Abstract

Keratoconus (KC) is the most common corneal ectatic disorder affecting >300,000 people in the US. KC normally has its onset in adolescence, progressively worsening through the third to fourth decades of life. KC patients report significant impaired vision-related quality of life. Genetic factors play an important role in KC pathogenesis. To identify novel genes in familial KC patients, we performed whole exome and genome sequencing in a four-generation family. We identified potential variants in the PPIP5K2 and PCSK1 genes. Using in vitro cellular model and in vivo gene-trap mouse model, we found critical evidence to support the role of PPIP5K2 in normal corneal function and KC pathogenesis. The gene-trap mouse showed irregular corneal surfaces and pathological corneal thinning resembling KC. For the first time, we have integrated corneal tomography and pachymetry mapping into characterization of mouse corneal phenotypes which could be widely implemented in basic and translational research for KC diagnosis and therapy in the future.

Details

Title
PPIP5K2 and PCSK1 are Candidate Genetic Contributors to Familial Keratoconus
Author
Mariam Lofty Khaled 1 ; Bykhovskaya, Yelena 2 ; Gu, Chunfang 3 ; Liu, Alice 4 ; Drewry, Michelle D 5 ; Chen, Zhong 5 ; Mysona, Barbara A 6 ; Parker, Emily 5   VIAFID ORCID Logo  ; McNabb, Ryan P 4   VIAFID ORCID Logo  ; Yu, Hongfang 5 ; Lu, Xiaowen 5 ; Wang, Jing 5 ; Li, Xiaohui 7 ; Al-Muammar, Abdulrahman 8 ; Rotter, Jerome I 7   VIAFID ORCID Logo  ; Porter, Louise F 9 ; Estes, Amy 10 ; Watsky, Mitchell A 6 ; Smith, Sylvia B 11 ; Xu, Hongyan 12 ; Abu-Amero, Khaled K 8 ; Kuo, Anthony 4 ; Shears, Stephen B 3 ; Rabinowitz, Yaron S 2 ; Liu, Yutao 13   VIAFID ORCID Logo 

1  Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA; Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt 
2  Department of Surgery and Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA 
3  Inositol Signaling Group, Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA 
4  Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA 
5  Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA 
6  Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA, USA 
7  Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics and Medicine at Harbor-UCLA, Torrance, CA, USA 
8  Department of Ophthalmology, Glaucoma Research Chair, King Saud University, Riyadh, Saudi Arabia 
9  Department of Eye and Vision Science, University of Liverpool, and St Paul’s Eye Unit, Royal Liverpool Hospital, Liverpool, UK 
10  James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA, USA; Department of Ophthalmology, Augusta University, Augusta, GA, USA 
11  Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA, USA; Department of Ophthalmology, Augusta University, Augusta, GA, USA 
12  Department of Population Health Science, Augusta University, Augusta, GA, USA 
13  Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA, USA; Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, USA 
Pages
1-16
Publication year
2019
Publication date
Dec 2019
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-019-55866-5
ProQuest document ID
2328313168
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.