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BIGH3 Mutation Spectrum in Corneal Dystrophies

¹ From the Hôpital Jules Gonin, Department of Ophthalmology, ² Division Autonome de Génétique Médicale, CHUV, Lausanne, Switzerland; ³ Augenklinik, Inselspital, Bern, Switzerland; the ⁴ Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee; ⁵ The Hospital for Sick Children, University of Toronto, Toronto, Canada; ⁶ Academic Unit, Manchester Royal Eye Hospital and Department of Molecular Genetics, St. Mary’s Hospital, Manchester, United Kingdom; ⁷ Clinica Oculistica, Università de L’Aquila, L’Aquila, Italy; ⁸ Klinik und Poliklinik für Augenheilkunde, Universität Regensburg, Regensburg, Germany; ⁹ Centro di Oftalmologia Barraquer, Barcelona, Spain; ¹⁰ Institute of Human Genetics, University of Greifswald, Greifswald, Germany; ¹¹ Universitäts-Augenklinik, Zurich, Switzerland; ¹² Clinica Oculistica, Università degli Studi di Cagliari, Cagliari, Italy; and the ¹³ Wills Eye Hospital, Philadelphia, Pennsylvania.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
PURPOSE. To investigate the molecular pathology underlying BIGH3-related corneal dystrophies (CDs) and to further delineate genotype-phenotype specificity.

METHODS. Sixty-one index patients with CDs were subjected to phenotypic and genotypic characterization. The corneal phenotypes of all patients were assessed by biomicroscopy and documented by slit lamp photography. The BIGH3 gene was amplified exon by exon from constitutional DNA to perform single-strand conformation polymorphism (SSCP) analysis, followed by direct bidirectional sequencing of abnormal conformers.

RESULTS. The phenotypes of CDs were classified as lattice CD in 30 patients, Groenouw type I in 12 (CDGGI), Avellino in 7 (CDA), Reis-Bückler in 8 (CDRB), and Thiel-Behnke in 4 (CDTB). Fifty occurrences of 16 distinct mutations were identified, including 8 novel mutations responsible for lattice type IIIA in three patients (CDLIIA), intermediate type I/IIIA (CDLI/IIIA) in four patients, and atypical CDL with deep deposits in one patient (CDL-deep).

CONCLUSIONS. Disease-causing mutations were identified in 80% of the patients (50/61). All mutations localize in two regions of kerato-epithelin: the amino acid R124 and BIGH3 fasc domain 4. This study also confirms the mutation hot spot at positions R124 and R555 with nearly 50% of the mutations targeting these two amino acids (24/50). In addition the corneal phenotypes induced by changes at R124 and R555 are amino acid specific: R124C in CDLI, R555W and R124S in CDGGI, R124H in CDA, R124L in CRRB, and R555Q in CDTB. In CDLIIIA, CDLI/IIIA, and CDL-deep the genotype-phenotype correlation is domain specific, with all changes occurring at the boundary or within the fasc4 domain.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
The 5q31-linked CDs represent a clinically heterogeneous group of disorders caused by allelic mutations of the BIGH3 (TGFBI) gene, markedly correlating to specific phenotypes. These conditions are inherited as autosomal dominant traits with complete penetrance and incomplete dominance.^{1 2} In a previous report,³ we showed that the occurrence of four distinct heterozygous recurrent mutations was responsible for four specific phenotypes of CD: R555W in granular Groenouw type I CD (CDGGI), R124C in lattice type I CD (CDLI), R124H in Avellino CD (CDA), and R555Q in Thiel-Behnke CD (TBCD) initially described as Reis- Bückler (CDRB; honeycomb type). Soon thereafter, the list of BIGH3-related phenotypes was further extended to the superficial granular CDRB (geographic type)⁴ and to lattice type IIIA CD (CDLIIIA)⁵ in association with R124L and P501T, respectively. In addition to CDRB, two distinct superficial variants of granular dystrophy were described as the result of homozygosity for R555W in the diffuse placoid form² and R124H in the juvenile confluent form.¹ Clinical visual impairment results from progressive loss of corneal transparency secondary to the corneal deposition of aberrantly processed kerato-epithelin mutants.⁶

