title: Pathogenic mutations in TULP1 responsible for retinitis pigmentosa identified in consanguineous familial cases.
abstract: To identify pathogenic mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in consanguineous familial cases.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
authors.forename: Inayat
authors.initials: I
authors.lastname: Ullah
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Firoz
authors.initials: F
authors.lastname: Kabir
authors.affiliation: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Iqbal
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Clare Brooks S
authors.initials: CB
authors.lastname: Gottsch
authors.affiliation: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
authors.forename: Muhammad Asif
authors.initials: MA
authors.lastname: Naeem
authors.affiliation: Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan; National Centre for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.
authors.forename: Muhammad Zaman
authors.initials: MZ
authors.lastname: Assir
authors.affiliation: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
authors.forename: Shaheen N
authors.initials: SN
authors.lastname: Khan
authors.affiliation: Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan; National Centre for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.
authors.forename: Javed
authors.initials: J
authors.lastname: Akram
authors.affiliation: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan; Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan; National Centre for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
authors.affiliation: Shiley Eye Institute, University of California, San Diego, CA.
authors.forename: Radha
authors.initials: R
authors.lastname: Ayyagari
authors.affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD.
authors.forename: J Fielding
authors.initials: JF
authors.lastname: Hejtmancik
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: S Amer
authors.initials: SA
authors.lastname: Riazuddin
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001483:Base Sequence; D002648:Child; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D003198:Computer Simulation; D003241:Consanguinity; D017124:Conserved Sequence / Q000235:genetics; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics*; D005190:Family; D005260:Female; D005819:Genetic Markers; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D012174:Retinitis Pigmentosa / Q000235:genetics*; D055815:Young Adult
chemical_list: D005136:Eye Proteins; D005819:Genetic Markers; D022821:RNA Splice Sites; C105443:TULP1 protein, human