21 results on '"Riazuddin, Sheikh"'
Search Results
2. Novel mutations in LTBP2 identified in familial cases of primary congenital glaucoma.
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Rauf, Bushra, Irum, Bushra, Khan, Shahid Y., Kabir, Firoz, Naeem, Muhammad Asif, Riazuddin, Sheikh, Ayyagari, Radha, and Riazuddin, S. Amer
- Published
- 2020
3. Novel mutations in RPE65 identified in consanguineous Pakistani families with retinal dystrophy
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Kabir, Firoz, Naz, Shagufta, Riazuddin, S. Amer, Naeem, Muhammad Asif, Khan, Shaheen N., Husnain, Tayyab, Akram, Javed, Sieving, Paul A., Hejtmancik, J. Fielding, and Riazuddin, Sheikh
- Subjects
Male ,cis-trans-Isomerases ,Base Sequence ,Fundus Oculi ,DNA Mutational Analysis ,Molecular Sequence Data ,Pedigree ,Consanguinity ,Haplotypes ,Chromosomes, Human, Pair 1 ,Mutation ,Retinal Dystrophies ,Electroretinography ,Humans ,Family ,Female ,Genetic Predisposition to Disease ,Pakistan ,Amino Acid Sequence ,Lod Score ,Conserved Sequence ,Research Article - Abstract
Purpose To identify pathogenic mutations responsible for retinal dystrophy in three consanguineous Pakistani families. Methods A thorough ophthalmic examination including fundus examination and electroretinography was performed, and blood samples were collected from all participating members. Genomic DNA was extracted, and genome-wide linkage and/or exclusion analyses were completed with fluorescently labeled short tandem repeat microsatellite markers. Two-point Lod scores were calculated, and coding exons along with exon-intron boundaries of RPE65 gene were sequenced, bidirectionally. Results Ophthalmic examinations of the patients affected in all three families suggested retinal dystrophy with an early, most probably congenital, onset. Genome-wide linkage and/or exclusion analyses localized the critical interval in all three families to chromosome 1p31 harboring RPE65. Bidirectional sequencing of RPE65 identified a splice acceptor site variation in intron 2: c.95–1G>A, a single base substitution in exon 3: c.179T>C, and a single base deletion in exon 5: c.361delT in the three families, respectively. All three variations segregated with the disease phenotype in their respective families and were absent from ethnically matched control chromosomes. Conclusions These results strongly suggest that causal mutations in RPE65 are responsible for retinal dystrophy in the affected individuals of these consanguineous Pakistani families.
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- 2013
4. Mapping of a novel locus associated with autosomal recessive congenital cataract to chromosome 8p
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Sabir, Namerah, Riazuddin, S. Amer, Kaul, Haiba, Iqbal, Farheena, Nasir, Idrees A., Zafar, Ahmad U., Qazi, Zaheeruddin A., Butt, Nadeem H., Khan, Shaheen N., Husnain, Tayyab, Hejtmancik, J. Fielding, and Riazuddin, Sheikh
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Genetic Markers ,Male ,genetic structures ,Chromosome Mapping ,Genes, Recessive ,eye diseases ,Cataract ,Pedigree ,Haplotypes ,Genetic Loci ,Humans ,Family ,Female ,Genetic Predisposition to Disease ,Lod Score ,Research Article ,Chromosomes, Human, Pair 8 - Abstract
Purpose To identify the disease locus for autosomal recessive congenital cataracts in a consanguineous Pakistani family. Methods All affected individuals underwent a detailed ophthalmologic examination. Blood samples were collected and genomic DNA was extracted. A genome-wide scan was completed with fluorescently-labeled microsatellite markers on genomic DNA from affected and unaffected family members. Logarithms of odds (LOD) scores were calculated under a fully penetrant autosomal recessive model of inheritance. Results Ophthalmic examination suggested that affected individuals have bilateral cataracts. Linkage analysis localized the critical interval to chromosome 8p with LOD scores of 3.19, and 3.08 at θ=0, obtained with markers D8S549 and D8S550, respectively. Haplotype analyses refined the critical interval to 37.92 cM (16.28 Mb) region, flanked by markers, D8S277 proximally and D8S1734 distally. Conclusions Here, we report a new locus for autosomal recessive congenital cataract mapped to chromosome 8p in a consanguineous Pakistani family.
