Muhammad Shakil1,2,3, Gaurav V Harlalka2, Shamshad Ali4, Siying Lin2, Ilaria D'Atri2, Shabbir Hussain1, Abdul Nasir5, Muhammad Aiman Shahzad6, Muhammad Ikram Ullah1,7, Jay E Self8, Emma L Baple2, Andrew H Crosby2, Saqib Mahmood9,10. 1. Department of Biochemistry, University of Health Sciences (UHS), Lahore, Pakistan. 2. RD&E (Wonford) NHS Foundation Trust, University of Exeter Medical School, Barrack Road, Exeter, Devon, EX2 5DW, UK. 3. Department of Biochemistry, Services Institute of Medical Sciences, Services Hospital, Lahore, Pakistan. 4. Department of Ophthalmology, Services Institute of Medical Sciences, Services Hospital, Lahore, Pakistan. 5. Synthetic Protein Engineering Lab (SPEL), Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, South Korea. 6. Department of Human Genetics and Molecular Biology, University of Health Sciences (UHS), Lahore, Pakistan. 7. Department of Clinical Laboratory Sciences, Jouf University, Sakaka-2014, Saudi Arabia. 8. Clinical and Experimental Sciences, University of Southampton, Southampton, UK. 9. Department of Human Genetics and Molecular Biology, University of Health Sciences (UHS), Lahore, Pakistan. sqb_medgen@yahoo.com. 10. Institute of Biomedical and Allied Health Sciences, University of Health Sciences (UHS), Lahore, Pakistan. sqb_medgen@yahoo.com.
Abstract
PURPOSE: To investigate eight previously unreported Pakistani families with genetically undefined OCA for mutations in TYR. METHODS: Sanger sequencing of TYR has been performed in eight families with OCA phenotype. Mutation analysis was performed to establish the pathogenic role of novel mutation. Bioinformatics analysis was performed to predict the structural and functional impacts on protein due to the mutation. RESULTS: In this study, we identified six likely pathogenic variants of TYR (c.272 G>A, c.308 G>A, c.346C>T, c.715 C>T, c.832 C>T and c.1255 G>A), including one novel variant (c.308 G>A; p.Cys103Tyr), segregating as appropriate in each family. Cys103 lies in the highly conserved region of the tyrosinase enzyme, and p.Cys103Tyr is predicted to disturb enzymatic function via alteration of the configurational orientation of TYR leading to a more rigid polypeptide structure. We have also reviewed the mutation spectrum of TYR in Pakistani ethnicity. Published data on OCA families proposed that ~40% have been associated with genetic variations in the TYR gene. The mutations reported in this study have now been described with varying frequencies in Pakistani families, including very rare/unique mutations. CONCLUSION: A literature review of TYR gene mutations in Pakistani populations, combined with our genetic data, identified a number of gene mutations likely to represent regional ancestral founder mutations of relevance to Pakistani populations, in addition to sporadic and recurrent 'hotspot' mutations present repeatedly in other regions worldwide.
PURPOSE: To investigate eight previously unreported Pakistani families with genetically undefined OCA for mutations in TYR. METHODS: Sanger sequencing of TYR has been performed in eight families with OCA phenotype. Mutation analysis was performed to establish the pathogenic role of novel mutation. Bioinformatics analysis was performed to predict the structural and functional impacts on protein due to the mutation. RESULTS: In this study, we identified six likely pathogenic variants of TYR (c.272 G>A, c.308 G>A, c.346C>T, c.715 C>T, c.832 C>T and c.1255 G>A), including one novel variant (c.308 G>A; p.Cys103Tyr), segregating as appropriate in each family. Cys103 lies in the highly conserved region of the tyrosinase enzyme, and p.Cys103Tyr is predicted to disturb enzymatic function via alteration of the configurational orientation of TYR leading to a more rigid polypeptide structure. We have also reviewed the mutation spectrum of TYR in Pakistani ethnicity. Published data on OCA families proposed that ~40% have been associated with genetic variations in the TYR gene. The mutations reported in this study have now been described with varying frequencies in Pakistani families, including very rare/unique mutations. CONCLUSION: A literature review of TYR gene mutations in Pakistani populations, combined with our genetic data, identified a number of gene mutations likely to represent regional ancestral founder mutations of relevance to Pakistani populations, in addition to sporadic and recurrent 'hotspot' mutations present repeatedly in other regions worldwide.
Authors: Hadia Gul; Muhammad Zeeshan Ali; Ejazullah Khan; Muhammad Zubair; Muhammad Badar; Saadullah Khan; Abdul Haleem Shah; Muzammil Ahmad Khan Journal: J Pak Med Assoc Date: 2017-05 Impact factor: 0.781