Pathogenic mutations in TULP1 responsible for retinitis pigmentosa identified in consanguineous familial cases

Inayat Ullah, Firoz Kabir, Muhammad Iqbal, Clare Brooks S Gottsch, Muhammad Asif Naeem, Muhammad Zaman Assir, Shaheen N. Khan, Javed Akram, Sheikh Riazuddin, Radha Ayyagari, J. Fielding Hejtmancik, Sheikh Amer Riazuddin

Research output: Contribution to journalArticle

Abstract

Purpose: To identify pathogenic mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in consanguineous familial cases. Methods: Seven large familial cases with multiple individuals diagnosed with retinitis pigmentosa were included in the study. Affected individuals in these families underwent ophthalmic examinations to document the symptoms and confirm the initial diagnosis. Blood samples were collected from all participating members, and genomic DNA was extracted. An exclusion analysis with microsatellite markers spanning the TULP1 locus on chromosome 6p was performed, and two-point logarithm of odds (LOD) scores were calculated. All coding exons along with the exon–intron boundaries of TULP1 were sequenced bidirectionally. We constructed a single nucleotide polymorphism (SNP) haplotype for the four familial cases harboring the K489R allele and estimated the likelihood of a founder effect. Results: The ophthalmic examinations of the affected individuals in these familial cases were suggestive of RP. Exclusion analyses confirmed linkage to chromosome 6p harboring TULP1 with positive two-point LOD scores. Subsequent Sanger sequencing identified the single base pair substitution in exon14, c.1466A>G (p.K489R), in four families. Additionally, we identified a two-base deletion in exon 4, c.286_287delGA (p.E96Gfs77*); a homozygous splice site variant in intron 14, c.1495+4A>C; and a novel missense variation in exon 15, c.1561C>T (p.P521S). All mutations segregated with the disease phenotype in the respective families and were absent in ethnically matched control chromosomes. Haplotype analysis suggested (p<10−6) that affected individuals inherited the causal mutation from a common ancestor. Conclusions: Pathogenic mutations in TULP1 are responsible for the RP phenotype in seven familial cases with a common ancestral mutation responsible for the disease phenotype in four of the seven families.

Original languageEnglish (US)
Pages (from-to)797-815
Number of pages19
JournalMolecular Vision
Volume22
StatePublished - 2016

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Retinitis Pigmentosa
Mutation
Exons
Chromosomes
Phenotype
Haplotypes
Founder Effect
Base Pairing
Microsatellite Repeats
Introns
Single Nucleotide Polymorphism
Alleles
DNA

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Ullah, I., Kabir, F., Iqbal, M., Gottsch, C. B. S., Naeem, M. A., Assir, M. Z., ... Riazuddin, S. A. (2016). Pathogenic mutations in TULP1 responsible for retinitis pigmentosa identified in consanguineous familial cases. Molecular Vision, 22, 797-815.

Pathogenic mutations in TULP1 responsible for retinitis pigmentosa identified in consanguineous familial cases. / Ullah, Inayat; Kabir, Firoz; Iqbal, Muhammad; Gottsch, Clare Brooks S; Naeem, Muhammad Asif; Assir, Muhammad Zaman; Khan, Shaheen N.; Akram, Javed; Riazuddin, Sheikh; Ayyagari, Radha; Fielding Hejtmancik, J.; Riazuddin, Sheikh Amer.

In: Molecular Vision, Vol. 22, 2016, p. 797-815.

Research output: Contribution to journalArticle

Ullah, I, Kabir, F, Iqbal, M, Gottsch, CBS, Naeem, MA, Assir, MZ, Khan, SN, Akram, J, Riazuddin, S, Ayyagari, R, Fielding Hejtmancik, J & Riazuddin, SA 2016, 'Pathogenic mutations in TULP1 responsible for retinitis pigmentosa identified in consanguineous familial cases', Molecular Vision, vol. 22, pp. 797-815.
Ullah I, Kabir F, Iqbal M, Gottsch CBS, Naeem MA, Assir MZ et al. Pathogenic mutations in TULP1 responsible for retinitis pigmentosa identified in consanguineous familial cases. Molecular Vision. 2016;22:797-815.
Ullah, Inayat ; Kabir, Firoz ; Iqbal, Muhammad ; Gottsch, Clare Brooks S ; Naeem, Muhammad Asif ; Assir, Muhammad Zaman ; Khan, Shaheen N. ; Akram, Javed ; Riazuddin, Sheikh ; Ayyagari, Radha ; Fielding Hejtmancik, J. ; Riazuddin, Sheikh Amer. / Pathogenic mutations in TULP1 responsible for retinitis pigmentosa identified in consanguineous familial cases. In: Molecular Vision. 2016 ; Vol. 22. pp. 797-815.
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abstract = "Purpose: To identify pathogenic mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in consanguineous familial cases. Methods: Seven large familial cases with multiple individuals diagnosed with retinitis pigmentosa were included in the study. Affected individuals in these families underwent ophthalmic examinations to document the symptoms and confirm the initial diagnosis. Blood samples were collected from all participating members, and genomic DNA was extracted. An exclusion analysis with microsatellite markers spanning the TULP1 locus on chromosome 6p was performed, and two-point logarithm of odds (LOD) scores were calculated. All coding exons along with the exon–intron boundaries of TULP1 were sequenced bidirectionally. We constructed a single nucleotide polymorphism (SNP) haplotype for the four familial cases harboring the K489R allele and estimated the likelihood of a founder effect. Results: The ophthalmic examinations of the affected individuals in these familial cases were suggestive of RP. Exclusion analyses confirmed linkage to chromosome 6p harboring TULP1 with positive two-point LOD scores. Subsequent Sanger sequencing identified the single base pair substitution in exon14, c.1466A>G (p.K489R), in four families. Additionally, we identified a two-base deletion in exon 4, c.286_287delGA (p.E96Gfs77*); a homozygous splice site variant in intron 14, c.1495+4A>C; and a novel missense variation in exon 15, c.1561C>T (p.P521S). All mutations segregated with the disease phenotype in the respective families and were absent in ethnically matched control chromosomes. Haplotype analysis suggested (p<10−6) that affected individuals inherited the causal mutation from a common ancestor. Conclusions: Pathogenic mutations in TULP1 are responsible for the RP phenotype in seven familial cases with a common ancestral mutation responsible for the disease phenotype in four of the seven families.",
author = "Inayat Ullah and Firoz Kabir and Muhammad Iqbal and Gottsch, {Clare Brooks S} and Naeem, {Muhammad Asif} and Assir, {Muhammad Zaman} and Khan, {Shaheen N.} and Javed Akram and Sheikh Riazuddin and Radha Ayyagari and {Fielding Hejtmancik}, J. and Riazuddin, {Sheikh Amer}",
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T1 - Pathogenic mutations in TULP1 responsible for retinitis pigmentosa identified in consanguineous familial cases