Histologically, these eight clinical entities can be classified into four categories, based on the type of deposits: hyalin in CDGGI and in the three superficial variants of granular dystrophy; amyloid in CDLI and CDLIIIA; hyalin and amyloid in CDA; and fibrocellular in TBCD. Genetically, all these mutations, except P501T in exon 11, target the two arginine residues at positions 124 and 555 in exons 4 and 12, respectively. This relatively simple picture gained in complexity when four additional mutations were reported in atypical and/or asymmetrical late-onset forms of CDL with deep stromal deposits (CDL-deep) and intermediate type I/IIIA (CDLI/IIIA).^{7 8 9}

The purpose of this study was to further characterize the pathologic molecular characteristics underlying 5q31-linked CDs by reporting novel disease-causing mutations and to clarify the nature of genotype-phenotype correlations.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
The present study was approved by the ethics committee of the University of Lausanne School of Medicine and adhered to the tenets of the Declaration of Helsinki. The corneal phenotype of all index patients was assessed by slit lamp examination and/or review of biomicroscopic photographs by an investigator blinded to the genetic status. The diagnosis was further documented by histopathology, when possible. Genomic DNA of the patients was isolated from blood peripheral leukocytes by organic extraction (Nucleon; Amersham, Amersham, UK). Constitutional DNAs were then subjected to exon-by-exon single-strand conformation polymorphism analysis (SSCP), followed by direct bidirectional sequencing of abnormal conformers, as previously described.³ Later in the study and because of the great number of single-nucleotide polymorphisms that were seen in our patients, direct sequencing of exons 4 and 12 was performed, followed, when no mutation was observed, by direct sequencing of all the other exons in preference to the SSCP approach. Amplification from genomic DNA was performed with the primers and conditions described in Table 1 . For SSCP analysis, aliquots of labeled amplified DNA were added to formamide loading buffer, denatured at 90°C for 5 minutes, and then loaded on a 1x mutation detection enhancement (MDE) gel (FMC Bioproducts, Rockland, ME) in 0.5x Tris-borate electrophoresis buffer (TBE). Electrophoresis (300–600 V) was performed overnight at 4°C and 20°C. DNA bands were revealed by autoradiograph. Direct sequencing of double-stranded PCR products was performed with specific 5' fluoresceinated primers, using one of two sequencers (ALF; Pharmacia, Uppsala, Sweden, or model 310; PE-Applied Biosystems, Foster City, CA), according to the manufacturers’ protocols.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

View larger version (76K): [in this window] [in a new window]   Figure 1. Corneal phenotype as shown by slit lamp examination. (A–C) CDGG1; (B) direct illumination (left) and retro-illumination (right); (D) CDTB; (E) CDRB (arrows: geographic areas); (F) CDA; (G) CDLI; (H) CDLIIIA; and (I) CDLI/IIIA.

View larger version (59K): [in this window] [in a new window]   Figure 2. DNA sequence fluorogram showing the eight novel BIGH3 mutations.

Wild-type: VITNVLQPPANRPQERGDELADSALEIFKQASAFSRASQRSVRLAPVYQKLLERMKH*

Mutation: (V627S) SSPMFCSLQPTDLRKEGMNLQTLRLRSSNKHQRFPGLPRGLCD*

These three patients had a similar history of late-onset progressive loss of vision and recurrent corneal erosions in the fourth and fifth decades of life. Slit lamp examination documented the presence of large, ropy lattice lines in the anterior stroma (Fig. 1I) . Successful surgery was performed in both patients with the N622K mutations (T1913G and T1913A) consisting of lamellar and perforating keratoplasty, respectively. Histologic examination using Congo red staining showed large amyloid deposits in the anterior stroma and notably beneath the Bowman layer. Excimer-mediated therapeutic photoablation was performed in the patient with delG1926.

