Loss of function mutations in RP1 are responsible for retinitis pigmentosa in consanguineous familial cases.

PurposeThis study was undertaken to identify causal mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in consanguineous families.MethodsLarge consanguineous families were ascertained from the Punjab province of Pakistan. An ophthalmic examination consisting of a fundus evaluation and electroretinography (ERG) was completed, and small aliquots of blood were collected from all participating individuals. Genomic DNA was extracted from white blood cells, and a genome-wide linkage or a locus-specific exclusion analysis was completed with polymorphic short tandem repeats (STRs). Two-point logarithm of odds (LOD) scores were calculated, and all coding exons and exon-intron boundaries of RP1 were sequenced to identify the causal mutation.ResultsThe ophthalmic examination showed that affected individuals in all families manifest cardinal symptoms of RP. Genome-wide scans localized the disease phenotype to chromosome 8q, a region harboring RP1, a gene previously implicated in the pathogenesis of RP. Sanger sequencing identified a homozygous single base deletion in exon 4: c.3697delT (p.S1233Pfs22*), a single base substitution in intron 3: c.787+1G>A (p.I263Nfs8*), a 2 bp duplication in exon 2: c.551_552dupTA (p.Q185Yfs4*) and an 11,117 bp deletion that removes all three coding exons of RP1. These variations segregated with the disease phenotype within the respective families and were not present in ethnically matched control samples.ConclusionsThese results strongly suggest that these mutations in RP1 are responsible for the retinal phenotype in affected individuals of all four consanguineous families

Loss of function mutations in RP1 are responsible for retinitis pigmentosa in consanguineous familial cases.

PurposeThis study was undertaken to identify causal mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in consanguineous families.MethodsLarge consanguineous families were ascertained from the Punjab province of Pakistan. An ophthalmic examination consisting of a fundus evaluation and electroretinography (ERG) was completed, and small aliquots of blood were collected from all participating individuals. Genomic DNA was extracted from white blood cells, and a genome-wide linkage or a locus-specific exclusion analysis was completed with polymorphic short tandem repeats (STRs). Two-point logarithm of odds (LOD) scores were calculated, and all coding exons and exon-intron boundaries of RP1 were sequenced to identify the causal mutation.ResultsThe ophthalmic examination showed that affected individuals in all families manifest cardinal symptoms of RP. Genome-wide scans localized the disease phenotype to chromosome 8q, a region harboring RP1, a gene previously implicated in the pathogenesis of RP. Sanger sequencing identified a homozygous single base deletion in exon 4: c.3697delT (p.S1233Pfs22*), a single base substitution in intron 3: c.787+1G>A (p.I263Nfs8*), a 2 bp duplication in exon 2: c.551_552dupTA (p.Q185Yfs4*) and an 11,117 bp deletion that removes all three coding exons of RP1. These variations segregated with the disease phenotype within the respective families and were not present in ethnically matched control samples.ConclusionsThese results strongly suggest that these mutations in RP1 are responsible for the retinal phenotype in affected individuals of all four consanguineous families

Mutations in GRM6 identified in consanguineous Pakistani families with congenital stationary night blindness.

PurposeThis study was undertaken to investigate the causal mutations responsible for autosomal recessive congenital stationary night blindness (CSNB) in consanguineous Pakistani families.MethodsTwo 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.ResultsAccording 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.ConclusionsWe identified a novel nonsense and a previously reported missense mutation in GRM6 that were responsible for autosomal recessive CSNB in patients of Pakistani decent