Alternative titles; symbols
SNOMEDCT: 419900000; ORPHA: 98957; DO: 0060449;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p32.1 | Corneal dystrophy, gelatinous drop-like | 204870 | Autosomal recessive | 3 | TACSTD2 | 137290 |
A number sign (#) is used with this entry because of evidence that gelatinous drop-like corneal dystrophy (GDLD) can be caused by homozygous or compound heterozygous mutation in the M1S1 gene (TACSTD2; 137290), which encodes the monoclonal antibody-defined, tumor-associated antigen GA733-1, on chromosome 1p32.
Gelatinous drop-like corneal dystrophy is an autosomal recessive disorder characterized by severe corneal amyloidosis leading to blindness. Clinical manifestations, which appear in the first decade of life, include blurred vision, photophobia, and foreign-body sensation. By the third decade, raised, yellowish-gray, gelatinous masses severely impair visual acuity, and lamellar keratoplasty is required for most patients (summary by Tsujikawa et al., 1999).
Corneal amyloidosis is characterized by central raised gelatinous masses, making the surface of the cornea resemble a mulberry. Lewkojewa (1930) reported 2 affected brothers. In the kindred of Kirk et al. (1973), 3 sibs were affected while 4 other sibs and the parents and other relatives were unaffected. Stock and Kielar (1976) reported corneal amyloidosis in 2 brothers and a sister. Cataracts were present in 2 of the 3.
Mondino et al. (1981) concluded that the amyloid deposits of this disorder differ from those of lattice corneal dystrophy. Others (e.g., Gorevic et al., 1991), however, classified this disorder as type III lattice corneal dystrophy (systemic amyloidosis is associated only with type II, the Finnish form (105120); types I (122200) and II are autosomal dominant.) The 3 types are distinguished on clinical and histologic grounds.
This form of corneal amyloidosis appears to be more frequent in Japan (Hida et al., 1987), where it was described by Nakaizumi (1914) and named gelatinous drop-like corneal dystrophy. The cornea is involved in a thick lattice. Amyloid deposition is marked in Bowman layer and epithelium and moderate in the anterior stroma with no location in the conjunctiva and adnexa and no systemic amyloid.
Shimazaki et al. (1995) investigated the natural history of the disorder in 7 Japanese patients with familial subepithelial amyloidosis of the cornea (FSA). Four patients were followed for more than 25 years, with a mean follow-up period of 20.6 years. A total of 35 keratoplasties were performed in the 7 patients, followed by severe recurrence of disease in each patient. Histopathologic studies demonstrated amyloid deposition between the basal cell of the epithelium and Bowman layer in the early phase of recurrence.
From the frequency of parental consanguinity, Fujiki et al. (1986) estimated the prevalence of GDLD to be about 1 in 31,546 in Japan, which means that about 3,500 persons aged 5 to 79 are affected.
To localize the gene responsible for GDLD, Tsujikawa et al. (1998) performed linkage analysis of 10 consanguineous Japanese families with a total of 13 affected members. Homozygosity mapping provided a maximum lod score of 9.80 at the D1S2741 marker locus on 1p. Haplotype analysis further defined the disease locus within a region of approximately 2.6 cM between D1S2890 and D1S2801.
The fact that GDLD is much more frequent in Japan and only a few cases of the disorder had been reported in other countries suggested a founder mutation in strong linkage disequilibrium with close markers in the 1p31 region. In fact, Tsujikawa et al. (1998) found disequilibrium between D1S220 and GDLD, indicating that the 2 loci are in close proximity. Using linkage analysis, Tsujikawa et al. (1999) mapped GDLD drop-like corneal dystrophy to a 400-kb critical region that included M1S1 (137290).
Ren et al. (2002) extended molecular studies of GDLD to patients with diverse ethnic backgrounds. They performed linkage analyses in 8 unrelated GDLD families from India, the U.S., Europe, and Tunisia. In 7 of these families, the disease locus mapped to a 16-cM interval on the short arm of chromosome 1 that included the region of the M1S1 gene.
The transmission pattern of GDLD in the families reported by Tsujikawa et al. (1999) was consistent with autosomal recessive inheritance.
Tsujikawa et al. (1999) identified 4 mutations in the M1S1 gene (137290.0001-137290.0004) in homozygous or compound heterozygous state in 26 affected members of 20 Japanese GDLD families. The most common mutation was Q118X (137290.0001), which was found in 82.5% (33/40) of the disease alleles.
Ren et al. (2002) sequenced a 1.2-kb fragment containing the entire coding region of the M1S1 gene in patients with GDLD from diverse ethnic backgrounds (US, India, Europe, Tunisia). Seven novel mutations were identified in 6 families and 2 unrelated individuals. No sequence abnormalities were detected in a single family in which the GDLD locus was also excluded from the M1S1 region by linkage analysis. These findings demonstrated allelic and locus heterogeneity for GDLD.
