A novel homozygous missense substitution p.Thr313Ile in the PDE6B gene underlies autosomal recessive retinitis pigmentosa in a consanguineous Pakistani family

Author:

Aziz Nobia1,Ullah Mukhtar2,Rashid Abdur3,Hussain Zubair4,Shah Khadim4,Awan Azeem5,Khan Muhammad1,Ullah Inam1,Rehman Atta Ur6

Affiliation:

1. Department of Biotechnology and Genetic Engineering, Faculty of Biological and Health Sciences, Hazara University, Mansehra

2. Institute of Molecular and Clinical Ophthalmology Basel, University of Basel

3. Department of Higher Education Archives and Libraries Peshawar, Government of Khyber Pakhtunkhwa

4. Department of Biotechnology, COMSATS University Islamabad, Abbottabad Campus

5. LRBT Secondary Eye Hospital, Reerah Galla, Balakot Road, Mansehra, Khyber Pakhtunkhwa

6. Department of Zoology, Faculty of Biological and Health Sciences, Hazara University, Mansehra

Abstract

Abstract Background Retinitis pigmentosa (RP) is one of the most frequent hereditary retinal diseases that often starts with night blindness and eventually leads to legal blindness. Our study aimed to identify the underlying genetic cause of autosomal recessive retinitis pigmentosa (arRP) in a consanguineous Pakistani family. Methods Following a detailed ophthalmological examination of the patients by an ophthalmologist, whole-exome sequencing was performed on the proband’s DNA to delineate the genetic cause of RP in the family. In-depth computational methods, in-silico analysis, and familial co-segregation study were performed for variant detection and validation. Results We studied an inbred Pakistani family with two siblings affected by retinitis pigmentosa. The proband, a 32 years old female, was clinically diagnosed with RP at the age of 6 years. A classical night blindness symptom was reported in the proband since her early childhood. OCT report showed a major reduction in the outer nuclear layer and the ellipsoid zone width, leading to the progression of the disease. Exome sequencing revealed a novel homozygous missense mutation (c.938C > T;p.Thr313Ile) in exon 12 of the PDE6B gene. The mutation p.Thr313Ile co-segregated with RP phenotype in the family. The altered residue (p.Thr313) was super conserved evolutionarily across different vertebrate species, and all available in silico tools classified the mutation as highly pathogenic. Conclusion We present a novel homozygous pathogenic mutation in the PDE6B gene as the underlying cause of arRP in a consanguineous Pakistani family. Our findings highlight the importance of missense mutations in the PDE6B gene and expand the known mutational repertoire of PDE6B-related RP.

Publisher

Research Square Platform LLC

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