- Published
- 2010
5. Autosomal recessive congenital cataract in consanguineous Pakistani families is associated with mutations in GALK1
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Yasmeen, Afshan, Riazuddin, S. Amer, Kaul, Haiba, Mohsin, Sadia, Khan, Mohsin, Qazi, Zaheeruddin A., Nasir, Idrees A., Zafar, Ahmad U., Khan, Shaheen N., Husnain, Tayyab, Akram, Javed, Hejtmancik, J. Fielding, and Riazuddin, Sheikh
- Subjects
Male ,Base Sequence ,DNA Mutational Analysis ,Molecular Sequence Data ,Genes, Recessive ,eye diseases ,Cataract ,Pedigree ,Consanguinity ,Galactokinase ,Mutation ,Humans ,Family ,Female ,Genetic Predisposition to Disease ,Pakistan ,Amino Acid Sequence ,Lod Score ,Sequence Alignment ,Research Article - Abstract
Purpose To identify the pathogenic mutations responsible for autosomal recessive congenital cataracts in consanguineous Pakistani families. Methods All affected individuals underwent detailed ophthalmologic and medical examination. Blood samples were collected and genomic DNA was extracted. A genome-wide scan was performed with polymorphic microsatellite markers on genomic DNA from affected and unaffected family members and logarithm of odds (LOD) scores were calculated. All coding exons of galactokinase (GALK1) were sequenced to identify pathogenic lesions. Results Clinical records and ophthalmological examinations suggested that affected individuals have nuclear cataracts. Linkage analysis localized the critical interval to chromosome 17q with a maximum LOD score of 5.54 at θ=0, with D17S785 in family PKCC030. Sequencing of GALK1, a gene present in the critical interval, identified a single base pair deletion: c.410delG, which results in a frame shift leading to a premature termination of GALK1: p.G137fsX27. Additionally, we identified a missense mutation: c.416T>C, in family PKCC055 that results in substitution of a leucine residue at position 139 with a proline residue: p.L139P, and is predicted to be deleterious to the native GALK1 structure. Conclusions Here, we report pathogenic mutations in GALK1 that are responsible for autosomal recessive congenital cataracts in consanguineous Pakistani families.
- Published
- 2010
6. Autosomal recessive congenital cataract linked to EPHA2 in a consanguineous Pakistani family
- Author
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Kaul, Haiba, Riazuddin, S. Amer, mariam shahid, Kousar, Samra, Butt, Nadeem H., Zafar, Ahmad U., Khan, Shaheen N., Husnain, Tayyab, Akram, Javed, Hejtmancik, J. Fielding, and Riazuddin, Sheikh
- Subjects
Male ,Base Sequence ,Receptor, EphA2 ,DNA Mutational Analysis ,Molecular Sequence Data ,Genes, Recessive ,eye diseases ,Cataract ,Pedigree ,Consanguinity ,Haplotypes ,Chromosomes, Human, Pair 1 ,Humans ,Family ,Female ,Pakistan ,Amino Acid Sequence ,Lod Score ,Sequence Alignment ,Conserved Sequence ,Research Article - Abstract
Purpose To investigate the genetic basis of autosomal recessive congenital cataracts in a consanguineous Pakistani family. Methods All affected individuals underwent a detailed ophthalmological and clinical examination. Blood samples were collected and genomic DNAs were extracted. A genome-wide scan was performed with polymorphic microsatellite markers. Logarithm of odds (LOD) scores were calculated, and Eph-receptor type-A2 (EPHA2), residing in the critical interval, was sequenced bidirectionally. Results The clinical and ophthalmological examinations suggested that all affected individuals have nuclear cataracts. Genome-wide linkage analyses localized the critical interval to a 20.78 cM (15.08 Mb) interval on chromosome 1p, with a maximum two-point LOD score of 5.21 at θ=0. Sequencing of EPHA2 residing in the critical interval identified a missense mutation: c.2353G>A, which results in an alanine to threonine substitution (p.A785T). Conclusions Here, we report for the first time a missense mutation in EPHA2 associated with autosomal recessive congenital cataracts.
- Published
- 2010
7. A new locus for autosomal recessive congenital cataract identified in a Pakistani family
- Author
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Kaul, Haiba, Riazuddin, S. Amer, Yasmeen, Afshan, Mohsin, Sadia, Khan, Mohsin, Nasir, Idrees A., Khan, Shaheen N., Husnain, Tayyab, Akram, Javed, Hejtmancik, J. Fielding, and Riazuddin, Sheikh
- Subjects
Male ,Infant ,Genes, Recessive ,eye diseases ,Cataract ,Pedigree ,Genetic Loci ,Humans ,Family ,Female ,Pakistan ,Lod Score ,Chromosomes, Human, Pair 7 ,Research Article - Abstract
Purpose To identify the disease locus for autosomal recessive congenital cataract in a consanguineous Pakistani family. Methods All affected individuals underwent detailed ophthalmologic and medical examination. Blood samples were collected and DNA was extracted. A genome-wide scan was performed with polymorphic microsatellite markers on genomic DNA from affected and unaffected family members, and logarithm of odds (LOD) scores were calculated. Results The clinical records and ophthalmological examinations suggested that all affected individuals have nuclear cataracts. Maximum LOD scores of 5.01, 4.38, and 4.17 at θ=0 were obtained with markers D7630, D7S657, and D7S515, respectively. Fine mapping refined the critical interval and suggested that markers in a 27.78 cM (27.96 Mb) interval are flanked by markers D7S660 and D7S799, which co-segregate with the disease phenotype in family PKCC108. Conclusions We have identified a new locus for autosomal recessive congenital cataract, localized to chromosome 7q21.11-q31.1 in a consanguineous Pakistani family.
