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.
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: Maleeha Azam; Rob W J Collin; Syed Tahir Abbas Shah; Aftab Ali Shah; Muhammad Imran Khan; Alamdar Hussain; Ahmed Sadeque; Tim M Strom; Alberta A H J Thiadens; Susanne Roosing; Anneke I den Hollander; Frans P M Cremers; Raheel Qamar Journal: Mol Vis Date: 2010-04-29 Impact factor: 2.367
Authors: Alberta A H J Thiadens; Anneke I den Hollander; Susanne Roosing; Sander B Nabuurs; Renate C Zekveld-Vroon; Rob W J Collin; Elfride De Baere; Robert K Koenekoop; Mary J van Schooneveld; Tim M Strom; Janneke J C van Lith-Verhoeven; Andrew J Lotery; Norka van Moll-Ramirez; Bart P Leroy; L Ingeborgh van den Born; Carel B Hoyng; Frans P M Cremers; Caroline C W Klaver Journal: Am J Hum Genet Date: 2009-07-16 Impact factor: 11.025
Authors: Muhammad Ansar; Regie Lyn P Santos-Cortez; Muhammad Arif Nadeem Saqib; Fareeha Zulfiqar; Kwanghyuk Lee; Naeem Mahmood Ashraf; Ehsan Ullah; Xin Wang; Sundus Sajid; Falak Sher Khan; Muhammad Amin-ud-Din; Joshua D Smith; Jay Shendure; Michael J Bamshad; Deborah A Nickerson; Abdul Hameed; Saima Riazuddin; Zubair M Ahmed; Wasim Ahmad; Suzanne M Leal Journal: Hum Genet Date: 2015-06-11 Impact factor: 4.132
Authors: Muhammad Imran Khan; Maleeha Azam; Muhammad Ajmal; Rob W J Collin; Anneke I den Hollander; Frans P M Cremers; Raheel Qamar Journal: Genes (Basel) Date: 2014-03-11 Impact factor: 4.096