| Project/Area Number |
10470363
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Ophthalmology
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| Research Institution | KINKI UNIVERSITY, SHOOL OF MEDICINE (1999)
Osaka University (1998) |
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Principal Investigator |
SHIMOMURA Yoshikaza KINKI UNIVERSITY, OPHTHALMOLOGY, PROFESSOR, 医学部, 教授 (20162737)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Syushi OSAKA UNIVERSITY, OPHTHALMOLOGY, ASSISTANT PROFESSOR, 医学部, 助手 (80294065)
FUKUDA Masahiko KINKI UNIVERSITY, OPHTHALMOLOGY, ASSISTANT PROFESSOR, 医学部, 講師 (40218938)
前田 直之 大阪大学, 医学部, 助手 (00273623)
渡辺 仁 大阪大学, 医学部, 講師 (60252673)
井上 幸次 大阪大学, 医学部, 助教授 (10213183)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥5,600,000 (Direct Cost: ¥5,600,000)
Fiscal Year 1999: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1998: ¥4,000,000 (Direct Cost: ¥4,000,000)
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| Keywords | gelationous drop-like corneal dystrophy / MISI gene / protein trunction test / Q118X / Avellino corneal dystrophy / keratoepithelin / homozygous / M1S1遺伝子 / 632delA / Q207X / S170X / 遺伝性角膜変性症 / 原因遺伝子座 / 顆粒状角膜変性症 / 第1番染色体短腕 |
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| Research Abstract |
1. Severe corneal dystrophy phenotype caused by homozygous R124H keratoepithelin mutations.
The R124H keratoepithlin mutation is the same mutation recently reported to be responsible for Avellino corneal dystrophy. The homozygous R124H keratoepithelin mutatuins are the cause of the severe variant of granular corneal dystrophy characterized by juvenile-onset and confluent superficial opacity.
2. Identification of the gene responsible for gelatinous drop-like corneal dystrophy.
To localize a gene responsible for gelatinous drop-like corneal dystrophy, we 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 DIS2741 marker locus on the short arm of chromosome 1. Halotype analysis further defined the disease locus within a region of 〜2.6 cM between DIS2890 and DIS2801. Then, we reported DNA sequencing. cDNA cloning and mutational analyses of four deleterious mutations (Q118X, 632delA, Q207X and S107X) in MISI(formerly TROP2 and GA733-1), encoding a gastrointestinal tumour-assosiated antigen. The Q118X mutation was the most common alteration in the gelatinous drop-like corneal dystrophy patients examined, accounting for 33 of 40 disease alleles in our panel of families. Protein expression analysis 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.
3. Rapid detection of MISI mutations by the protein trunction test
Homozygous or compound heterozygous mutations were detected in all patients by a single reaction of the protein trunction test. This result matched those using the polymerase chain reaction fragment length polymorphism and direct sequence analysis. The Q118X mutation was present in 63 of the 70 alleles, accounting for 90% of the disease-associated chromosomes in Japanese patients.
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