PUBLICATION
Molecular characterization of SLC24A5 variants and evaluation of Nitisinone treatment efficacy in a zebrafish model of OCA6
- Authors
- Yousaf, S., Sethna, S., Chaudhary, M.A., Shaikh, R.S., Riazuddin, S., Ahmed, Z.M.
- ID
- ZDB-PUB-200422-76
- Date
- 2020
- Source
- Pigment cell & melanoma research 33(4): 556-565 (Journal)
- Registered Authors
- Keywords
- NCKX5, Na+/Ca2+ exchanger, OCA6, SLC24A5, albinism, hypopigmentation
- MeSH Terms
-
- Adolescent
- Adult
- Aged
- Albinism, Oculocutaneous/genetics*
- Animals
- Antiporters/genetics*
- Child
- Chromosome Segregation/genetics
- Cyclohexanones/pharmacology*
- Disease Models, Animal
- Family
- Female
- Fundus Oculi
- Genetic Variation*
- Humans
- Larva/drug effects
- Male
- Middle Aged
- Morpholinos/pharmacology
- Nitrobenzoates/pharmacology*
- Pakistan
- Pedigree
- Phenotype
- Skin Pigmentation/drug effects
- Treatment Outcome
- Young Adult
- Zebrafish/genetics*
- Zebrafish Proteins/genetics*
- PubMed
- 32274888 Full text @ Pigment Cell Melanoma Res.
Citation
Yousaf, S., Sethna, S., Chaudhary, M.A., Shaikh, R.S., Riazuddin, S., Ahmed, Z.M. (2020) Molecular characterization of SLC24A5 variants and evaluation of Nitisinone treatment efficacy in a zebrafish model of OCA6. Pigment cell & melanoma research. 33(4):556-565.
Abstract
Skin pigmentation is a highly heterogeneous trait with diverse consequences worldwide. SLC24A5, encoding a potent K+ -dependent Na+ /Ca2+ exchanger, is among the known color-coding genes that participate in melanogenesis by maintaining pH in melanosomes. Deficient SLC24A5 activity results in oculocutaneous albinism (OCA) type 6 in humans. In this study, by utilizing a exome sequencing (ES) approach, we identified two new variants [p. (Gly110Arg) and p. (IIe189Ilefs*1)] of SLC24A5 cosegregating with the OCA phenotype, including nystagmus, strabismus, foveal hypoplasia, albinotic fundus and vision impairment, in three large consanguineous Pakistani families. Both of these variants failed to rescue the pigmentation in zebrafish slc24a5 morphants, confirming the pathogenic effects of the variants. We also phenotypically characterized a commercially available zebrafish mutant line (slc24a5ko ) that harbors a nonsense (p.Tyr208*) allele of slc24a5. Similar to morphants, homozygous slc24a5ko mutants had significantly reduced melanin content and pigmentation. Next, we used these slc24a5ko zebrafish mutants to test the efficacy of nitisinone, a compound known to increase ocular and fur pigmentation in OCA1 (TYR)-mutant mice. Treatment of slc24a5ko mutant zebrafish embryos with varying doses of nitisinone did not improve melanin production and pigmentation, suggesting that treatment with nitisinone is unlikely to be therapeutic in OCA6 patients.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping