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Mutations in PRSS56 are Associated with Primary Congenital Glaucoma

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Abstract Number: 2834

AuthorBlock: Subhabrata Chakrabarti1, Goutham Pyatla1, Cassandre Labelle-Dumais2, Swanand Koli2, Anil K. Mandal3, Sirisha Senthil3, Meha Kabra1, Nicholas Tolman4, Syed Hameed1, Rohit Chandramohan Khanna5, Inderjeet Kaur1, Simon John4, Saidas Nair2,6
1Brien Holden Eye Research Centre, L V Prasad Eye Institute, Hyderabad, Telangana, India; 2Ophthalmology, University of California, San Francisco, California, United States; 3Jasti V Ramanamma Children’s Eye Care Centre, L V Prasad Eye Institute, Hyderabad, Telangana, India; 4Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, Maine, United States; 5Gullapalli Pratibha Rao International Centre for Advancement of Rural Eye Care, L V Prasad Eye Institute, Hyderabad, India; 6Anatomy, University of California, San Francisco, California, United States;

DisclosureBlock: Subhabrata Chakrabarti, None; Goutham Pyatla, None; Cassandre Labelle-Dumais, None; Swanand Koli, None; Anil K. Mandal, None; Sirisha Senthil, None; Meha Kabra, None; Nicholas Tolman, None; Syed Hameed, None; Rohit Chandramohan Khanna, None; Inderjeet Kaur, None; Simon John, None; Saidas Nair, None;

Primary congenital glaucoma (PCG) has been implicated to mutations in three candidate genes (CYP1B1, LTBP2 and TEK). But the overall mutation spectrum across these genes accounts for less than half of all PCG cases globally. Using a large panel of 180 genes that are involved in other forms of glaucoma and anterior segment anomalies, the present study was designed to probe their functional involvement in PCG.

The targeted gene panel (designed using the Ion Ampliseq designer) was used to screen PCG cases that did not harbor homozygous mutations in the PCG-associated genes (n=323) along with ethnically matched normal controls (n=1291). Screening was accomplished by deep sequencing on an Ion Proton platform using the Ion Ampliseq chemistry and the raw data was analyzed by GATK and imported to the Ion Reporter software (version 5.2) and aligned to the hg19 sequence for further analysis. Bioinformatic analysis (SIFT, PolyPhen and Grantham) for individual variations and threshold quality scores with a depth of coverage between 100-500X were considered. The potential mutations were further validated by Sanger sequencing (ABI 3130 XL) using BigDye chemistry. Finally, we functionally characterized the mutated gene utilizing a genetic mouse model.

Among the genes that exhibited mutations in PCG, the PRSS56 exhibited 44 variations in patients. Among these, 8 novel heterozygous nonsynonymous variants consisting of 6 missense and 2 frameshifts leading to protein truncation were observed that collectively accounted for 2.47% (95%CI, 1.26%-4.81%) of all PCG cases. Four of the PRSS56 missense variants co-occurred with heterozygous variants in CYP1B1 and LTBP2, indicating a possible digenic inheritance. All these rare variations were highly conserved across different species, absent in the normal controls and 1000G database and were rarely found in the ExAC cohort. Histological analysis of eyes from mice carrying mutant allele of Prss56 showed ocular drainage tissue specific defects that likely contributes to high intraocular pressure.

The present study suggests the involvement of PRSS56 gene in the pathogenesis of PCG. Additionally, our mouse data points to a possible role of PRSS56 in the maintenance and normal functioning of ocular angle structures.

Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details.
Primary congenital glaucoma is a disease of the eye that occurs largely in children in the developing world. A genetic defect inherited from both the parents’ result in this disease and causes damage to different structures in the front of the eye. So far three genes are known to cause PCG in less than half of the cases worldwide. This study was undertaken to discover and understand the roles of other genes that may be causing PCG. Using a large number of patients who do not carry genetic defects in the known PCG genes, we screened a huge set of genes to find out the responsible gene. We discovered a new gene that shows multiple defects in patients with PCG. When this gene is disabled in mice, they show damages to the frontal structures of the eye similar to PCG patients suggesting that defects in this gene could be one of the potential causes of this disease.