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- 2010
8. Novel CYP1B1 mutations in consanguineous Pakistani families with primary congenital glaucoma
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Firasat, Sabika, Riazuddin, S. Amer, Khan, Shaheen N., and Riazuddin, Sheikh
- Subjects
Male ,Base Sequence ,DNA Mutational Analysis ,Molecular Sequence Data ,Glaucoma ,Pedigree ,Consanguinity ,Asian People ,Cytochrome P-450 Enzyme System ,Chromosomes, Human, Pair 2 ,Cytochrome P-450 CYP1B1 ,Mutation ,Humans ,Family ,Female ,Pakistan ,Amino Acid Sequence ,Aryl Hydrocarbon Hydroxylases ,Lod Score ,Sequence Alignment ,Research Article - Abstract
Purpose To identify the disease-causing mutations in three consanguineous Pakistani families with multiple members affected by primary congenital glaucoma. Methods Blood samples were collected, and DNA was extracted. Linkage analysis for reported primary congenital glaucoma loci was performed using closely spaced polymorphic microsatellite markers on genomic DNA from affected and unaffected family members. All coding exons, the exon-intron boundaries, and the 5′ untranslated region of CYP1B1 were sequenced. Results The alleles of chromosome 2p markers segregate with the disease phenotype in all three families with positive LOD scores. The sequencing results identified three novel mutations (L177R, L487P, and D374E) and one previously reported mutation (E229K) in CYP1B1 that segregate with the disease phenotype in their respective families. None of these sequence variations were present in 96 ethnically matched control samples. Conclusions These results strongly suggest that missense mutations in CYP1B1 are most likely to be responsible for primary congenital glaucoma in these families.
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- 2008
9. Pathogenic mutations in TULP1 responsible for retinitis pigmentosa identified in consanguineous familial cases.
- Author
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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, Hejtmancik, J. Fielding, and Riazuddin, S. Amer
- Published
- 2016
10. Loss of function mutations in RP1 are responsible for retinitis pigmentosa in consanguineous familial cases.
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Kabir, Firoz, Ullah, Inayat, Ali, Shahbaz, Gottsch, Alexander D. H., Naeem, Muhammad Asif, Assir, Muhammad Zaman, Khan, Shaheen N., Akram, Javed, Riazuddin, Sheikh, Ayyagari, Radha, Hejtmancik, J. Fielding, and Riazuddin, S. Amer
- Published
- 2016
11. Mutations in GRM6 identified in consanguineous Pakistani families with congenital stationary night blindness.
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Naeem MA, Gottsch AD, Ullah I, Khan SN, Husnain T, Butt NH, Qazi ZA, Akram J, Riazuddin S, Ayyagari R, Hejtmancik JF, and Riazuddin SA
- Subjects
- Adult, Aged, Amino Acid Sequence, Animals, Base Sequence, Electroretinography, Exons, Eye Diseases, Hereditary pathology, Female, Gene Expression, Genes, Recessive, Genetic Diseases, X-Linked pathology, Homozygote, Humans, Male, Molecular Sequence Data, Myopia pathology, Night Blindness pathology, Pakistan, Pedigree, Sequence Alignment, Sequence Analysis, DNA, Chromosomes, Human, Pair 5, Consanguinity, Eye Diseases, Hereditary genetics, Genetic Diseases, X-Linked genetics, Mutation, Myopia genetics, Night Blindness genetics, Receptors, Glutamate genetics
- Abstract
Purpose: This study was undertaken to investigate the causal mutations responsible for autosomal recessive congenital stationary night blindness (CSNB) in consanguineous Pakistani families., Methods: Two consanguineous families with multiple individuals manifesting symptoms of stationary night blindness were recruited. Affected individuals underwent a detailed ophthalmological examination, including fundus examination and electroretinography. Blood samples were collected and genomic DNA was extracted. Exclusion analyses were completed by genotyping closely spaced microsatellite markers, and two-point logarithm of odds (LOD) scores were calculated. All coding exons, along with the exon-intron boundaries of GRM6, were sequenced bidirectionally., Results: According to the medical history available to us, affected individuals in both families had experienced night blindness from the early years of their lives. Fundus photographs of affected individuals in both the families appeared normal, with no signs of attenuated arteries or bone spicule pigmentation. The scotopic electroretinogram (ERG) response were absent in all of the affected individuals, while the photopic measurements show reduced b-waves. During exclusion analyses, both families localized to a region on chromosome 5q that harbors GRM6, a gene previously associated with autosomal recessive CSNB. Bidirectional sequencing of GRM6 identified homozygous single base pair changes, specifically c.1336C>T (p.R446X) and c.2267G>A (p.G756D) in families PKRP170 and PKRP172, respectively., Conclusions: We identified a novel nonsense and a previously reported missense mutation in GRM6 that were responsible for autosomal recessive CSNB in patients of Pakistani decent.
