title: Autosomal recessive retinitis pigmentosa in a Pakistani family mapped to CNGA1 with identification of a novel mutation.
abstract: OBJECTIVE
  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.
authors.affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-1860, USA.
authors.forename: Qingjiong
authors.initials: Q
authors.lastname: Zhang
authors.forename: Fareeha
authors.initials: F
authors.lastname: Zulfiqar
authors.forename: S Amer
authors.initials: SA
authors.lastname: Riazuddin
authors.forename: Xueshan
authors.initials: X
authors.lastname: Xiao
authors.forename: Zahoor
authors.initials: Z
authors.lastname: Ahmad
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
authors.forename: J Fielding
authors.initials: JF
authors.lastname: Hejtmancik
mesh_terms: D001483:Base Sequence; D002874:Chromosome Mapping; D003241:Consanguinity; D054815:Cyclic Nucleotide-Gated Cation Channels; D017931:DNA Primers / Q000737:chemistry; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D005808:Genes, Recessive; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D007473:Ion Channels / Q000235:genetics*; D008297:Male; D010154:Pakistan / Q000453:epidemiology; D010375:Pedigree; D012174:Retinitis Pigmentosa / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D017931:DNA Primers; D005136:Eye Proteins; D007473:Ion Channels