The molecular identities of many essential components of melanocytes and the pathways of melanogenesis and melanin synthesis are still unknown, leaving a gap in the scientific community's complete understanding of the makeup and mechanisms of pigmentation and pigmentary disorders. Oculocutaneous albinism (OCA) represents one of the major causes of childhood vision impairment in United States. Clinically, OCA is manifested by hypopigmentation of skin, hair, iris and retinal pigment epithelium, foveal hypoplasia, photoreceptor rod cell deficit, misrouting of the optic nerves at the chiasm, photophobia and nystagmus. At present, mutations in at least 18 loci have been causally linked with OCA, and genetic defects at six loci have been shown to be necessary and sufficient to cause nonsyndromic OCA. Polymorphisms in the nonsyndromic OCA genes also increase susceptibility for skin cancer. However, the known loci/genes do not account for all cases of OCA, which strongly suggests that other loci/genes have yet to be found. The long-term goal of this research is to fully understand the mechanisms of inherited pigmentary disorders and to develop therapeutic agents for the treatment and prevention of OCA. The objective of this particular application is to identify and characterize four novel genetic determinants of OCA. Our hypothesis is that if a mutated gene causes loss of pigmentation, then the normal function of that gene will be necessary for normal melanocytes and/or melanin synthesis. The rationale for the proposed research is that identifying all causative genes for OCA and understanding their normal function is essential for preventing pigmentation loss, as well as the resulting vision lossand potential skin cancer, and for the development of therapeutic agents to treat these impairments. Thus, the proposed research is relevant to that part of NIH's mission that pertains to developing fundamental knowledge that will potentially help to reduce the burdens of human disability. Guided by strong preliminary data, we will test our hypothesis through identification and evaluation of four novel OCA genes. Specifically, the proposed experimental design includes: identification of four genes using massive parallel sequencing, functional evaluation of new OCA proteins in zebrafish embryos, expression studies in the mouse neural crest melanoblasts and in the epidermal and retinal pigment epithelium melanocytes and identification of pathogenic alleles in the US population. The proposed studies will employ contemporary human and zebrafish genetic, molecular, biochemical, psychophysical and cell biology techniques. The proposed work is innovative, as it stems from preliminary data mapping four new OCA loci, which represent a significant increase from the six currently known genes. This work is also innovative in its use of combination of advanced technologies to identify and functionally characterize four novel OCA genes. The proposed research is significant because the completion of these studies will provide molecular insights to fully understanding and being able to effectively treat pigmentation disorder in humans. Results of this work hold great clinicalrelevance, with the potential to improve the molecular epidemiology of pigmentary disorders and aid in genetic diagnosis and counseling.

Public Health Relevance

Through this proposal we seek to identify four novel genes responsible for nonsy- ndromic OCA in humans. Advancing the understanding of the genetic basis of disease; as well as the molecular mechanisms in the melanocytes is a prerequisite to developing therapeutic strategies for pigment loss and vision impairment. Thus the proposed research is relevant to NIH's mission to develop fundamental knowledge that will help reduce the burdens of human disability.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
High Priority, Short Term Project Award (R56)
Project #
Application #
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Tseng, Hung H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cincinnati Children's Hospital Medical Center
United States
Zip Code
Shahzad, Mohsin; Yousaf, Sairah; Waryah, Yar M et al. (2017) Molecular outcomes, clinical consequences, and genetic diagnosis of Oculocutaneous Albinism in Pakistani population. Sci Rep 7:44185
Yousaf, Sairah; Shahzad, Mohsin; Kausar, Tasleem et al. (2016) Identification and clinical characterization of Hermansky-Pudlak syndrome alleles in the Pakistani population. Pigment Cell Melanoma Res 29:231-5
Shaikh, Rehan S; Reuter, Peggy; Sisk, Robert A et al. (2015) Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy. Eur J Hum Genet 23:473-80
Shahzad, Mohsin; Sires Campos, Julia; Tariq, Nabeela et al. (2015) Identification and functional characterization of natural human melanocortin 1 receptor mutant alleles in Pakistani population. Pigment Cell Melanoma Res 28:730-5