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Molecular characterization of FZD4, LRP5, and TSPAN12 in familial exudative vitreoretinopathy : 가족성삼출유리체망막병증에서 FZD4, LRP5, TSPAN12의 분자유전학적 연구

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Authors

서수현

Advisor
박성섭
Major
의과대학 의학과
Issue Date
2014-02
Publisher
서울대학교 대학원
Keywords
Familial exudative vitreoretinopathyFZD4LRP5TSPAN12
Description
학위논문 (석사)-- 서울대학교 대학원 : 의학과, 2014. 2. 박성섭.
Abstract
Introduction: Familial exudative vitreoretinopathy (FEVR) is a rare hereditary disorder characterized by failure of peripheral retinal vascularization. Clinical manifestation of the disease can be variable, ranging from nonsymptomatic vascular anomalies in the peripheral retina to bilateral retinal detachments with blindness. FEVR is genetically heterogeneous, and it is found in various modes of inheritance. Autosomal dominant inheritance is the most common form in FEVR and FZD4, LRP5, and TSPAN12 are known to be associated with the disease. These genes are essential components of wingless (Wnt) pathway and pathogenic mutations affecting the function of these genes result in abnormal retinal vascular formation. In the Korean population, there had not been any report on the molecular identification of FEVR. We performed mutation screening for FZD4, LRP5 and TSPAN12 in patients with clinical diagnosis of FEVR. Identification of the molecular spectrum in Korean FEVR patients will be helpful in establishing an effective testing strategy, as well as providing informative genetic counseling for the family members of the proband.
Methods: Mutational studies were carried out in 42 unrelated patients with diagnosis of FEVR during 2008 to 2012 at Seoul National University Hospital. Diagnosis of FEVR was established by ophthalmic examinations. All patients had been previously screened for NDP mutation, which were found to be negative. Sequencing analyses for three causal genes (FZD4, LRP5, and TSPAN12) were performed. Gross deletions and duplications were screened via Multiplex Ligation-dependent Probe Amplification.
Results: Two previously reported mutations (c.313A>G, c.1282_1285delGACA), four novel pathogenic mutations (c.160C>T, c.539_540delAG, c.653_676dup24, c.1210_1211delTT) and a whole gene deletion of FZD4 were found in 11 patients. Three novel missense variants (c.456C>G, c.470T>C, c.676T>A) were also found. A previously reported mutation of c.3361A>G in LRP5 was detected in three patients, and two novel missense variants (c.731C>G, c.4098C>G) were detected in two patients. In case of TSAPN12, a previously reported mutation, c.212_218delGCTGTTT was found in one patient, and three more novel missense variants (c.56T>G, c.194C>T, c.484G>A) were found in another three patients.
Conclusions: In this study, we have identified four known mutations, four novel pathogenic mutations and a whole gene deletion in 15 patients. In cases of novel missense variants detected in nine patients, five of them were considered as pathogenic according to the predictions by in-silico analyses and allele frequencies in normal control group. Among 20 patients with pathogenic mutation detected, 13 were due to FZD4 mutations, showing the largest proportion of this gene in attribution to the autosomal dominant FEVR (13/42 patients, 31.0%). By applying this result, testing strategy of FEVR starting with screening for FZD4 mutations can be applied in the clinical fields. Genetic counseling of asymptomatic family members as well as proband will be helpful in further management and prevention of the disease progression.
Language
English
URI
https://hdl.handle.net/10371/132675
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