- Published
- 2015
12. Splice-site mutations identified in PDE6A responsible for retinitis pigmentosa in consanguineous Pakistani families.
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Khan SY, Ali S, Naeem MA, Khan SN, Husnain T, Butt NH, Qazi ZA, Akram J, Riazuddin S, Ayyagari R, Hejtmancik JF, and Riazuddin SA
- Subjects
- Adult, Chromosomes, Human, Pair 5 genetics, Consanguinity, DNA Mutational Analysis, Female, Genes, Recessive, Genetic Markers, Humans, Lod Score, Male, Middle Aged, Pakistan, Pedigree, RNA Splice Sites, Retinitis Pigmentosa pathology, Retinitis Pigmentosa physiopathology, Young Adult, Cyclic Nucleotide Phosphodiesterases, Type 6 genetics, Eye Proteins genetics, Mutation, Retinitis Pigmentosa genetics
- Abstract
Purpose: This study was conducted to localize and identify causal mutations associated with autosomal recessive retinitis pigmentosa (RP) in consanguineous familial cases of Pakistani origin., Methods: Ophthalmic examinations that included funduscopy and electroretinography (ERG) were performed to confirm the affectation status. Blood samples were collected from all participating individuals, and genomic DNA was extracted. A genome-wide scan was performed, and two-point logarithm of odds (LOD) scores were calculated. Sanger sequencing was performed to identify the causative variants. Subsequently, we performed whole exome sequencing to rule out the possibility of a second causal variant within the linkage interval. Sequence conservation was performed with alignment analyses of PDE6A orthologs, and in silico splicing analysis was completed with Human Splicing Finder version 2.4.1., Results: A large multigenerational consanguineous family diagnosed with early-onset RP was ascertained. An ophthalmic clinical examination consisting of fundus photography and electroretinography confirmed the diagnosis of RP. A genome-wide scan was performed, and suggestive two-point LOD scores were observed with markers on chromosome 5q. Haplotype analyses identified the region; however, the region did not segregate with the disease phenotype in the family. Subsequently, we performed a second genome-wide scan that excluded the entire genome except the chromosome 5q region harboring PDE6A. Next-generation whole exome sequencing identified a splice acceptor site mutation in intron 16: c.2028-1G>A, which was completely conserved in PDE6A orthologs and was absent in ethnically matched 350 control chromosomes, the 1000 Genomes database, and the NHLBI Exome Sequencing Project. Subsequently, we investigated our entire cohort of RP familial cases and identified a second family who harbored a splice acceptor site mutation in intron 10: c.1408-2A>G. In silico analysis suggested that these mutations will result in the elimination of wild-type splice acceptor sites that would result in either skipping of the respective exon or the creation of a new cryptic splice acceptor site; both possibilities would result in retinal photoreceptor cells that lack PDE6A wild-type protein., Conclusions: we report two splice acceptor site variations in PDE6A in consanguineous Pakistani families who manifested cardinal symptoms of RP. Taken together with our previously published work, our data suggest that mutations in PDE6A account for about 2% of the total genetic load of RP in our cohort and possibly in the Pakistani population as well.
