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

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:

lab to clinics flow chart

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.

Albinism

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.

Selected publications

Chertkof J, Hufnagel RB, Blain D, Gropman AL, Brooks BP. Retinoschisis associated with Kearns-Sayre syndrome. Ophthalmic Genet. 2020 Oct;41(5):497-500. doi: 10.1080/13816810.2020.1799416. Epub 2020 Aug 13.

Soleilhavoup C, Travaglio M, Patrick K, Garção P, Boobalan E, Adolfs Y, Spriggs RV, Moles-Garcia E, Dhiraj D, Oosterveen T, Ferri SL, Abel T, Brodkin ES, Pasterkamp RJ, Brooks BP, Panman L. Nolz1 expression is required in dopaminergic axon guidance and striatal innervation. Nat Commun. 2020 Jun 19;11(1):3111. doi: 10.1038/s41467-020-16947-6.

Daich Varela M, Huryn LA, Hufnagel RB, Zein WM, Blain D, Brooks BP. Ocular and Systemic Findings in Adults with Uveal Coloboma. Ophthalmology. 2020 May 17:S0161-6420(20)30467-X. doi: 10.1016/j.ophtha.2020.05.028. Online ahead of print.

George A, Cogliati T, Brooks BP. Genetics of syndromic ocular coloboma: CHARGE and COACH syndromes. Exp Eye Res. 2020 Apr;193:107940. doi: 10.1016/j.exer.2020.107940. Epub 2020 Feb 4.

Kalaskar VK, Alur RP, Li LK, Thomas JW, Sergeev YV, Blain D, Hufnagel RB, Cogliati T, Brooks BP. High-throughput custom capture sequencing identifies novel mutations in coloboma-associated genes: Mutation in DNA-binding domain of retinoic acid receptor beta affects nuclear localization causing ocular coloboma. Hum Mutat. 2020 Mar;41(3):678-695. doi: 10.1002/humu.23954. Epub 2019 Dec 9.

Lahrouchi N, George A, Ratbi I, Schneider R, Elalaoui SC, Moosa S, Bharti S, Sharma R, Abu-Asab M, Onojafe F, Adadi N, Lodder EM, Laarabi FZ, Lamsyah Y, Elorch H, Chebbar I, Postma AV, Lougaris V, Plebani A, Altmueller J, Kyrieleis H, Meiner V, McNeill H, Bharti K, Lyonnet S, Wollnik B, Henrion-Caude A, Berraho A, Hildebrandt F, Bezzina CR, Brooks BP, Sefiani A. Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly. Nat Commun. 2019 Mar 12;10(1):1180. doi: 10.1038/s41467-019-08547-w.

Adams DR, Menezes S, Jauregui R, Valivullah ZM, Power B, Abraham M, Jeffrey BG, Garced A, Alur RP, Cunningham D, Wiggs E, Merideth MA, Chiang PW, Bernstein S, Ito S, Wakamatsu K, Jack RM, Introne WJ, Gahl WA, Brooks BP. One-year pilot study on the effects of nitisinone on melanin in patients with OCA-1B. JCI Insight. 2019 Jan 24;4(2):e124387. doi: 10.1172/jci.insight.124387. Online ahead of print.

Onojafe IF, Megan LH, Melch MG, Aderemi JO, Alur RP, Abu-Asab MS, Chan CC, Bernardini IM, Albert JS, Cogliati T, Adams DR, Brooks BP. Minimal Efficacy of Nitisinone Treatment in a Novel Mouse Model of Oculocutaneous Albinism, Type 3. Invest Ophthalmol Vis Sci. 2018 Oct 1;59(12):4945-4952. doi: 10.1167/iovs.16-20293.

Brooks BP, Zein WM, Thompson AH, Mokhtarzadeh M, Doherty DA, Parisi M, Glass IA, Malicdan MC, Vilboux T, Vemulapalli M, Mullikin JC, Gahl WA, Gunay-Aygun M. Joubert Syndrome: Ophthalmological Findings in Correlation with Genotype and Hepatorenal Disease in 99 Patients Prospectively Evaluated at a Single Center.  Ophthalmology. 2018 Dec;125(12):1937-1952. doi: 10.1016/j.ophtha.2018.05.026. Epub 2018 Jul 25.

Brooks BP, Jeffrey B. Methodological Insights for Randomized Clinical Trials of Retinitis Pigmentosa: Lessons Learned From a Trial of Valproic Acid. JAMA Ophthalmol. 2018 Aug 1;136(8):857-858. doi: 10.1001/jamaophthalmol.2018.1167.

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 BPUveal 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.

Pediatric, Developmental & Genetic Ophthalmology Section key staff

Key staff table
Name Title Email Phone
Prasad Alur, Ph.D. Lab Manager alurr@mail.nih.gov 301-496-7111
Elangovan Boobalan, Ph.D. Research Associate elangovanb@mail.nih.gov 301-451-3175
Brian P. Brooks, M.D., Ph.D. Senior Investigator brooksb@nei.nih.gov 301-451-2238
Sunit Dutta, Ph.D. Staff Scientist duttasun@mail.nih.gov 301-594-5840
Aman George, Ph.D. Staff Scientist aman.george@nih.gov 301-451-2265
Vijay Kalaskar, Ph.D. Research Fellow vijay.kalaskar@nih.gov 301-443-8416
Maryam Mokhtarzadeh, M.D. Special Volunteer maryam.mokhtarzadeh@nih.gov 301-496-3577
Uma Neelathi, Ph.D. Research Associate uma.neelathi@nih.gov 301-594-5850
Evan Selzer Special Volunteer evan.selzer@nih.gov

Pediatric, Developmental & Genetic Ophthalmology Section alumni

Name Title Time Period
Emma Attar Student IRTA
Cuilee Sha Postbac IRTA

News from this lab

Researchers use patients’ cells to test gene therapy for rare eye disease

January 28, 2021

Scientists at the National Eye Institute (NEI) have developed a promising gene therapy strategy for a rare disease that causes severe vision loss in childhood.
Side-by-side photos of trial participant before and after treatment

Nitisinone Increases Melanin in People With Albinism

February 20, 2019

A small pilot clinical study at the National Eye Institute (NEI) suggests that the drug nitisinone increases melanin production in some people with oculocutaneous albinism type 1B (OCA-1B), a rare genetic disease that causes pale skin and hair and poor vi
James Golladay and Aman George hold up grant award check

Knights Templar Eye Foundation awards research grant to NEI scientist

June 21, 2018

National Eye Institute (NEI) Postdoctoral Fellow Aman George, Ph.D., has received a $65,000 grant from the Knights Templar Eye Foundation to identify new drug treatments for vision impairment in children with a type of albinism.
Last updated: December 8, 2020