The studies proposed in this application will expand our understanding of lens biology through functional analysis of causal mutations liable for cataractogenesis. This proposal employs two specific aims to accomplish the proposed goals. In the first aim, we will identify genes that harbor cataract causing mutations using a combination of traditional genetics tools and a more recent exon capture technique coupled with next generation sequencing. Our methodology represents a powerful paradigm to unveil mutations that trigger cataractogenesis. In the second aim, we will expand on our recent discovery, that loss of function mutations in the novel autophagy component FYCO1 cause cataract, by elucidating its physiological significance in lens development and maintenance of lens transparency and examining the possible role of autophagy in cataractogenesis. Establishment of autophagy as an essential pathway for the maintenance of lens transparency will not only advance our knowledge of lens function, it will truly reveal a new paradigm in the field of lens biology that will provide a basis for multiple new and important lens studies.

Public Health Relevance

This application will investigate the functional significance of causal mutations associated with congenital cataracts and their potential role in the development and/or maintenance of the human lens transparency. Successful execution of this proposal will lead to development of better treatments and therapeutic approaches for a debilitating disorder that is the principal cause of visual impairment in children worldwide and is responsible for about one third of cases of blindness in infants.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Study Section
Biology of the Visual System Study Section (BVS)
Program Officer
Araj, Houmam H
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Johns Hopkins University
Schools of Medicine
United States
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Khan, Shahid Y; Ali, Muhammad; Kabir, Firoz et al. (2018) Identification of novel transcripts and peptides in developing murine lens. Sci Rep 8:11162
Khan, Shahid Y; Ali, Muhammad; Kabir, Firoz et al. (2018) Proteome Profiling of Developing Murine Lens Through Mass Spectrometry. Invest Ophthalmol Vis Sci 59:100-107
Khan, Shahid Y; Kabir, Firoz; M'Hamdi, Oussama et al. (2018) Whole genome sequencing data for two individuals of Pakistani descent. Sci Data 5:180174
Chen, Jianjun; Wang, Qiwei; Cabrera, Patricia E et al. (2017) Molecular Genetic Analysis of Pakistani Families With Autosomal Recessive Congenital Cataracts by Homozygosity Screening. Invest Ophthalmol Vis Sci 58:2207-2217
Khan, Shahid Y; Vasanth, Shivakumar; Kabir, Firoz et al. (2016) FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1. Nat Commun 7:10953
Khan, Shahid Y; Hackett, Sean F; Riazuddin, S Amer (2016) Non-coding RNA profiling of the developing murine lens. Exp Eye Res 145:347-351
Jiao, Xiaodong; Kabir, Firoz; Irum, Bushra et al. (2016) A Common Ancestral Mutation in CRYBB3 Identified in Multiple Consanguineous Families with Congenital Cataracts. PLoS One 11:e0157005
Irum, Bushra; Khan, Shahid Y; Ali, Muhammad et al. (2016) Mutation in LIM2 Is Responsible for Autosomal Recessive Congenital Cataracts. PLoS One 11:e0162620
Irum, Bushra; Khan, Shahid Y; Ali, Muhammad et al. (2016) Deletion at the GCNT2 Locus Causes Autosomal Recessive Congenital Cataracts. PLoS One 11:e0167562
Khan, Shahid Y; Hackett, Sean F; Lee, Mei-Chong W et al. (2015) Transcriptome Profiling of Developing Murine Lens Through RNA Sequencing. Invest Ophthalmol Vis Sci 56:4919-26

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