Alternative titles; symbols
SNOMEDCT: 419039007; ORPHA: 98962; DO: 0080530;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q31.1 | Corneal dystrophy, Groenouw type I | 121900 | Autosomal dominant | 3 | TGFBI | 601692 |
A number sign (#) is used with this entry because of evidence that Groenouw type I granular corneal dystrophy (CDGG1) is caused by heterozygous mutation in the gene encoding keratoepithelin (TGFBI; 601692) on chromosome 5q31.
Several other forms of autosomal dominant corneal dystrophy are caused by mutations in the TGFBI gene, including Reis-Bucklers corneal dystrophy (CDRB; 608470), Thiel-Behnke corneal dystrophy (CDTB; 602082), lattice type I corneal dystrophy (CDL1; 122200), lattic type IIIA corneal dystrophy (CDL3A; 608471), and Avellino corneal dystrophy (ACD; 607541).
Groenouw type I, or granular type I, corneal dystrophy (CDGG1) is an autosomal dominant disorder characterized by irregular aggregates of hyaline material in the corneal stroma. These aggregates can cause significant visual disturbance and may require corneal transplantation for restoration of visual acuity or for relief from recurrent corneal erosions (summary by Stone et al., 1994).
Granular corneal dystrophy was described by Groenouw (1890, 1898, 1917). Groenouw (1933) described the disorder in an autosomal dominant pattern through 4 generations. In the macular, granular, and lattice dystrophies, the changes are in the corneal stroma rather than the epithelium. In the granular and the lattice types, the histologic findings are hyaline degeneration with absence of acid mucopolysaccharide deposition. See corneal dystrophy, macular type (Groenouw type II; 217800). The opacity in the granular type consists of grayish white granules with sharp borders mainly in a disc-shaped area in the center of the cornea. The peripheral cornea is usually clear and the cornea between granules is clear. Hyaline material separates the epithelium from Bowman membrane. Although this type can have its onset in the first 10 years, visual acuity during childhood is usually good.
Forsius (1981) stated that he had observed a Finnish family in which onset was between age 15 and 20 years; see Forsius et al. (1983). Although Forsius (1981) suggested that this might represent a special 'Finnish type,' with a very mild course and good prognosis, Moller (1989, 1991) concluded that the disorder did not differ from that in patients in other countries or from the description by Groenouw (1933).
Moller (1989) concluded that Reis-Bucklers corneal dystrophy may be the same entity as Groenouw type I granular corneal dystrophy.
In an offspring of a first-cousin marriage with both parents mildly affected, Moller and Ridgway (1990) observed severe granular corneal dystrophy which they suggested might represent the homozygous state. Because of early onset and severe course, 2 corneal grafts in each eye were required before the age of 17. Family I, studied by Moller (1990), comprised 94 patients in 7 generations, of whom 75 were alive at the time of study. Abnormalities were confined to the eye. All patients developed cataract late in life. Corneal grafts remained clear.
Moller (1990) reported a total of 5 Danish families with Groenouw type I granular corneal dystrophy, all showing autosomal dominant inheritance.
Okada et al. (1998) described a Japanese family with affected members in at least 5 generations. Three members were the offspring of a consanguineous marriage of 2 affected individuals and presented with a severe placoid type of corneal dystrophy; these members were homozygous for a mutation in the TGFBI gene (R555W; 601692.0001). The phenotype of the other affected members, who were heterozygous for the R555W mutation, was typical granular corneal dystrophy.
The transmission pattern of CDGG1 in the Danish families reported by Moller (1990) was consistent with autosomal dominant inheritance.
Dinh et al. (1999) reviewed 50 excimer laser phototherapeutic keratectomy (PTK) procedures. Preoperative diagnoses included Reis-Bucklers dystrophy, granular dystrophy, anterior basement membrane dystrophy (121820), lattice dystrophy (see 122200), and Schnyder crystalline dystrophy (121800). The authors concluded that PTK can restore and preserve useful visual function for a significant period of time in patients with anterior corneal dystrophies. Even though corneal dystrophies are likely to recur eventually after PTK, successful re-treatment with PTK is possible.
