title: Genetic analysis of four Pakistani families with achromatopsia and a novel S4 motif mutation of CNGA3.
abstract: BACKGROUND
  To identify the causative variants of achromatopsia (ACHM) in four Pakistani families presenting autosomal recessive ACHM.
  
  
  METHODS
  Four families (50, 55, 70 and 74) exhibiting features of achromatopsia were subjected to homozygosity mapping with STS markers flanking known ACHM loci. Mutation screening was done for two of the families linked to CNGA3 and CNGB3 by direct sequencing of the coding regions and exon-intron boundaries of genes to find the pathogenic variant.
  
  
  RESULTS
  Homozygosity mapping showed co-segregation of CNGA3 in family 50 and CNGB3 in family 74. Sequencing of coding regions of CNGA3 in family 50 revealed a novel missense mutation, c.827A>G, in exon 7, which results in p.N276S substitution. N276S is located in the S4 motif of the CNGA3 protein and is conserved in all channel proteins. Bioinformatics analysis showed that the N276S substitution altered the channel conformation by shifting the helix. No pathogenic variation was identified in any affected members of family 74 in the coding sequence of CNGB3. The other two families, 55 and 70, were not linked to any known ACHM loci, indicating further heterogeneity of the ACHM phenotype.
  
  
  CONCLUSIONS
  We describe a novel S4 motif mutation of CNGA3 in a Pakistani family.
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Muhammad Arif Nadeem
authors.initials: MA
authors.lastname: Saqib
authors.forename: Bilal Malik
authors.initials: BM
authors.lastname: Awan
authors.forename: Mehwish
authors.initials: M
authors.lastname: Sarfraz
authors.forename: Muhammad Nasim
authors.initials: MN
authors.lastname: Khan
authors.forename: Sajid
authors.initials: S
authors.lastname: Rashid
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ansar
mesh_terms: D000368:Aged; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics*; D003117:Color Vision Defects / Q000235:genetics*; D003241:Consanguinity; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics*; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010154:Pakistan; D010375:Pedigree; D016133:Polymerase Chain Reaction
chemical_list: C518238:CNGA3 protein, human; D054815:Cyclic Nucleotide-Gated Cation Channels