Nature Genetics
21, 420 - 423 (1999)
doi:10.1038/7759
Identification of the gene responsible for gelatinous drop-like corneal dystrophyMotokazu Tsujikawa1, 2, Hiroki Kurahashi1, Toshihiro Tanaka3, Kohji Nishida4, Yoshikazu Shimomura2, Yasuo Tano2
& Yusuke Nakamura1, 31
Division of Clinical Genetics, Department of Medical Genetics, Biomedical Research Center, Osaka University Medical School, Japan. 2
Department of Ophthalmology, Osaka University Medical School, Japan. 3
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Japan. 4
Department of Ophthalmology, Kyoto Prefectural University of Medicine, Japan.
Correspondence should be addressed to Yusuke Nakamura yusuke@ims.u-tokyo.ac.jpGelatinous drop-like corneal dystrophy (GDLD; OMIM 204870) is an autosomal recessive disorder characterized by severe corneal amyloidosis leading to blindness1,
2,
3,
4, with an incidence of 1 in 300,000 in Japan5. Our previous genetic linkage study localized the gene responsible to a 2.6-cM interval on chromosome 1p (ref. 6). Clinical manifestations, which appear in the first decade of life, include blurred vision, photophobia and foreign-body sensation. By the third decade, raised, yellowish-grey, gelatinous masses severely impair visual acuity, and lamellar keratoplasty is required for most patients5. Here we report DNA sequencing, cDNA cloning and mutational analyses of four deleterious mutations (Q118X, 632delA, Q207X and S170X) in M1S1 (formerly TROP2 and GA733-1), encoding a gastrointestinal tumour-associated antigen. The Q118X mutation was the most common alteration in the GDLD patients examined, accounting for 33 of 40 (82.5%) disease alleles in our panel of families. Protein expression anaysis revealed aggregation of the mutated, truncated protein in the perinuclear region, whereas the normal protein was distributed diffusely in the cytoplasm with a homogenous or fine granular pattern. Our successful identification of the gene that is defective in GDLD should facilitate genetic diagnosis and potentially treatment of the disease, and enhance general understanding of the mechanisms of amyloidosis.
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