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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

Pedigree structure and mutation analysis of the Indonesian arRP family. A: In the family pedigree, affected individuals are indicated with filled symbols whereas unaffected relatives are indicated with open symbols. Genotypes are indicated below the pedigree symbols. M represents the c.1012C>T: (p.R338*) substitution, and + represents the wild-type allele. B: Shown are sequence chromatograms of RP1 corresponding to the three affected individuals (II:4, II:6, II:7), the proband’s father I:1), and one unaffected sibling (II:2). The substituted nucleotides are indicated with arrows.
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f1: Pedigree structure and mutation analysis of the Indonesian arRP family. A: In the family pedigree, affected individuals are indicated with filled symbols whereas unaffected relatives are indicated with open symbols. Genotypes are indicated below the pedigree symbols. M represents the c.1012C>T: (p.R338*) substitution, and + represents the wild-type allele. B: Shown are sequence chromatograms of RP1 corresponding to the three affected individuals (II:4, II:6, II:7), the proband’s father I:1), and one unaffected sibling (II:2). The substituted nucleotides are indicated with arrows.

Mentions: An Indonesian family of Javanese origin with three affected individuals and two available unaffected relatives was included in this study (Figure 1). Affected family members were diagnosed by an ophthalmologist at the Dr. Kariadi Hospital in Semarang, Central Java, Indonesia. This study was approved by the ethical review boards of the centers involved. Informed consent adhering to the tenets of the Declaration of Helsinki was obtained from all participating affected individuals and unaffected family members. In addition, 184 ethnically matched and unrelated control individuals took part in this study.


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)

Pedigree structure and mutation analysis of the Indonesian arRP family. A: In the family pedigree, affected individuals are indicated with filled symbols whereas unaffected relatives are indicated with open symbols. Genotypes are indicated below the pedigree symbols. M represents the c.1012C>T: (p.R338*) substitution, and + represents the wild-type allele. B: Shown are sequence chromatograms of RP1 corresponding to the three affected individuals (II:4, II:6, II:7), the proband’s father I:1), and one unaffected sibling (II:2). The substituted nucleotides are indicated with arrows.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Pedigree structure and mutation analysis of the Indonesian arRP family. A: In the family pedigree, affected individuals are indicated with filled symbols whereas unaffected relatives are indicated with open symbols. Genotypes are indicated below the pedigree symbols. M represents the c.1012C>T: (p.R338*) substitution, and + represents the wild-type allele. B: Shown are sequence chromatograms of RP1 corresponding to the three affected individuals (II:4, II:6, II:7), the proband’s father I:1), and one unaffected sibling (II:2). The substituted nucleotides are indicated with arrows.
Mentions: An Indonesian family of Javanese origin with three affected individuals and two available unaffected relatives was included in this study (Figure 1). Affected family members were diagnosed by an ophthalmologist at the Dr. Kariadi Hospital in Semarang, Central Java, Indonesia. This study was approved by the ethical review boards of the centers involved. Informed consent adhering to the tenets of the Declaration of Helsinki was obtained from all participating affected individuals and unaffected family members. In addition, 184 ethnically matched and unrelated control individuals took part in this study.

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