga gene, the Nop mutation the Crygb gene,7 and Lop12 the Crygd gene.8 For the Cryge gene, four cataract alleles have been reported so far: the Elo mouse,9 the Cat2t mutant,7 the Crygenz,10 and the CrygeAey1.11 Just recently, also a temperature-sensitive mutation of the Crygs gene was characterized in the murine Opj cataract.12 However, to date no mutation has been detected in the Crygc and Crygf genes. Moreover, several hereditary cataracts in humans have been shown to be caused by mutations in CRYG genes.13 14 15 16

The mutant Chl3 was found to cause nuclear and radial cataract, by slit lamp screening of mice after paternal treatment with the alkylating agent chlorambucil,17 which is used in therapy for rheumatism. Allelism testing indicated this mutation to be allelic or tightly linked with the Cat2nz mutation,18 which was previously identified as a mutation in the Crygenz mutation.7 The chromosomal location and lens phenotype indicate that the Cryg cluster and the Cryba2 gene are good candidate genes for the gene affected. Molecular analysis revealed that the third exon of the Crygc gene is altered in the Chl3 mutation. In addition to this molecular characterization, some morphologic characteristics of the mutants will be presented.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Discussion
 References
 
Animals
The mutation Chl3 was detected among offspring after paternal treatment with chlorambucil (10 mg/kg, according to Russell et al.17 ) in (102/ElxC3H/El)F1 mice. Cataracts were identified at weaning, by means of slit lamp examination (SLM30; Zeiss, Oberkochen, Germany). Homozygous mutant lines have been maintained by brother x sister matings. For control, wild-type C3H/El mice were used. All breedings were performed in the National Research Center for Environment and Health (GSF) animal facility according to the German Law on the Protection of Animals and the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.

Morphologic Analysis
For gross documentation, lenses from 3-week-old mice were enucleated under a dissecting microscope (MZ APO; Leica, Heidelberg, Germany) and photographed at x20 magnification. For detailed histologic analysis, eyes from 3-day and 3-week-old mice were fixed for 24 hours in Carnoy’s solution, dehydrated, and embedded in paraffin or plastic medium (JB-4Plus; Polysciences, Inc., Eppelheim, Germany) according to the manufacturer’s procedure. Sectioning was performed with an ultramicrotome (Ultratom OMU3; Reichert, Walldorf, Germany). Serial transverse 2-µm sections were cut with a dry glass knife and collected in water drops on glass slides. After drying, the sections were stained with methylene blue and basic fuchsin. Paraffin-embedded sections were stained by hematoxylin-eosin or propidium iodide. The sections were evaluated using a light microscope (Axioplan, Zeiss). Images were acquired by means of a scanning camera (Progress 3008; Jenoptik, Jena, Germany) equipped with a screen-capture program (KS100; Carl Zeiss Vision, Hallbergmoos, Germany) and imported into an image-processing program (Adobe Illustrator 9.0 or Photoshop 6.0; Adobe, Unterschleissheim, Germany).

Isolation of RNA, DNA, and PCR Conditions
Genomic DNA was prepared from spleen or tail tips of 3-week-old mice according to standard procedures. RNA was isolated from lenses (stored at -80°C) of newborn mice. cDNA synthesis and PCR using genomic DNA or cDNA as a template were performed essentially as reported previously.7 For amplification of the smaller 280-bp fragment from Crygc (exon 3), we used a new left-side primer (5'-CCTCAGTGAGGTGCGCTCGC-3') based on the already existing Crygc sequence (GenBank/EMBL accession number Z22574; GenBank is provided in the public domain by the National Center for Biotechnology Information, Bethesda, MD, and is available at http://www.ncbi.nlm.nih.gov/genbank; EMBL is provided in the public domain by European Molecular Biology Laboratory, Heidelberg, Germany, and is available at http://www.embl-heidelberg.de) in combination with the right-side primer for Crygc (exon 3) under the same PCR conditions as described previously.7 Besides the Cryg genes, the closely linked Cryba2 (GenBank/EMBL accession number NM_021541) was tested as a candidate, as described recently.11 PCR products were sequenced commercially (SequiServe, Vaterstetten, Germany), either after cloning into the pCR2.1 vector (Invitrogen, Leek, The Netherlands) or directly after elution from the agarose gel, using kits from Qiagen (Hilden, Germany) or Bio-Rad (Munich, Germany) and subsequent precipitation by ethanol and glycogen. HaeIII-digested PCR fragments were analyzed in a 12.5% polyacrylamide gel.

