Association of pathogenic mutations in TULP1 with retinitis pigmentosa in consanguineous Pakistani families

Muhammad Iqbal, Muhammad Asif Naeem, S. Amer Riazuddin, Shahbaz Ali, Tahir Farooq, Zaheeruddin A. Qazi, Shaheen N. Khan, Tayyab Husnain, Saima Riazuddin, Paul A. Sieving, J. Fielding Hejtmancik, Sheikh Riazuddin

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: To identify pathogenic mutations responsible for autosomal recessive retinitis pigmentosa in 5 consanguineous Pakistani families. Methods: Affected individuals in the families underwent a detailed ophthalmological examination that consisted of fundus photography and electroretinography. Blood samples were collected from all participating family members, and genomic DNA was extracted. A genome-wide linkage scan was performed, followed by exclusion analyses among our cohort of nuclear consanguineous families with microsatellite markers spanning the TULP1 locus on chromosome 6p. Two-point logarithm of odds scores were calculated, and all coding exons of TULP1 were sequenced bidirectionally. Results: The results of ophthalmological examinations among affected individuals in these 5 families were suggestive of retinitis pigmentosa. The genome-wide linkage scan localized the disease interval to chromosome 6p, harboring TULP1 in 1 of 5 families, and sequential analyses identified a single base pair substitution in TULP1 that results in threonine to alanine substitution (p.T380A). Subsequently, we investigated our entire cohort of families with autosomal recessive retinitis pigmentosa and identified 4 additional families with linkage to chromosome 6p, all of them harboring a single base pair substitution in TULP1 that results in lysine to arginine substitution (p.K489R). Results of single-nucleotide polymorphism haplotype analyses were suggestive of a common founder in these 4 families. Conclusion: Pathogenic mutations in TULP1 are responsible for the autosomal recessive retinitis pigmentosa phenotype in these consanguineous Pakistani families, with a single ancestral mutation in TULP1 causing the disease phenotype in 4 of 5 families. Clinical Relevance: Clinical and molecular characterization of pathogenic mutations in TULP1 will increase our understanding of retinitis pigmentosa at a molecular level.

Original languageEnglish (US)
Pages (from-to)1351-1357
Number of pages7
JournalArchives of Ophthalmology
Volume129
Issue number10
DOIs
StatePublished - Oct 2011
Externally publishedYes

ASJC Scopus subject areas

  • Ophthalmology

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