About our work
The Pediatric, Developmental and Genetic Ophthalmology Section, headed by Brian P. Brooks, MD, PhD., seeks to understand the genetic, molecular and developmental basic of inherited eye diseases that affect children and to evaluate novel approaches to therapy for these conditions. The two main areas of research at present are: 1) the genetics of uveal coloboma and 2) treatments for oculocutaneous albinism. This section is part of the NEI Ophthalmic Genetics and Visual Function Branch.
Uveal coloboma is a potentially blinding, developmental abnormality of the eye caused by failure of the optic fissure to close during the 5th week of human gestation. The purpose of our clinical and basic research is to better understand the genetic and developmental mechanisms of optic fissure closure. Our short-term goal is to provide better diagnostics and genetic counseling for our patients; our long-term goal is to find preventions and/or treatments for this condition. Our approach is summarized in the following figure:
Our clinical studies are focused on understanding the coloboma phenotype more deeply, including deep ocular and systemic phenotyping, where appropriate, leveraging the unparalleled resources of the NIH Clinical Center. Genetic analysis using the tools of whole exome/whole genome sequencing are being undertaken to identify causative genes and improve genetic counseling for patients with coloboma see and what, if any, associated clinical conditions they might have.
A complementary approach to understanding genes important in optic fissure closure in humans is the laboratory use of animal models. We use mouse and zebrafish models to better understand how genes are regulated during the course of optic fissure closure. Specific mutant mouse strains are also being investigated to discover genes that might cause coloboma in humans. These studies have identified that two zinc finger proteins, Nlz1 and Nlz2, regulate optic fissure closure, perhaps through a Pax2-dependent mechanism. We are currently trying to understand the developmental role of these and other genes from our screen in the normal process of optic fissure closure and to search for causative mutations in humans.
Oculocutaneous albinism (OCA) is an inherited disease characterized by reduced melanin pigment in the hair, skin and eyes. Patients with OCA have reduced best-corrected visual acuity, likely due to developmental eye defects such as foveal hypoplasia and abnormal routing of ganglion cell axons at the level of the optic chiasm. The precise reason why changes in melanin pigmentation during development result in developmental eye abnormalities is unclear. However, we hypothesize that improving the process of melanin production may secondarily improve the visual potential of patients with albinism, if given during an appropriate developmental window.
To this end, we are trying to identify compounds that might improve melanin pigmentation in laboratory models and, therefore, be candidates for pilot clinical trials. For example, we have found that treatment of a mouse model of one form of albinism, OCA1b, with an FDA-approved drug, nitisinone, improves eye and fur pigmentation. We are conducting a pilot, proof-of-concept clinical trial of this drug in five adults with OCA1b. We are also evaluating whether nitisinone improves melanin pigmentation in mouse models of other forms of albinism. Lastly, in collaboration with the National Center for Advanced Therapeutics (NCATS), we are screening pharmaceutical libraries for compounds that may activate the rate-limiting enzyme in melanin synthesis, tyrosinase.
Liu C, Widen SA, Williamson KA, Ratnapriya R, Gerth-Kahlert C, Rainger J, Alur RP, Strachan E, Manjunath SH, Balakrishnan A, Floyd JA, UK 10K Consortium, Li T, Waskiewicz A, Brooks BP, Lehmann OJ, Fitzpatrick DR, Swaroop A.A secreted WNT-ligan binding domain of FZD5 generated by a frameshift mutation causes autosomal dominant coloboma.Hum Mol Genet. 25: 1382-91 (2016).
Dutta S, Sriskanda S, Boobalan E, Alur RP, Elkalhoun A, Brooks BP.Nlz1 is required for cilia formation in zebrafish embryogenesis.Dev Biol.406:203-211 (2015).
Babcock HE, Dutta S, Alur RP, Brocker C, Vasiliou V, Vitale S, Abu-Asab M, Brooks BP.Aldh7a1 regulates eye and limb development in zebrafish.PLoS ONE. 9:e101782 (2014). PMCID: PMC4086958.
Huynh N, Blain D, Glaser T, Doss L, Zein WM, Lang DM, Baker EH, Hill S, Brewer CC, Kopp JB, Bardakjian TM, Maumenee IH, Bateman BJ, Brooks BP.Systemic diagnostic testing in patients with apparently isolated uveal coloboma.Am J Ophthalmol.156:1159-68 (2013).PMCID: PMC4167417.
Huynh N, Brooks BP.Uveal coloboma.JAMA Ophthalmol.131:1274 (2013).PMID: 24114131
Dolinska MB, Kovaleva E, Backlund P, Wingfield PT, Brooks BP*, Sergeev YV*.Albinism-causing mutations in recombinant human tyrosinase alter intrinsic enzyme activity.PLoS ONE. Jan2;9(1):e84494 (2014).PMID 24392141. * Co-corresponding, co-senior authors.
Onojafe IF, Adams DR, Simeonov DR, Zhang J, Chan CC, Bernardini IM, Sergeev YV, Dolinska MB, Alur RP, Brilliant MH, Gahl WA, Brooks BP. Nitisinone improves eye and skin pigmentation defects in a mouse model of oculocutaneous albinism.J Clin Invest. 121: 3914-23. (2011) PMCID: PMC3223618.
Alur RP, Camasamudram V, Brown JD, Mehtani M, Onojafe IF, Sergeev YV, Boobalan E, Jone MP, Tang K, Liu H, Chun-hong X, Gong X, Brooks BP.Papillorenal syndrome-causing missense mutations in PAX2/Pax2 result in hypomorphic alleles in mouse and human.PloS Genet. 6(3):e1000870. (2010) PMCID: PMC2832668.
Brown JD, Dutta S, Bharti K, Bonner RF, Munson PJ, Dawid IB, Akhtar AL, Onojafe IF, Alur RP, Gross JM, Hejtmancik JF, Jiao X, Chan WY, Brooks BP.Expression profiling during ocular development identifies two Nlz genes with a critical role in optic fissure closure.. 106:1462-7 (2009) PMCID: PMC2631080.