General
Chemicals were from Merck (Darmstadt, Germany) or Sigma Chemical Co. (Deisenhofen, Germany). The enzymes used for cloning and reverse transcription were from Roche Molecular Biochemicals (Mannheim, Germany), and restriction enzymes were from MBI Fermentas (St.Leon-Rot, Germany), if not otherwise noted.

Result
Phenotype and Lens Morphology
Heterozygous Chl3 mutants expressed a nuclear and radial cataract, which was observed during slit lamp screening at the age of 3 weeks. Figure 1 demonstrates the cataractous zones of the isolated lenses of heterozygous and homozygous mutants. First histologic sections were obtained from 3-day-old mice (Fig. 2) . The major feature in the mutant lenses was the presence of the cell nuclei throughout the entire lens (Fig. 2B) , whereas in the wild type the cell nuclei were present only in the lens bow region. This was confirmed by staining with propidium iodide demonstrating intact cell nuclei in the central anterior region of the mutant lens (Fig. 2D) . The histologic examination of 3-week-old mice revealed an altered core of the lens with degenerated embryonic primary fiber cells (Fig. 3B) . The lens core had a clear border to the cortex. As for the earlier stage, cell nuclei were visible throughout the whole cataractous lens (Fig. 3D) . However, in the central region of the lens they were obviously smaller than in the lens bow area. These pyknotic cell nuclei indicate a disturbed denucleation process and changes in the terminal differentiation of the secondary fiber cells. Other parts of the eye were obviously not affected.



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  		Figure 1. Isolated lenses of 3-month-old mice. Lenses were photographed at x20 magnification in dark-field illumination. Wild-type lenses (A) were transparent and optically homogeneous. Heterozygotes (B) expressed a nuclear and radial opacity with an apparent inhomogeneity of the optical properties of the inner nuclear volume compared with the subcortical region. Homozygous mutants (C) expressed a more severe cataract phenotype and slight microphthalmia.

 


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  		Figure 2. Chl3 lenses at the age of 3 days. Central lens paraffin sections of 3-day-old wild-type and homozygous Chl3 mutants were stained with hematoxylin and eosin (A, B). The typical situation in the wild type is shown in (A); whereas the smaller Chl3 lens (B) demonstrated the presence of cell nuclei in a wave-like band throughout the entire lens. The intact cell nuclei in these lenses were confirmed by staining with propidium iodide in adjacent sections. In the wild-type (C), intact cell nuclei were detected by propidium iodide only in the cortical area. In the center of the lens, a diffuse, nonspecific staining was obvious. In the homozygous mutants, the propidium iodide staining confirmed the observation with hematoxylin-eosin. C, cornea; L, lens; LB, lens bow; LE, lens epithelium; R, retina. Bar, 100 µm.

 


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  		Figure 3. Histologic analysis of Chl3 lenses at the age of 3 weeks. Central sections of plastic resin–embedded lenses from 3-week-old wild-type (A, C) and homozygous Chl3 mice (B, D) were stained by methylene blue and basic fuchsin. In the wild-type, the center of the lens was homogeneous (A), and the magnification of the lens bow region (C) shows that the nuclei were arranged properly and were completely degraded as cells progressed to the deeper cortex. In the homozygous Chl3 mutants (B) the core of the lens was cataractous and clearly separated from the cortical area. The nuclei of the primary fiber cells were not fully degraded, and their remnants remained in the lens (arrows). (D) Higher magnification of the lens bow region shows that the nuclei were not fully degraded (arrows). Other parts of the mutant eye were not affected. C, cornea; L, lens; LB, lens bow; LE, lens epithelium; R, retina. Bar, 100 µm.

