| Title:
|
COL18A1 mutation identified as cause of iridocorneal angle closure: first identification of a causative gene for this major PACG presentation
|
| Author(s):
|
Fatemeh Suri, Elahe Elahi, Shahin Yazdani, Iman Safari, Paniz Rasooli, Mohammad Reza Jafarinasab.
|
| Presentation Type:
|
Oral
|
| Subject:
|
Molecular Biology and Genetics
|
| Others:
|
|
|
Presenting Author:
|
|
| Name:
|
Fatemeh Suri
|
| Affiliation :(optional)
|
Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
|
| E mail:
|
fatemehsuri@gmail.com
|
| Phone:
|
|
|
Mobile: |
09128213692
|
|
Abstract (Max 200 words)
|
|
| Purpose:
|
Glaucoma is the major cause of irreversible blindness worldwide. Primary angle closure glaucoma (PACG) is one of the three major forms of glaucoma wherein angle closure in the anterior segment of the eye hinders aqueous humor outflow and causes elevated intraocular pressure. Primary angle closure suspect (PACS) and primary angle closure (PAC) refer to conditions wherein there are indications of angle closure, in the absence of glaucomatous optic neuropathy. PACG is most common in the Far East; it may be the most prevalent form of glaucoma worldwide. Various evidences suggest that genetic factors are involved in the etiology of PACG. Although association studies and candidate gene approaches have implicated possible roles for several genes, a PACG causing gene or a strongly associated locus in humans has not yet been identified. Here, we describe genetic analysis of a pedigree with at least ten PACS, PAC, or PACG diagnosed members for identification of PACG causing gene.
|
| Methods:
|
Whole genome linkage analysis with SNP markers was performed to identify a disease locus in the pedigree. Exome sequencing was initially performed using the DNA of three members of the pedigree, and subsequently on the DNA of 7 additional members. Candidate variations were screened for segregation in the pedigree and subsequently in 400 unrelated healthy Iranians by Sanger sequencing and allele-specific PCR protocols respectively.
|
| Results:
|
Analysis under the dominant model identified a 2.1Mb locus with logarithm of odds (LOD) score of 1.627 on chromosome 21q22.3. Analysis of exome sequences showed that c.550G>A in COL18A1 was the only sequence variation in the entire genome with a minimum allele frequency of ≤ 0.03 and absent in Iranian controls that was present in all affected individuals.
|
| Conclusion:
|
Segregation analysis, screenings of control individuals, bioinformatics predictions, available phenotypic data on mouse knockouts, the role of COL18A1 in the etiology of Knobloch syndrome that is consistently accompanied by optic anomalies, available functional data on the encoded protein, and the recognized role of collagens and the extracellular matrix in glaucoma pathogenesis all support the proposition that the observed COL18A1 mutation is cause of the angle closure conditions in the pedigree.
|
| Attachment:
|
|