Intermediate Type CDLI/IIIA.
Another four novel mutations occurred in four presumed unrelated patients from France, (n = 1), Switzerland (n = 2), and Italy (n = 1). All patients had a positive family history of CD. The phenotype was atypical and the age of onset delayed to between the third and fifth decades of life. In two patients from one family from the United States, we observed a C-to-G transversion at position 1660, which generated a T538R mutation. The patients had experienced corneal erosions as teenagers. Histopathology obtained after perforating keratoplasty in a 17-year-old patient confirmed the presence of amyloid deposits predominating subepithelially.

Two index patients were found to have a G-to-A transition at base 1915, resulting in a G623D mutation. The first symptoms were red, painful eyes and photophobia at approximately the third and fourth decades of life, sometimes complicated by corneal erosions. Biomicroscopic examination showed discrete subepithelial and very tiny linear deposits in the anterior stroma, leaving the middle and posterior third of the stroma free of opacifications (Fig. 1H) .

One index patient had an A-to-C transversion at cDNA position 1924, resulting in an H626P mutation. The corneal phenotype was characterized by a dense haze associated with lattice lines. Histology from the first perforating keratoplasty was not available, but analysis of a subsequent corneal button showed multiple fusiform amyloid deposits in the corneal stroma.

The last novel mutation identified consisted of a T-to-G transversion in position 1600, causing an L518R substitution at the protein level in a patient from Italy. This mutation is associated with a severe phenotype characterized by subepithelial and stromal amyloid deposits, as was documented by light microscopy after perforating keratoplasty performed in the patient at age 47.

Finally, the F540 mutation was observed in a patient originating from Arbus, Sardinia, who initially had a diagnosis of CDRB.¹¹ Closer examination of the cornea revealed lattice I/IIIA CD composed of tiny branching subepithelial deposits, leaving the stroma entirely free of lesion. Taking into consideration the delayed age of onset with corneal erosions during the third decade of life, this phenotype should not be classified as CDRB, as previously reported, but rather as a lattice-intermediate form of CD, although there is no available histopathologic proof.

CDL-Deep.
We also identified a T-to-A transversion at nucleotide 1939 resulting in a V631D mutation. This mutation is in total linkage disequilibrium with a C-to-T single nucleotide polymorphism at position 452 (P135P) in all 15 affected members of three Italian families from Andria, Italy. The geographical location of these three families, together with the linkage disequilibrium observed for P135P, suggests that these families share a common ancestor. In this CD, the first clinical symptoms appear between 45 and 50 years of age. Typically, the patients report photophobia, sometimes followed by corneal erosions and, ultimately, visual loss. Clinically, the disease is initially characterized by pre-Descemet stellate deposition associated with round Descemet indentations, producing an irregular appearance of the posterior corneal surface reminiscent of the polymorphic degeneration phenotype.^{12 13} These features could explain the photophobia. Radial lattice lines appear later within the midstroma. This posterior-to-anterior progression of the disease is in contrast to the anterior-to-posterior evolution of typical CDLI. In addition the corneal involvement may be asymmetrical, because of asynchronous onset with unilateral disease, at least, at initial examination. The anterior third of the stroma is mostly intact, as is the corneal epithelium. Penetrating keratoplasty is usually necessary at approximately 50 years of age.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
We reviewed the phenotype and searched for mutations in the BIGH3 gene in 61 families affected with different forms of CD. Using a combined approach based on SSCP and direct sequencing of both strands of all exons, we identified mutations in more than 80% of the families. Mutation hot spots have been reported at positions R124 and R555. Our analysis confirms these previous results: Almost half (24/50) of the mutations identified by us are located at these two amino acids. A worldwide study would probably increase this number. Indeed, we can assume that we have been contacted by medical centers only when the classic mutations have not been observed. Our analysis also indicates a strong correlation between specific mutations at these positions and the phenotype observed in several CD subtypes. These families are divided into two groups: group A in which the phenotype-genotype correlation is amino acid specific (R124 and R5555) and group B in which a continuum of lattice phenotypes is associated with domain-specific mutations (fasc4).