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- 2015
13. AIPL1 implicated in the pathogenesis of two cases of autosomal recessive retinal degeneration.
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Li D, Jin C, Jiao X, Li L, Bushra T, Naeem MA, Butt NH, Husnain T, Sieving PA, Riazuddin S, Riazuddin SA, and Hejtmancik JF
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- Adaptor Proteins, Signal Transducing, Adult, Amino Acid Sequence, Carrier Proteins chemistry, Electroretinography, Eye Proteins chemistry, Family, Female, Fundus Oculi, Haplotypes genetics, Humans, Lod Score, Male, Middle Aged, Molecular Sequence Data, Mutation genetics, Pakistan, Pedigree, Protein Structure, Tertiary, RNA Splice Sites genetics, Carrier Proteins genetics, Chromosomes, Human, Pair 17 genetics, Eye Proteins genetics, Genes, Recessive genetics, Retinal Degeneration genetics
- Abstract
Purpose: To localize and identify the gene and mutations causing autosomal recessive retinal dystrophy in two consanguineous Pakistani families., Methods: Consanguineous families from Pakistan were ascertained to be affected with autosomal recessive retinal degeneration. All affected individuals underwent thorough ophthalmologic examinations. Blood samples were collected, and genomic DNA was extracted using a salting out procedure. Genotyping was performed using microsatellite markers spaced at approximately 10 cM intervals. Two-point linkage analysis was performed with the lod score method. Direct DNA sequencing of amplified genomic DNA was performed for mutation screening of candidate genes., Results: Genome-wide linkage scans yielded a lod score of 3.05 at θ=0 for D17S1832 and 3.82 at θ=0 for D17S938, localizing the disease gene to a 12.22 cM (6.64 Mb) region flanked by D17S1828 and D17S1852 for family 61032 and family 61227, which contains aryl hydrocarbon receptor interacting protein-like 1 (AIPL1), a gene previously implicated in recessive Leber congenital amaurosis and autosomal dominant cone-rod dystrophy. Sequencing of AIPL1 showed a homozygous c.773G>C (p.Arg258Pro) sequence change in all affected individuals of family 61032 and a homozygous c.465G>T (p.(H93_Q155del)) change in all affected members of family 61227., Conclusions: The results strongly suggest that the c.773G>C (p.R258P) and c.465G>T (p.(H93_Q155del)) mutations in AIPL1 cause autosomal recessive retinal degeneration in these consanguineous Pakistani families.
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- 2014
14. Mutations in the β-subunit of rod phosphodiesterase identified in consanguineous Pakistani families with autosomal recessive retinitis pigmentosa.
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Ali S, Riazuddin SA, Shahzadi A, Nasir IA, Khan SN, Husnain T, Akram J, Sieving PA, Hejtmancik JF, and Riazuddin S
- Subjects
- Adult, Alleles, Animals, Base Sequence, Chromosomes, Human, Pair 4 chemistry, Chromosomes, Human, Pair 4 genetics, Consanguinity, Female, Gene Frequency, Genes, Recessive, Haplotypes, Humans, Lod Score, Male, Middle Aged, Molecular Sequence Data, Pakistan, Pedigree, Retinitis Pigmentosa pathology, Sequence Homology, Amino Acid, Asian People genetics, Cyclic Nucleotide Phosphodiesterases, Type 6 genetics, Eye Proteins genetics, Mutation, Missense, Retinal Rod Photoreceptor Cells pathology, Retinitis Pigmentosa genetics
- Abstract
Purpose: This study was designed to identify pathogenic mutations causing autosomal recessive retinitis pigmentosa (RP) in consanguineous Pakistani families., Methods: Two consanguineous families affected with autosomal recessive RP were identified from the Punjab Province of Pakistan. All affected individuals underwent a thorough ophthalmologic examination. Blood samples were collected, and genomic DNAs were extracted. Exclusion analysis was completed, and two-point LOD scores were calculated. Bidirectional sequencing of the β subunit of phosphodiesterase 6 (PDE6β) was completed., Results: During exclusion analyses both families localized to chromosome 4p, harboring PDE6β, a gene previously associated with autosomal recessive RP. Sequencing of PDE6β identified missense mutations: c.1655G>A (p.R552Q) and c.1160C>T (p.P387L) in families PKRP161 and PKRP183, respectively. Bioinformatic analyses suggested that both mutations are deleterious for the native three-dimensional structure of the PDE6β protein., Conclusions: These results strongly suggest that mutations in PDE6β are responsible for the disease phenotype in the consanguineous Pakistani families.
- Published
- 2011
15. Mapping of a new locus associated with autosomal recessive congenital cataract to chromosome 3q.
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Sabir N, Riazuddin SA, Butt T, Iqbal F, Nasir IA, Zafar AU, Qazi ZA, Butt NH, Khan SN, Husnain T, Hejtmancik JF, and Riazuddin S
- Subjects
- Adolescent, Child, Child, Preschool, Family, Female, Genetic Markers, Humans, Lod Score, Male, Pedigree, Cataract congenital, Cataract genetics, Chromosome Mapping methods, Chromosomes, Human, Pair 3 genetics, Genes, Recessive genetics, Genetic Loci genetics, Genetic Predisposition to Disease
- Abstract
Purpose: To localize the disease interval for autosomal recessive congenital cataracts in a consanguineous Pakistani family., Methods: All affected individuals underwent detailed ophthalmologic examination. Blood samples were collected and genomic DNA was extracted. A genome-wide scan was performed with fluorescently-labeled microsatellite markers on genomic DNA from affected and unaffected family members and logarithm of odds (LOD) scores were calculated., Results: Clinical records and ophthalmological examinations suggested that affected individuals have bilateral congenital cataracts. Genome-wide linkage analysis localized the critical interval to chromosome 3q with a maximum LOD score of 3.87 at θ=0; with marker D3S3609. Haplotype analyses refined the critical interval to a 23.39 cM (18.01 Mb) interval on chromosome 3q, flanked by D3S1614 proximally and D3S1262, distally., Conclusions: Here, we report a new locus for autosomal recessive congenital cataract localized to chromosome 3q in a consanguineous Pakistani family.
