Molecular characterization of SLC24A5 variants and evaluation of Nitisinone treatment efficacy in a zebrafish model of OCA6
| Autor: | Saima Riazuddin, Sairah Yousaf, Zubair M. Ahmed, Muhammad Ali Chaudhary, Saumil Sethna, Rehan S. Shaikh |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Nitisinone Skin Pigmentation Antiporters Morpholinos Melanin 0302 clinical medicine Chromosome Segregation Pakistan Child Zebrafish Exome sequencing Genetics biology Middle Aged Oculocutaneous albinism Pedigree Phenotype Treatment Outcome Oncology Albinism Oculocutaneous Larva 030220 oncology & carcinogenesis Albinism Female medicine.drug Adult Adolescent Fundus Oculi Dermatology SLC24A5 Article General Biochemistry Genetics and Molecular Biology Young Adult 03 medical and health sciences medicine Animals Humans Family Allele Aged Cyclohexanones Genetic Variation Zebrafish Proteins biology.organism_classification medicine.disease eye diseases Disease Models Animal 030104 developmental biology Nitrobenzoates biology.protein sense organs |
| Zdroj: | Pigment Cell Melanoma Res |
| ISSN: | 1755-148X 1755-1471 |
| DOI: | 10.1111/pcmr.12879 |
| Popis: | Skin pigmentation is a highly heterogeneous trait with diverse consequences worldwide. SLC24A5, encoding a potent K(+)-dependent Na(+)/Ca(2+) 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 (slc24a5(ko)) that harbors a nonsense (p.Tyr208*) allele of slc24a5. Similar to morphants, homozygous slc24a5(ko) mutants had significantly reduced melanin content and pigmentation. Next, we used these slc24a5(ko) zebrafish mutants to test the efficacy of nitisinone, a compound known to increase ocular and fur pigmentation in OCA1 (TYR)-mutant mice. Treatment of slc24a5(ko) 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. |
| Databáze: | OpenAIRE |
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