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Identification of a novel nonsense mutation in RP1 that causes autosomal recessive retinitis pigmentosa in an Indonesian family.

Siemiatkowska AM, Astuti GD, Arimadyo K, den Hollander AI, Faradz SM, Cremers FP, Collin RW - Mol. Vis. (2012)

Bottom Line: Unaffected family members either carried two wild-type alleles or were heterozygous carriers of the mutation.Most of the previously reported RP1 mutations are inherited in an autosomal dominant mode, and appear to cluster in exon 4.Here, we identified a novel homozygous p.R338* mutation in exon 4 of RP1, and speculate on the mutational mechanisms of different RP1 mutations underlying dominant and recessive RP.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

ABSTRACT

Purpose: The purpose of this study was to identify the underlying molecular genetic defect in an Indonesian family with three affected individuals who had received a diagnosis of retinitis pigmentosa (RP).

Methods: Clinical evaluation of the family members included measuring visual acuity and fundoscopy, and assessing visual field and color vision. Genomic DNA of the three affected individuals was analyzed with Illumina 700k single nucleotide polymorphism (SNP) arrays, and homozygous regions were identified using PLINK software. Mutation analysis was performed with sequence analysis of the retinitis pigmentosa 1 (RP1) gene that resided in one of the homozygous regions. The frequency of the identified mutation in the Indonesian population was determined with TaqI restriction fragment length polymorphism analysis.

Results: A novel homozygous nonsense mutation in exon 4 of the RP1 gene, c.1012C>T (p.R338*), was identified in the proband and her two affected sisters. Unaffected family members either carried two wild-type alleles or were heterozygous carriers of the mutation. The mutation was not present in 184 Indonesian control samples.

Conclusions: Most of the previously reported RP1 mutations are inherited in an autosomal dominant mode, and appear to cluster in exon 4. Here, we identified a novel homozygous p.R338* mutation in exon 4 of RP1, and speculate on the mutational mechanisms of different RP1 mutations underlying dominant and recessive RP.

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Related in: MedlinePlus

RP1 gene and identified mutations. Schematic representation of the location of mutations in the RP1 gene. Below are mutations responsible for dominant retinitis pigmentosa (adRP) whereas mutations above the gene cause autosomal recessive RP (arRP). The mutation identified in this study is indicated with a black rectangle. The portion of the gene that encodes the doublecortin (DCX) domains (amino acids 36–118 and 154–233) is indicated with green, and the Drosophila melanogaster bifocal (BIF) domain (amino acids 486−635) is depicted in red. Missense changes, for which the pathogenicity is uncertain, are not included in this scheme. Four groups of arRP-causing mutations are marked with numbers. GR.1=protein-truncating mutations that reside in exon 2 or exon 3 (nonsense-mediated mRNA decay); GR.2=missense mutations; GR.3=protein-truncating mutations near the 3′ end of the gene, preserving residual activity; GR.4=truncating mutations located in the proximal part of exon 4.
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f3: RP1 gene and identified mutations. Schematic representation of the location of mutations in the RP1 gene. Below are mutations responsible for dominant retinitis pigmentosa (adRP) whereas mutations above the gene cause autosomal recessive RP (arRP). The mutation identified in this study is indicated with a black rectangle. The portion of the gene that encodes the doublecortin (DCX) domains (amino acids 36–118 and 154–233) is indicated with green, and the Drosophila melanogaster bifocal (BIF) domain (amino acids 486−635) is depicted in red. Missense changes, for which the pathogenicity is uncertain, are not included in this scheme. Four groups of arRP-causing mutations are marked with numbers. GR.1=protein-truncating mutations that reside in exon 2 or exon 3 (nonsense-mediated mRNA decay); GR.2=missense mutations; GR.3=protein-truncating mutations near the 3′ end of the gene, preserving residual activity; GR.4=truncating mutations located in the proximal part of exon 4.

Mentions: The many mutations in exon 4 of RP1, which cause autosomal dominant RP, all tend to cluster in a “hot spot” region between amino acid residues 500 and 1053 (Figure 3) [6-24]. Since these mutations are expected to be insensitive to nonsense-mediated decay due to the absence of a downstream intron, they result in the production of truncated proteins [33]. Previously, mutant RP1 mRNA was found to be present in a human lymphoblast cell line carrying the p.R677* variant, providing evidence that this mRNA indeed escapes the nonsense-mediated mRNA decay process. The resulting truncated proteins lack important functional domains, but are still able to interact with wild-type RP1 and/or microtubule-associated proteins [35]. This hypothesis is supported by a previous study, which showed that in Rp1-myc mice that expressed only the 661 N-terminal amino acids of RP1, truncated proteins are produced and localize correctly to the axonemes of photoreceptor cells [36]. Due to the retained ability to interact with microtubule-associated proteins and/or wild-type RP1, these mutated proteins are thought to abolish the function of the normal RP1 molecules in a dominant-negative fashion.