- Published
- 2010
16. Novel SIL1 mutations in consanguineous Pakistani families mapping to chromosomes 5q31.
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Riazuddin SA, Amiri-Kordestani L, Kaul H, Butt T, Jiao X, Riazuddin S, and Hejtmancik JF
- Subjects
- Adolescent, Brain pathology, Child, DNA Mutational Analysis, Female, Genetic Linkage, Humans, Male, Pakistan, Pedigree, Tomography, X-Ray Computed, Chromosomes, Human, Pair 5 genetics, Consanguinity, Guanine Nucleotide Exchange Factors genetics, Mutation, Missense, Spinocerebellar Degenerations genetics
- Abstract
Purpose: To investigate the genetic basis of Marinesco-Sjogren syndrome (MSS) in consanguineous Pakistani families., Methods: Two consanguineous Pakistani families with congenital cataract and muscular dystrophy were enrolled for this study. Detailed ophthalmic and systemic examination including slit lamp microscopy, electromyogram and computed tomography scans were performed to characterize the syndrome. Blood samples were collected from affected and unaffected individuals and a genome wide scan consisting of 382 polymorphic microsatellite markers was performed. Coding exons, exon-intron boundaries, 5' UTR, and 3' UTR of the candidate gene SIL1 residing in the linkage interval was sequenced bi-directionally., Results: Clinical examination of the affected members of families 60067 and 60078 revealed features of MSS. The linked interval at chromosome 5q31 harbors SIL1. Sequencing of SIL1 in family 60067 revealed a homozygous substitution; c1240C>T, leading to a premature substitution; p.Q414X. Similarly, sequencing of SIL1 in family 60078 identified a homozygous change; c.274C>T, leading to a non conservative substitution; p.R92W., Conclusion: In conclusion, our data report two novel missense mutations in two consanguineous Pakistani families affected with MSS.
- Published
- 2009
17. Primary congenital glaucoma localizes to chromosome 14q24.2-24.3 in two consanguineous Pakistani families.
- Author
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Firasat S, Riazuddin SA, Hejtmancik JF, and Riazuddin S
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- Child, Child, Preschool, Family, Female, Humans, Infant, Infant, Newborn, Lod Score, Male, Pakistan, Pedigree, Asian People genetics, Chromosomes, Human, Pair 14 genetics, Consanguinity, Glaucoma congenital, Glaucoma genetics
- Abstract
Purpose: Two consanguineous Pakistani families with autosomal recessive primary congenital glaucoma were recruited to identify the disease locus., Methods: Ophthalmic examinations including slit lamp biomicroscopy and applanation tonometry were employed to classify the phenotype. Blood samples were collected and genomic DNA was extracted. A genome wide scan was performed on both families with 382 polymorphic microsatellite markers. Two point LOD scores were calculated, and haplotypes were constructed to define the disease interval., Results: Clinical records and ophthalmic examinations suggest that affected individuals in families PKGL005 and PKGL025 have primary congenital glaucoma. Maximum two-point LOD scores of 5.88 with D14S61 at theta=0 and 6.19 with D14S43 at theta=0 were obtained for families PKGL005 and PKGL025, respectively. Haplotype analysis defined the disease locus as spanning a 6.56 cM (~4.2 Mb) genetic interval flanked by D14S289 proximally and D14S85 distally., Conclusions: Linkage analysis localizes autosomal recessive primary congenital glaucoma to chromosome 14q24.2-24.3 in consanguineous Pakistani families.
- Published
- 2008
18. Localization of autosomal recessive congenital cataracts in consanguineous Pakistani families to a new locus on chromosome 1p.
