The transcription factor FOXC1 is a major cause of the autosomal dominant genetic disease Axenfeld-Rieger syndrome (ARS). Most ARS patients suffer from early-onset glaucoma which eventually leads to blindness; however extra-ocular phenotypes are also common. Cardiac septal defects and valve insufficiency arises in 10-15% of FOXC1-associated ARS cases but the etiology is poorly understood. Chrystal et al. have now uncovered a possible mechanism for this cardiac defect – improper left-right patterning of the organ.
Recently published in the journal Genes, this research demonstrates that foxc1 is necessary for correct situs (left-right asymmetry) of the heart and the gut within zebrafish. Mutation of foxc1 leads to a loss of expression of the key left-right patterning gene lefty2 during a critical time in heart development. Consistently, mutation of LEFTY2 in humans is associated with congenital heart defects. This work enforces the importance of checking cardiac health in ARS sufferers, especially where FOXC1 mutations are identified.
Beyond studying eyes, some of our AVN labs also pay attention to surrounding structures. Congratulations to Pranidhi Baddam (PhD Student) from the Graf lab for recent publications in the Journal of Anatomy and Disease Model and Mechanisms. Her work characterizes normal maturation of nasal septum cartilage, and the abnormal midfacial development in mice with neural crest-specific deletion of Bmp7. Credit also to Tiffany Kung and Daniela Roth as students in the Graf lab who contributed to the work.
Baddam P, Kung T, Adesida AB, Graf D. Histological and molecular characterization of the growing nasal septum in mice. J Anat. 2021 Mar;238(3):751-764. doi: 10.1111/joa.13332. Epub 2020 Oct 12. PMID: 33043993; PMCID: PMC7855085.
Baddam P, Biancardi V, Roth DM, Eaton F, Thereza-Bussolaro C, Mandal R, Wishart DS, Barr A, MacLean J, Flores-Mir C, Pagliardini S, Graf D. Neural crest-specific deletion of Bmp7 leads to midfacial hypoplasia, nasal airway obstruction, and disordered breathing modelling Obstructive Sleep Apnea. Dis Model Mech. 2021 Jan 11:dmm.047738. doi: 10.1242/dmm.047738. Epub ahead of print. PMID: 33431521.
The recent special issue of the American Journal of Medical Genetics; Seminar in Medical Genetics (Volume 184, Issue 3) includes contributions from four AVN labs: Waskiewicz, Lehmann, Walter, and MacDonald. Check out the issue to learn more about ocular coloboma, retinal dystrophies, and more: AJMG Ocular Genetics
Nate defended his MSc thesis (Form and Function of Photoreceptors in kcnv2 Mutant Zebrafish: Implications for the Human Disease KCNV2 Retinopathy) last Thursday. After giving a great talk, he passed without revisions! Congrats to Nate on being the first student to graduate from the Hocking lab, and all the best to him as he starts his first year of medical school at the University of Alberta.
Darpan Malhotra defended his PhD in June 2019, with Bob Molday doubling as his external examiner and our AVN Research Day keynote speaker (see photo of Bob, Darpan, and Joe). The Casey lab is still publishing papers based on Darpan’s impressive body of work about the SLC4A11 corneal transporter. To learn more, check out these publications:
Malhotra, D. and Casey, J.R. (2020) Molecular Mechanisms of Fuchs and Congenital Hereditary Endothelial Corneal Dystrophies Reviews in Physiology, Biochemistry and Pharmacology, In Press.
Malhotra, D., Jung,M., Fecher-Trost, C., Lovatt, M., Peh, G.S.L, Noskov, S., Mehta, J.S., Zimmermann, R., and Casey, J.R. (2020) Defective Cell Adhesion Function of Solute Transporter, SLC4A11, in Endothelial Corneal Dystrophies, Human Molecular Genetics, 29, 97-116.
Malhotra, D., Chiu, A.M., Loganathan, S.K., Lukowski, C.M. and Casey, J.R. (2019) Identification of SLC4A11 Translational Product in Human Cornea, Scientific Reports, 9, 9681.
Lab research is always full of ups and downs, but it’s been more topsy-turvy than ever in 2020. We thought we’d take this opportunity to highlight accomplishments of our AVN labs over the past year. Stay tuned over the coming weeks….
A recent paper from the Hocking Lab describes a simple method for obtaining electroretinogram measurements from zebrafish. Excitingly, it works for larval, juvenile and adult fish. Well done Nate Nadolski on your success following painstaking work to develop the new procedure.
Nadolski NJ, Wong CXL, Hocking JC. Electroretinogram analysis of zebrafish retinal function across development. Doc Ophthalmol. 2020. doi:10.1007/s10633-020-09783-y
A paper in press at Human Molecular Genetics (Lahola-Chomiak et al., https://www.ncbi.nlm.nih.gov/pubmed/30561643) reports the results of a collaboration led by Dr. Michael Walter, and involving the Lehmann and Allison labs. This work discovered the first causative gene for pigmentary glaucoma, a common subtype of glaucoma, which represents the leading cause of irreversible blindness worldwide.
Dr. Walter’s team first identified a mutation in the premelanosome (PMEL) gene in DNA samples from two Mennonite cousins before identifying additional PMEL mutations in a cohort of patients with pigmentary glaucoma. Molecular analyses demonstrate that these mutations alter the function of the PMEL protein, and CRISPR-CAS9 mutagenesis of pmel in zebrafish resulted in both pigment defects and glaucoma-like phenotypes. In parallel, colleagues at Harvard and the University of Flinders (Drs. Wiggs and Craig), identified PMEL mutations in additional pigmentary glaucoma cases, strongly supporting the role of PMEL mutations in PG. Overall, these results improve understanding of the etiology of a major form of blindness, with opportunities for novel approaches for diagnosing and eventually treating this common form of glaucoma.
Figure 1. Typical signs of pigmentary glaucoma (pigment granules on the corneal endothelium, heavy pigmentation of the trabecular meshwork, and iris trans-ilumination defects.
Figure 2. pmel CRISPR-generated zebrafish mutant demonstrating globe enlargement (a feature of congenital glaucoma in infants).
Nicole is working on her PhD thesis under two AVN members, Dr. Ian McDonald and Dr. Ted Allison. Congratulations to Nicole for receiving a CIHR Canada Graduate Scholarship to support her during her studies.