In a large 7-generation Danish pedigree, Eiberg et al. (1993, 1994) found by linkage analysis that the CDGG1 gene is located on 5q between interleukin-9 (146931) at 5q22-q32 and D5S119 at 5q31.3-q33.3. Study of 2 smaller pedigrees with a milder form of the disease, both independent of the large pedigree, gave positive lod scores and, thus, no indication of heterogeneity of the disease. Stone et al. (1994) likewise mapped the gene for granular corneal dystrophy to 5q. Two other seemingly phenotypically distinct forms of corneal dystrophy were mapped to the same region: lattice corneal dystrophy type I and ACD, in which both lattice corneal dystrophy type I and granular dystrophy coexist in the same patients (Folberg et al., 1988). Lattice, granular, and Avellino dystrophies all cause significant visual disturbances and may eventually require corneal transplantation for restoration of visual acuity or relief from recurrent corneal erosions.
Duke-Elder and Leigh (1965) suggested that some of the corneal dystrophies are not independent entities but rather phenotypic variations in the expression of a single gene. This suggestion is supported by the findings that both lattice corneal dystrophy type I and granular corneal dystrophy map to the same chromosomal region on 5q and are observed together in the same pedigree in the case of ACD. Similarly, 2 types of macular corneal dystrophy distinguished on phenotypic grounds appear to be due to defects in the same gene because both disorders map to the same site on 16q; see 217800.
Munier et al. (1997) generated a YAC contig of the linked area and, following cDNA selection, recovered the gene that encodes keratoepithelin. In 6 families they identified missense mutations. All detected mutations occurred at the CpG dinucleotide of 2 arginine codons: R555W in a CDGG1 family (601692.0001), R555Q in a CDTB family (601692.0002), R124C in 2 CDL1 families (601692.0003), and R124H in 2 ACD families (601692.0004). As the last 2 sequences are characterized by amyloid deposits, Munier et al. (1997) concluded that the R124-mutated keratoepithelin forms amyloidogenic intermediates that precipitate in the cornea. The observations established a common molecular origin of the four 5q31-linked corneal dystrophies.
In a Japanese family in which members over 5 generations had GDGG1, Okada et al. (1998) found that 3 members were the offspring of a consanguineous marriage of 2 affected individuals and presented with a severe placoid type of corneal dystrophy. The phenotype of other affected members was typical granular corneal dystrophy. The severely affected family members were homozygous for the R555W mutation in the TGFBI gene, whereas the others were heterozygous for the mutation. Okada et al. (1998) claimed that granular corneal dystrophy was the first ophthalmic disease in which homozygosity for a dominant allele had been molecularly identified.
Kim et al. (2002) studied the molecular properties of wildtype and mutant BIGH3 proteins: specifically, the arg124-to-leu (R124L; 601692.0007) (CDRB), R124C (CDL1), R124H (ACD), R555W (CDGG1), and R555Q (CDTB) mutations commonly found in 5q31-linked corneal dystrophies. They found that the mutations did not significantly affect the fibrillar structure, interactions with other extracellular matrix proteins, or adhesion activity in cultured corneal epithelial cells. In addition, the mutations apparently produced degradation products similar to those of wildtype BIGH3. BIGH3 polymerizes to form a fibrillar structure and strongly interacts with type I collagen (see 120150), laminin (see 150320), and fibronectin (135600). Mutations did not significantly affect these properties. Kim et al. (2002) concluded that mutant forms of BIGH3 might require other cornea-specific factors to form the abnormal accumulations seen in 5q31-linked corneal dystrophies.
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Duke-Elder, S., Leigh, A. G. Diseases of the Outer Eye. Part 2. In: Duke-Elder, S. (ed): System of Ophthalmology. Vol. VIII. St. Louis: C. V. Mosby 1965. Pp. 921-976.
Eiberg, H., Moller, H. U., Berendt, I., Mohr, J. Assignment of granular corneal dystrophy Groenouw type I (CDGG1) to chromosome 5q: close linkage to IL9 and D5S120. (Abstract) Human Genome Mapping Workshop 93, Kobe, Japan 1993. P. 10.
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