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Butt T, Yao W, Kaul H, Xiaodong J, Gradstein L, Zhang Y, Husnain T, Riazuddin S, Hejtmancik JF, and Riazuddin SA
- Subjects
- Chromosome Mapping, Cornea abnormalities, Genetic Linkage, Humans, Lod Score, Nystagmus, Pathologic genetics, Pakistan, Asian People genetics, Cataract congenital, Cataract genetics, Chromosomes, Human, Pair 1, Consanguinity, Genes, Recessive
- Abstract
Purpose: To identify the disease locus for autosomal recessive congenital cataracts in two consanguineous Pakistani families., Methods: Two Pakistani families were ascertained, ophthalmologic examination including slit lamp biomicroscopy was performed on all members, blood samples were collected and DNA was extracted. A genome-wide scan was performed using 382 polymorphic microsatellite markers on genomic DNA from affected and unaffected family members. Two-point logarithm of odds (LOD) scores were calculated using the LINKAGE program package., Results: All the affected individuals of family PKCC009 show bilateral membranous cataract, whereas the affected individuals of family PKCC039 show bilateral posterior sub-capsular cataract. Other ocular abnormalities include corneal opacities, microcornea and nystagmus in the affected individuals of PKCC009. Maximum two point LOD scores were obtained with D1S186 (4.14 at theta = 0), D1S432 (4.01 at theta = 0), D1S2892 (4.11 at theta = 0), and D1S2797 (4.07 at theta = 0) for family PKCC009 and with D1S496 (4.73 at theta = 0), D1S2892 (4.34 at theta = 0), D1S3721 (4.83 at theta = 0), and D1S2797 (4.32 at theta = 0) for family PKCC039. The common linked region, 20.76 cM (20.80 Mb), is flanked by markers D1S2729 and D1S2890 and co-segregates with the disease in both families, placing the disease locus on chromosome 1p34.3-p32.2., Conclusions: Linkage analysis of autosomal recessive cataracts in two consanguineous Pakistani families localizes a novel locus for autosomal recessive congenital cataract on chromosome 1p.
- Published
- 2007
19. Mutations in the gene encoding the alpha-subunit of rod phosphodiesterase in consanguineous Pakistani families.
- Author
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Riazuddin SA, Zulfiqar F, Zhang Q, Yao W, Li S, Jiao X, Shahzadi A, Amer M, Iqbal M, Hussnain T, Sieving PA, Riazuddin S, and Hejtmancik JF
- Subjects
- Base Sequence, Chromosomes, Human, Pair 5, Cytosine, DNA Transposable Elements, Fundus Oculi, Genes, Recessive, Humans, Isoenzymes genetics, Lod Score, Molecular Sequence Data, Mutation, Pakistan, Retinitis Pigmentosa pathology, Thymine, Asian People genetics, Consanguinity, Phosphoric Diester Hydrolases genetics, Retinal Rod Photoreceptor Cells enzymology, Retinitis Pigmentosa enzymology, Retinitis Pigmentosa genetics
- Abstract
Purpose: To localize and identify the gene and mutations causing autosomal recessive retinitis pigmentosa (RP) in consanguineous Pakistani families., Methods: Families were ascertained and patients underwent complete ophthalmological examinations. Blood samples were collected and DNA was extracted. A genome-wide scan was performed using 382 polymorphic microsatellite markers on genomic DNA from affected and unaffected family members, and lod scores were calculated., Results: A genome-wide scan of 50 families gave a lod score of 7.4172 with D5S2015 using HOMOG1. RP in all 4 linked families mapped to a 13.85 cM (14.87 Mb) region on chromosome 5q31-33 flanked by D5S2090 and D5S422. This region harbors the PDE6A gene, which is known to cause autosomal recessive RP. Sequencing of PDE6A showed a homozygous single base pair change; c.889C->T, single base pair insertion; c.2218-2219insT, and single base pair substitution in the splice acceptor site; IVS10-2A->G in each of three families. In the fourth family linked to this region, no disease-causing mutation was identified in the PDE6A gene., Conclusions: These results provide strong evidence that mutations in PDE6A result in recessive RP in three consanguineous Pakistani families. Although a fourth family was linked to markers in the 5q31-33 interval, no mutation was identified in PDE6A.