AU - Ullah, Inayat

AU - Kabir, Firoz

AU - Iqbal, Muhammad

AU - Gottsch, Clare Brooks S

AU - Naeem, Muhammad Asif

AU - Assir, Muhammad Zaman

AU - Khan, Shaheen N.

AU - Akram, Javed

AU - Riazuddin, Sheikh

AU - Ayyagari, Radha

AU - Fielding Hejtmancik, J.

AU - Riazuddin, Sheikh Amer

PY - 2016

Y1 - 2016

N2 - Purpose: To identify pathogenic mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in consanguineous familial cases. Methods: Seven large familial cases with multiple individuals diagnosed with retinitis pigmentosa were included in the study. Affected individuals in these families underwent ophthalmic examinations to document the symptoms and confirm the initial diagnosis. Blood samples were collected from all participating members, and genomic DNA was extracted. An exclusion analysis with microsatellite markers spanning the TULP1 locus on chromosome 6p was performed, and two-point logarithm of odds (LOD) scores were calculated. All coding exons along with the exon–intron boundaries of TULP1 were sequenced bidirectionally. We constructed a single nucleotide polymorphism (SNP) haplotype for the four familial cases harboring the K489R allele and estimated the likelihood of a founder effect. Results: The ophthalmic examinations of the affected individuals in these familial cases were suggestive of RP. Exclusion analyses confirmed linkage to chromosome 6p harboring TULP1 with positive two-point LOD scores. Subsequent Sanger sequencing identified the single base pair substitution in exon14, c.1466A>G (p.K489R), in four families. Additionally, we identified a two-base deletion in exon 4, c.286_287delGA (p.E96Gfs77*); a homozygous splice site variant in intron 14, c.1495+4A>C; and a novel missense variation in exon 15, c.1561C>T (p.P521S). All mutations segregated with the disease phenotype in the respective families and were absent in ethnically matched control chromosomes. Haplotype analysis suggested (p<10−6) that affected individuals inherited the causal mutation from a common ancestor. Conclusions: Pathogenic mutations in TULP1 are responsible for the RP phenotype in seven familial cases with a common ancestral mutation responsible for the disease phenotype in four of the seven families.

AB - Purpose: To identify pathogenic mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in consanguineous familial cases. Methods: Seven large familial cases with multiple individuals diagnosed with retinitis pigmentosa were included in the study. Affected individuals in these families underwent ophthalmic examinations to document the symptoms and confirm the initial diagnosis. Blood samples were collected from all participating members, and genomic DNA was extracted. An exclusion analysis with microsatellite markers spanning the TULP1 locus on chromosome 6p was performed, and two-point logarithm of odds (LOD) scores were calculated. All coding exons along with the exon–intron boundaries of TULP1 were sequenced bidirectionally. We constructed a single nucleotide polymorphism (SNP) haplotype for the four familial cases harboring the K489R allele and estimated the likelihood of a founder effect. Results: The ophthalmic examinations of the affected individuals in these familial cases were suggestive of RP. Exclusion analyses confirmed linkage to chromosome 6p harboring TULP1 with positive two-point LOD scores. Subsequent Sanger sequencing identified the single base pair substitution in exon14, c.1466A>G (p.K489R), in four families. Additionally, we identified a two-base deletion in exon 4, c.286_287delGA (p.E96Gfs77*); a homozygous splice site variant in intron 14, c.1495+4A>C; and a novel missense variation in exon 15, c.1561C>T (p.P521S). All mutations segregated with the disease phenotype in the respective families and were absent in ethnically matched control chromosomes. Haplotype analysis suggested (p<10−6) that affected individuals inherited the causal mutation from a common ancestor. Conclusions: Pathogenic mutations in TULP1 are responsible for the RP phenotype in seven familial cases with a common ancestral mutation responsible for the disease phenotype in four of the seven families.

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