Identification of a novel nonsense mutation in RP1 that causes autosomal recessive retinitis pigmentosa in an Indonesian family.

Siemiatkowska AM, Astuti GD, Arimadyo K, den Hollander AI, Faradz SM, Cremers FP, Collin RW - Mol. Vis. (2012)

RP1 gene and identified mutations. Schematic representation of the location of mutations in the RP1 gene. Below are mutations responsible for dominant retinitis pigmentosa (adRP) whereas mutations above the gene cause autosomal recessive RP (arRP). The mutation identified in this study is indicated with a black rectangle. The portion of the gene that encodes the doublecortin (DCX) domains (amino acids 36–118 and 154–233) is indicated with green, and the Drosophila melanogaster bifocal (BIF) domain (amino acids 486−635) is depicted in red. Missense changes, for which the pathogenicity is uncertain, are not included in this scheme. Four groups of arRP-causing mutations are marked with numbers. GR.1=protein-truncating mutations that reside in exon 2 or exon 3 (nonsense-mediated mRNA decay); GR.2=missense mutations; GR.3=protein-truncating mutations near the 3′ end of the gene, preserving residual activity; GR.4=truncating mutations located in the proximal part of exon 4.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472925&req=5

f3: RP1 gene and identified mutations. Schematic representation of the location of mutations in the RP1 gene. Below are mutations responsible for dominant retinitis pigmentosa (adRP) whereas mutations above the gene cause autosomal recessive RP (arRP). The mutation identified in this study is indicated with a black rectangle. The portion of the gene that encodes the doublecortin (DCX) domains (amino acids 36–118 and 154–233) is indicated with green, and the Drosophila melanogaster bifocal (BIF) domain (amino acids 486−635) is depicted in red. Missense changes, for which the pathogenicity is uncertain, are not included in this scheme. Four groups of arRP-causing mutations are marked with numbers. GR.1=protein-truncating mutations that reside in exon 2 or exon 3 (nonsense-mediated mRNA decay); GR.2=missense mutations; GR.3=protein-truncating mutations near the 3′ end of the gene, preserving residual activity; GR.4=truncating mutations located in the proximal part of exon 4.
Mentions: The many mutations in exon 4 of RP1, which cause autosomal dominant RP, all tend to cluster in a “hot spot” region between amino acid residues 500 and 1053 (Figure 3) [6-24]. Since these mutations are expected to be insensitive to nonsense-mediated decay due to the absence of a downstream intron, they result in the production of truncated proteins [33]. Previously, mutant RP1 mRNA was found to be present in a human lymphoblast cell line carrying the p.R677* variant, providing evidence that this mRNA indeed escapes the nonsense-mediated mRNA decay process. The resulting truncated proteins lack important functional domains, but are still able to interact with wild-type RP1 and/or microtubule-associated proteins [35]. This hypothesis is supported by a previous study, which showed that in Rp1-myc mice that expressed only the 661 N-terminal amino acids of RP1, truncated proteins are produced and localize correctly to the axonemes of photoreceptor cells [36]. Due to the retained ability to interact with microtubule-associated proteins and/or wild-type RP1, these mutated proteins are thought to abolish the function of the normal RP1 molecules in a dominant-negative fashion.

Bottom Line: Unaffected family members either carried two wild-type alleles or were heterozygous carriers of the mutation.Most of the previously reported RP1 mutations are inherited in an autosomal dominant mode, and appear to cluster in exon 4.Here, we identified a novel homozygous p.R338* mutation in exon 4 of RP1, and speculate on the mutational mechanisms of different RP1 mutations underlying dominant and recessive RP.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

ABSTRACT

Purpose: The purpose of this study was to identify the underlying molecular genetic defect in an Indonesian family with three affected individuals who had received a diagnosis of retinitis pigmentosa (RP).

Methods: Clinical evaluation of the family members included measuring visual acuity and fundoscopy, and assessing visual field and color vision. Genomic DNA of the three affected individuals was analyzed with Illumina 700k single nucleotide polymorphism (SNP) arrays, and homozygous regions were identified using PLINK software. Mutation analysis was performed with sequence analysis of the retinitis pigmentosa 1 (RP1) gene that resided in one of the homozygous regions. The frequency of the identified mutation in the Indonesian population was determined with TaqI restriction fragment length polymorphism analysis.

Results: A novel homozygous nonsense mutation in exon 4 of the RP1 gene, c.1012C>T (p.R338*), was identified in the proband and her two affected sisters. Unaffected family members either carried two wild-type alleles or were heterozygous carriers of the mutation. The mutation was not present in 184 Indonesian control samples.

Conclusions: Most of the previously reported RP1 mutations are inherited in an autosomal dominant mode, and appear to cluster in exon 4. Here, we identified a novel homozygous p.R338* mutation in exon 4 of RP1, and speculate on the mutational mechanisms of different RP1 mutations underlying dominant and recessive RP.

Show MeSH
Related in: MedlinePlus