 
Genomic Analysis
The chlorambucil-induced nuclear and radial cataract was localized to mouse chromosome 1 in the region of the Cryg gene cluster by allelism testing with the Crygenz mutation (previously referred to as Cat2nz).18 Crygenz/Chl3 compound heterozygotes expressing an extreme cataract phenotype were constructed and outcrossed to homozygous wild-type parents. Seventy-nine offspring were examined by slit lamp biomicroscopy, and all expressed cataract. Based on the chromosomal region, the Cryg gene cluster members as well as Cryba2 were considered candidates of the gene altered by the Chl3 mutation.

All six members of the Cryg gene cluster and Cryba2 were amplified using gene-specific PCR methods for the cDNA as well as for the genomic DNA. The amplified products were sequenced. No difference was found between the wild types and the Chl3 mutants in the Cryga, Crygb, Crygd, Cryge, Crygf, and Cryba2 cDNA. In the Cryg genes, some polymorphic sites were discovered in the Chl3 mutant and the wild types, as described previously.10 Two further polymorphic sites in the Crygc gene did not change the deduced amino acids (A->C at position 111; G->A at position 384).

The only difference between wild-type C3H and mutant Chl3 DNA, which leads to an alteration of the amino acid sequence, was identified in the Crygc gene (GenBank/EMBL accession number NM_007775) as a deletion of 6 bp at position 420-425 of the cDNA (Fig. 4) . The mutation was confirmed by the absence of the restriction site for HaeIII in the genomic DNA of five different animals of the mutant line. It was always present in five wild-type mice from different strains (Fig. 5) . Therefore, we conclude that this 6-bp deletion in the Crygc gene is responsible for the cataractous phenotype. The suggested new allele symbol is CrygcChl3.



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  		Figure 4. Sequence analysis of the Chl3 mutant. The Crygc DNA sequence from the wild-type mice is compared with that from the Chl3 mutants. The deduced amino acid composition is demonstrated above or below the DNA sequence. The deletion of 6 bp in exon 3 at position 420 to 425 (gray box) leads to a loss of two amino acids. The HaeIII recognition site (underlined) is destroyed by the mutation.

 


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  		Figure 5. Crygc digested by HaeIII. (A) A simple restriction map of a 280-bp fragment covering the 6-bp deletion ({Delta}) indicates the sizes of the three fragments in the wild type mouse. Because this deletion destroys the first HaeIII site, the resultant fragment is of 86 bp. The numbers above the line are according to the GenBank/EMBL database entry accession Z22574; Stop, the stop codon for Crygc translation. (B) A 280-bp fragment of exon 3 was amplified from genomic DNA and analyzed by polyacrylamide gel electrophoresis (12.5%) after digestion by HaeIII. The genomic DNA from all wild types (derived from the strains C3H/El, C57BL/6, JF1, and T-Stock) showed the 73-bp fragment, whereas the DNA from different homozygous Chl3 mutants always revealed the larger 86-bp fragment (numbers at the top indicate different homozygous CrygcChl3 mice). Right: Size of the fragments in base pairs; lane M: marker.