CDLI, CDTB, CDGGI, CDA, and CDRB belong in group A. Among the 42 families with these phenotypes, the disease-causing mutations were identified in 35 (83%) of them. All 11 families with the classic forms of CDLI exhibited the R124C classic mutation. Similar results were observed for CDTB in which the classic R555Q mutation was identified in all four families examined. So far, we have associated CDGGI with only two very specific mutations, R555W and R124S, and only the C124H and the R124L mutations were observed in CDA and CDRB, respectively, although in several families with these two phenotypes, no mutation could be identified. A review of the literature showed that only one other mutation representing most probably a "private" event, was associated with CD from group A: a complex mutation (R124L and T125-E126 on the same chromosome) in a form of CDGGI.¹⁴ No other mutation has so far been reported in association with CDs in group A.

The CDs in group B—CDLIIIA, CDLI/IIIA, and CDL-deep—are more heterogeneous, and molecular analysis detected mutations in 79% (15/19) of the families. Ten different mutations, of which eight are novel, were identified in 19 families with CDLIIIA, CDLI/IIIA, or CDL-deep. In addition, the Sardinian F540 mutation, previously associated with CDRB,³ was clinically reassessed and ultimately reclassified as CDLI/IIIA (late onset during the third decade of life and presence of tiny linear subepithelial deposits). A review of the literature indicates that group B is also associated with the largest variety of mutations: 17 of the 24 mutations reported so far in BIGH3 are associated with a large spectrum of atypical and/or asymmetrical lattice CDs covering a continuum of phenotypes between CDLI and CDLIIIA (CDLI excluded)—the common denominator being a disease-causing mutation in the fasc4 domain of KE.

No mutation was observed in 11 patients, including 4 with lattice I/IIIA, 1 with CDA, and 6 with CDRB. Family history was present in only five of them. The amyloid nature of the deposits was documented histologically in three of four of those with lattice-type CD, of which two had unusual posterior amyloid deposits. Gelsolin mutations responsible for lattice CD type II (D187N and D187Y) were excluded by sequencing in all four patients. The patient with CDA had a phenotype indistinguishable from its BIGH3-related counterpart. The six patients with CDRB were poorly characterized clinically, and none had the diagnosis confirmed histologically. It is possible that mutations in introns or in the promoter could be responsible for several of them. It is also possible, that cases have been misdiagnosed and actually represent phenocopies or even do not represent cases of ADCD5. We are analyzing the available corneal samples from these cases to investigate by immunohistology whether the deposits are made of KE.

From Figure 3 showing the position of the 24 mutations of BIGH3 reported so far, two important regions are discernible: the amino acid R124 and BIGH3 fasc domain 4. The importance of R124 has already been stressed,³ whereas there has not yet been a systematic worldwide study undertaken to analyze the implication of mutations at that position, but from discussion with colleagues conducting investigations in this field, we can estimate that mutations at R124 are present in more than half of all the patients with ADCD5. R124 represents therefore a key position for the generation of intracorneal amyloid deposits. Computer analysis of the structure at that position shows a high hydrophilic region and suggests that substitution of R124 by a cysteine would induce a ß turn in the protein. Additional studies on the structure of KE will help in understanding the role of this region in the making of amyloid.

View larger version (31K): [in this window] [in a new window]   Figure 3. Domains of BIGH3 and position of mutations (black arrows: novel mutations described in the present study).

	Footnotes

 
Supported by Swiss National Foundation Grant 32-053750.98.

Submitted for publication May 25, 2001; revised October 8, 2001; accepted October 24, 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: Francis L Munier, Hôpital Jules Gonin, Unité d’Oculogénétique, Avenue de France 15, CH-1004 Lausanne, Switzerland; francis.munier{at}chuv.hospvd.ch

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

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