Sabika Firasat1, Wajid Ali Khan2, Ume Sughra3,4, Haiba Kaul5, Shagufta Naz6, Bushra Noreen7, Rutaba Gul7, Kiran Afshan7. 1. Department of Zoology, Faculty of Biological Sciences, Quaid-i-Azam University, University Road, Islamabad, 45320, Pakistan. sabika.firasat@qau.edu.pk. 2. Cornea Department, Pakistan Institute of Ophthalmology (PIO), Al-Shifa Trust Eye Hospital, Jhelum Road, Rawalpindi, Pakistan. 3. Al-Shifa School of Public Health, Pakistan Institute of Ophthalmology (PIO), Al-Shifa Trust Eye Hospital, Jhelum Road, Rawalpindi, Pakistan. 4. Al-Shifa Research Centre, Pakistan Institute of Ophthalmology (PIO), Al-Shifa Trust Eye Hospital, Jhelum Road, Rawalpindi, Pakistan. 5. Genetics Division, Department of Livestock Production, University of Veterinary and Animal Sciences, Ravi Campus, Pattoki, Pakistan. 6. Department of Zoology, Lahore College for Women University, Lahore, Pakistan. 7. Department of Zoology, Faculty of Biological Sciences, Quaid-i-Azam University, University Road, Islamabad, 45320, Pakistan.
Abstract
BACKGROUND: Autosomal recessive corneal hereditary endothelial dystrophy (CHED) is a rare congenital disorder of cornea. Mutations in SLC4A11 gene are associated with CHED phenotype. CHED is also an early feature of Harboyan syndrome. The aim of the present study was to identify genetic mutations in the SLC4A11 gene in CHED cases belonging to inbred Pakistani families. Furthermore, all homozygous mutation carriers were investigated for hearing deficit. METHODS AND RESULTS: This study included consanguineous CHED families presented at Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan from June 2018 to September 2018. DNA was extracted from blood samples. Direct sequencing of SLC4A11 gene was performed. All identified variants were evaluated by in silico programs i.e., SIFT, PolyPhen-2, and MutationTaster. Pathogenicity of the two identified splice site variants was analyzed by Human Splicing Finder and MaxEnt Scan. Screening of five CHED families revealed a total of three previously un reported (p.Arg128Gly, c.2241-2A > T and c.1898-2A > C in family CHED19, CHED22 and CHED26 respectively) and two already reported homozygous disease causing variants (p.Arg869Cys and p.Val824Met in family CHED24 and CHED25 respectively) as predicted by mutation taster. All of these variants segregated with disease phenotype and were not detected in controls. CONCLUSION: Affected individuals of the five CHED families screened in this study had the disease due to SLC4A11 mutations and progressing to Harboyan syndrome. Identification of previously unreported mutations aid to heterogeneity of SLC4A11 and CHED pathogenesis as well as helped to provide genetic counseling to affected families.
BACKGROUND: Autosomal recessive corneal hereditary endothelial dystrophy (CHED) is a rare congenital disorder of cornea. Mutations in SLC4A11 gene are associated with CHED phenotype. CHED is also an early feature of Harboyan syndrome. The aim of the present study was to identify genetic mutations in the SLC4A11 gene in CHED cases belonging to inbred Pakistani families. Furthermore, all homozygous mutation carriers were investigated for hearing deficit. METHODS AND RESULTS: This study included consanguineous CHED families presented at Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan from June 2018 to September 2018. DNA was extracted from blood samples. Direct sequencing of SLC4A11 gene was performed. All identified variants were evaluated by in silico programs i.e., SIFT, PolyPhen-2, and MutationTaster. Pathogenicity of the two identified splice site variants was analyzed by Human Splicing Finder and MaxEnt Scan. Screening of five CHED families revealed a total of three previously un reported (p.Arg128Gly, c.2241-2A > T and c.1898-2A > C in family CHED19, CHED22 and CHED26 respectively) and two already reported homozygous disease causing variants (p.Arg869Cys and p.Val824Met in family CHED24 and CHED25 respectively) as predicted by mutation taster. All of these variants segregated with disease phenotype and were not detected in controls. CONCLUSION: Affected individuals of the five CHED families screened in this study had the disease due to SLC4A11 mutations and progressing to Harboyan syndrome. Identification of previously unreported mutations aid to heterogeneity of SLC4A11 and CHED pathogenesis as well as helped to provide genetic counseling to affected families.
Authors: Gonzalo L Vilas; Sampath K Loganathan; Anita Quon; Periasamy Sundaresan; Eranga N Vithana; Joseph Casey Journal: Hum Mutat Date: 2011-12-20 Impact factor: 4.878
Authors: Jayne S Weiss; Hans Ulrik Møller; Anthony J Aldave; Berthold Seitz; Cecilie Bredrup; Tero Kivelä; Francis L Munier; Christopher J Rapuano; Kanwal K Nischal; Eung Kweon Kim; John Sutphin; Massimo Busin; Antoine Labbé; Kenneth R Kenyon; Shigeru Kinoshita; Walter Lisch Journal: Cornea Date: 2015-02 Impact factor: 2.651
Authors: Darpan Malhotra; Sampath K Loganathan; Anthony M Chiu; Chris M Lukowski; Joseph R Casey Journal: Sci Rep Date: 2019-07-04 Impact factor: 4.379
Authors: Gonzalo L Vilas; Sampath K Loganathan; Jun Liu; Andri K Riau; James D Young; Jodhbir S Mehta; Eranga N Vithana; Joseph R Casey Journal: Hum Mol Genet Date: 2013-06-27 Impact factor: 6.150