 
The deduced amino acid sequence demonstrates a loss of two amino acids (Gly and Arg at positions 141 and 142) in the fourth Greek-key motif. PROSITE scanning reveals that this fourth Greek-key motif will not be formed (provided in the public domain by the Swiss Institute of Bioinformatics, Geneva, Switzerland and available at http://www.expasy.ch).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Discussion
References
 
In this report, we present a morphologic description and a molecular characterization of a cataract mutation in the mouse that was induced by chlorambucil. It led to the loss of 6 bp within the Crygc gene. This observation is as expected for the mode of action of chlorambucil to induce deletions rather than base pair substitutions.19 20 It is the first reported Crygc mutation and extends the association of mutations in five of the six Cryg genes with dominantly inherited cataracts in the mouse. The only Cryg gene that has not yet been associated with a dominant cataract mutation is the Crygf gene. Because the 6-bp deletion leads to the loss of two amino acids (Gly and Arg) in the highly conserved fourth Greek-key motif, the folding of this particular {gamma}-crystallin is expected to be altered.

The mutation in the Crygc gene leads to a nuclear and radial cataract. This phenotype seems unique among the cataracts caused by mutations in the Cryg genes, because these mutant lines exhibit mainly nuclear or total cataracts. The histologic observations demonstrated that the nuclei of the lens fiber cells are not degraded as they usually are at this stage of normal lens development. The persistence of the cell nuclei in the anterior region of the lens may be responsible for this particular nuclear and radial opacity observed by slit lamp. The disturbance of the denucleation process of the primary and secondary lens fiber cells seems to be a common feature in all Cryg mutants. It is not yet known whether a specific biochemical pathway may be affected or whether a nonspecific fiber cell destruction takes place in the {gamma}-crystallin mutants.

The CrygcChl3 mutation is the first mutation in the mouse Crygc gene, but the ninth mutation that has been reported to affect the Cryg gene cluster: The Crygeelo 9 and the CrygdLop12 8 mutations have been reported by other groups; we have characterized the Cryga1Neu, Crygbnop, Cryget, Crygens, Crygenz, and CrygeAey1 mutations.7 10 11 21 Currently, in humans, an increasing number of mutations in the CRYG genes has been associated with cataract formation: the Coppock-like cataract with the CRYGC gene; an aculeiform cataract, a punctate cataract, and a crystal cataract with CRYGD13 14 15 ; and a polymorphic congenital cataract mapped very close to the CRYGB gene.22 Most interesting, in the context of the new Crygc 6-bp deletion mutant in the mouse characterized herein, a 5-bp insertion in the human {gamma}C-crystallin encoding gene (CRYGC) was reported.16 It leads to a dominant variable zonular pulverulent cataract.

The high frequency of cataracts with different clinical phenotypes associated with mutations affecting one of the Cryg genes emphasizes the importance of the Cryg gene cluster. All Cryg mutations reported so far are associated with a dominant phenotype and appear to lead to structural alterations of the proteins. There are no reports on recessive forms of cataracts associated with {gamma}-crystallins. However, the evolutionary knock-out of two of these six genes as pseudogenes in humans ({psi}CRYGE, {psi}CRYGF) suggests either species differences of the genes required for normal eye development or that the loss of function of one or only a few {gamma}-crystallins might be without consequences.23 Furthermore, polymorphic sites within these genes have been reported in mouse8 10 and humans13 without any effect on the function of the proteins. One of the future focuses in {gamma}-crystallin research should therefore be to determine a clear genotype–phenotype correlation of these genes and their encoded proteins.


   Acknowledgements
 
The authors thank Carmen Arnhold, Erika Bürkle, Sibylle Frischholz, Bianca Hildebrand, Brigitta May, Dagmar Reinl, Monika Stadler, and Irmgard Zaus for expert technical assistance; Sabine Grünaug for contributions made to the study during her practical courses at the Technical University, Munich; and Utz Linzner (GSF-Bioinformatics Group, Institute of Experimental Genetics) for providing oligonucleotides.


   Footnotes
 
Submitted for publication May 29, 2001; revised August 27, 2001; accepted September 10, 2001.

Commercial relationships policy: N.

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Jochen Graw, GSF-National Research Center for Environment and Health, Institute of Mammalian Genetics, Ingolstadter Landstrasse 1, D-85764 Neuherberg, Germany; graw{at}gsf.de.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Discussion
 References
 

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