Ha et al. (2003) reported a novel mutation in the M1S1 gene (137290.0007) that resulted in GDLD in a Vietnamese family. Sequencing the M1S1 gene revealed a deletion of a 12-bp fragment from nucleotide position 772 to 783 and the insertion of nucleotide T in place of the missing fragment.
Fujiki, K., Kanai, A., Nakajima, A. Gelatinous drop-like corneal dystrophy in Japanese population. (Abstract) 7th International Congress of Human Genetics, Berlin 1986. Pp. 248-249.
Gorevic, P. D., Munoz, P. C., Gorgone, G., Purcell, J. J., Jr., Rodrigues, M., Ghiso, J., Levy, E., Haltia, M., Frangione, B. Amyloidosis due to a mutation of the gelsolin gene in an American family with lattice corneal dystrophy type II. New Eng. J. Med. 325: 1780-1785, 1991. [PubMed: 1658654] [Full Text: https://doi.org/10.1056/NEJM199112193252505]
Ha, N. T., Chau, H. M., Cung, L. X., Thanh, T. K., Fujiki, K., Murakami, A., Kanai, A. A novel mutation of M1S1 gene found in a Vietnamese patient with gelatinous droplike corneal dystrophy. Am. J. Ophthal. 135: 390-393, 2003. [PubMed: 12614764] [Full Text: https://doi.org/10.1016/s0002-9394(02)01952-9]
Hida, T., Proia, A. D., Kigasawa, K., Sanfilippo, F. P., Burchette, J. L., Jr., Akiya, S., Klintworth, G. K. Histopathologic and immunochemical features of lattice corneal dystrophy type III. Am. J. Ophthal. 104: 249-254, 1987. [PubMed: 3498367] [Full Text: https://doi.org/10.1016/0002-9394(87)90412-0]
Kirk, H. Q., Rabb, M., Hattenhauer, J., Smith, R. Primary familial amyloidosis of the cornea. Trans. Am. Acad. Ophthal. Otolaryng. 77: OP411-OP417, 1973. [PubMed: 4126001]
Lewkojewa, E. F. Ueber einen Fall primaerer Degenerationamyloidose der Kornea. Klin. Monatsbl. Augenheilkd. 85: 117-137, 1930.
Mondino, B. J., Rabb, M. F., Sugar, J., Sundar Raj, C. V., Brown, S. I. Primary familial amyloidosis of the cornea. Am. J. Ophthal. 92: 732-736, 1981. [PubMed: 7030080] [Full Text: https://doi.org/10.1016/s0002-9394(14)74671-9]
Nakaizumi, K. A rare case of corneal dystrophy. Acta Soc. Ophthal. Jpn. 18: 949-950, 1914.
Ramsey, M. S., Fine, B. S., Cohen, S. W. Localized corneal amyloidosis. Am. J. Ophthal. 73: 560-565, 1972. [PubMed: 4537070]
Ren, Z., Lin, P.-Y., Klintworth, G. K., Iwata, F., Munier, F. L., Schorderet, D. F., El Matri, L., Theendakara, V., Basti, S., Reddy, M., Hejtmancik, J. F. Allelic and locus heterogeneity in autosomal recessive gelatinous drop-like corneal dystrophy. Hum. Genet. 110: 568-577, 2002. [PubMed: 12107443] [Full Text: https://doi.org/10.1007/s00439-002-0729-z]
Shimazaki, J., Hida, T., Inoue, M., Saito, H., Tsubota, K. Long-term follow-up of patients with familial subepithelial amyloidosis of the cornea. Ophthalmology 102: 139-144, 1995. [PubMed: 7831029] [Full Text: https://doi.org/10.1016/s0161-6420(95)31067-6]
Stock, E. L., Kielar, R. A. Primary familial amyloidosis of the cornea. Am. J. Ophthal. 82: 266-271, 1976. [PubMed: 949079] [Full Text: https://doi.org/10.1016/0002-9394(76)90432-3]
Tsujikawa, M., Kurahashi, H., Tanaka, T., Nishida, K., Shimomura, Y., Tano, Y., Nakamura, Y. Identification of the gene responsible for gelatinous drop-like corneal dystrophy. Nature Genet. 21: 420-423, 1999. [PubMed: 10192395] [Full Text: https://doi.org/10.1038/7759]
Tsujikawa, M., Kurahashi, H., Tanaka, T., Okada, M., Yamamoto, S., Maeda, N., Watanabe, H., Inoue, Y., Kiridoshi, A., Matsumoto, K., Ohashi, Y., Kinoshita, S., Shimomura, Y., Nakamura, Y., Tano, Y. Homozygosity mapping of a gene responsible for gelatinous drop-like corneal dystrophy to chromosome 1p. Am. J. Hum. Genet. 63: 1073-1077, 1998. [PubMed: 9758629] [Full Text: https://doi.org/10.1086/302071]