- Published
- 2006
20. A variant form of Oguchi disease mapped to 13q34 associated with partial deletion of GRK1 gene.
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Zhang Q, Zulfiqar F, Riazuddin SA, Xiao X, Yasmeen A, Rogan PK, Caruso R, Sieving PA, Riazuddin S, and Hejtmancik JF
- Subjects
- Adolescent, Adult, Chromosome Mapping, Consanguinity, Dark Adaptation, Electroretinography, Exons genetics, Female, Genetic Linkage, Humans, Lod Score, Male, Night Blindness ethnology, Night Blindness physiopathology, Pakistan epidemiology, Pedigree, Polymerase Chain Reaction, Retina physiopathology, Retinal Diseases ethnology, Retinal Diseases physiopathology, Chromosomes, Human, Pair 13 genetics, G-Protein-Coupled Receptor Kinase 1 genetics, Gene Deletion, Night Blindness genetics, Retinal Diseases genetics
- Abstract
Purpose: The purpose of this paper is to map the locus for a variant form of Oguchi disease in a Pakistani family and to identify the causative mutation., Methods: Family 61029 was ascertained in the Punjab province of Pakistan. It includes three 13- to 19-year-old patients with night blindness and 12 unaffected family members. A complete ophthalmological examination including fundus photography and electroretinography (ERG) was performed on each family member. A genome-wide scan was performed using microsatellite markers at about 10 cM intervals, and two-point lod scores were calculated. Polymerase chain reaction (PCR) cycle dideoxynucleotide sequencing was used to screen candidate genes inside the linked region for mutations and to delineate the deletion. Multiplex PCR and long template PCR were used to detect deletions and to define the size of deletions. Evaluation of fundus changes and ERG, lod score estimation, and identification of a mutation in the GRK1 gene were carried out., Results: All patients had night blindness since early childhood. Irregular coarse pigmentation was observed in the peripheral retina of each patient. The fundus appearance before and after 4 h of dark adaptation was similar except that the peripheral retinal pigmentary changes were slightly less evident after extended dark adaptation. Minimal or no rod function with normal cone function on ERG recordings were detected in all three affected members. The rod showed slow recovery to nearly normal amplitude after 4 h in the dark ERG in one individual but not in two other patients. A genome-wide scan showed linkage only to D13S285. Fine mapping defined a region from D13S1315 to 13qter, with a lod score of 2.89 at theta=0 shown by D13S285 and 2.90 at theta=0 by the D13S261-D13S285-D13S1295-D13S293 haplotype. Analysis of the GRK1 gene, which is included in this interval, identified a c.827+623_883del mutation. This intragenic deletion cosegregates with the disease in the family and is only homozygous in affected individuals. This mutation was not detected in 96 controls., Conclusions: The retinal disease in the family reported here has several features differing from typical Oguchi disease, including an atypical Mizuo-Nakamura phenomenon and a non-recordable rod ERG even after 4 h of dark adaptation. Normal visual acuity, normal caliber of retinal blood vessels, and normal cone response on ERG recording suggest retinal dysfunction rather than degeneration (i.e., a variant form of Oguchi disease but unlikely to be retinitis pigmentosa). The disease in the Pakistani family localizes to 13q34 and is caused by a novel deletion including Exon 3 of the GRK1 gene.
- Published
- 2005
21. Autosomal recessive retinitis pigmentosa in a Pakistani family mapped to CNGA1 with identification of a novel mutation.
- Author
-
Zhang Q, Zulfiqar F, Riazuddin SA, Xiao X, Ahmad Z, Riazuddin S, and Hejtmancik JF
- Subjects
- Base Sequence, Consanguinity, Cyclic Nucleotide-Gated Cation Channels, DNA Primers chemistry, Female, Genes, Recessive, Genetic Linkage, Genotype, Humans, Male, Pakistan epidemiology, Pedigree, Retinitis Pigmentosa ethnology, Retinitis Pigmentosa pathology, Sequence Analysis, DNA, Sequence Deletion, Chromosome Mapping, Eye Proteins genetics, Frameshift Mutation, Ion Channels genetics, Retinitis Pigmentosa genetics
- Abstract
Purpose: To map the locus for autosomal recessive retinitis pigmentosa in a large Pakistani family and to determine the causative mutation., Methods: A large family with multiple individuals affected by autosomal recessive retinitis pigmentosa was ascertained in the Punjab province of Pakistan as part of an ongoing project between the CEMB, Lahore, Pakistan and the NEI to identify genetic causes of eye diseases. After initial analysis of previously identified autosomal recessive retinitis pigmentosa loci, a genome wide scan was performed using microsatellite markers at about 10 cM intervals. Two point lod scores were calculated and haplotypes were analyzed in order to define disease locus. Bidirectional dideoxynucleotide sequencing was used to screen for mutations in candidate genes., Results: In the genome wide scan, autosomal recessive retinitis pigmentosa in this Pakistani family showed linkage to an 11.7 cM region of chromosome 4p12 between D4S405 and D4S1592 with a maximum lod score of 2.90 with D4S405 at theta;=0.01 Sequence analysis of CNGA1 identified a 2 bp deletion in exon 8: c.626_627delTA resulting in a frameshift, p.Ser209fsX26 in the translated protein. This mutation results in deletion of the COOH terminal 482 of 690 total amino acids in CNGA1 and their replacement by 25 novel amino acids before a premature termination. The mutation is found in a homozygous state in all 7 affected individuals and was heterozygous in all 15 unaffected family members examined. The mutant allele of CNGA1 itself shows linkage to the disease with maximum lod score of 4.43 at theta;=0., Conclusions: The autosomal recessive retinitis pigmentosa in this family is caused by a mutation in CNGA1 gene. To our knowledge, this is the first report in which both linkage analysis and identification of a mutation support CNGA1 as a cause for autosomal recessive retinitis pigmentosa.
- Published
- 2004
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