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A novel crumbs homolog 1 mutation in a family with retinitis pigmentosa, nanophthalmos, and optic disc drusen.

Paun CC, Pijl BJ, Siemiatkowska AM, Collin RW, Cremers FP, Hoyng CB, den Hollander AI - Mol. Vis. (2012)

Bottom Line: After MFRP was excluded, genome-wide homozygosity mapping was performed with 250 K single nucleotide polymorphism (SNP) microarrays.Ophthalmological evaluation of both affected individuals in the family revealed a decreased axial length (18-19 mm), retinal dystrophy, macular edema, and hyperopia of >+8.0 diopters.In this study, we demonstrated that a similar disease complex can be caused by mutations in the CRB1 gene.

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 is to identify the genetic defect in a Turkish family with autosomal recessive retinitis pigmentosa, nanophthalmos, and optic disc drusen.

Methods: Ophthalmological examinations consisted of measuring the best-corrected visual acuity and the refractive error, electroretinography, optical coherence tomography, B-mode ultrasonography, and fundus photography. The involvement of the membrane frizzled-related protein (MFRP) gene in this family was studied with direct DNA sequencing of the coding exons of MFRP and with linkage analysis with microsatellite markers. After MFRP was excluded, genome-wide homozygosity mapping was performed with 250 K single nucleotide polymorphism (SNP) microarrays. Mutation analysis of the crumbs homolog 1 (CRB1) gene was performed with direct sequencing.

Results: Ophthalmological evaluation of both affected individuals in the family revealed a decreased axial length (18-19 mm), retinal dystrophy, macular edema, and hyperopia of >+8.0 diopters. Sequencing of MFRP did not reveal any pathogenic changes, and microsatellite marker analysis showed that the chromosomal region did not segregate within the disease in this family. Genome-wide homozygosity mapping using single nucleotide polymorphism microarrays revealed a 28-Mb homozygous region encompassing the CRB1 gene, and direct sequencing disclosed a novel homozygous missense mutation (p.Gly833Asp) in CRB1.

Conclusions: Previous studies associated mutations in the MFRP gene with the syndrome nanophthalmos-retinitis pigmentosa-foveoschisis-optic disc drusen. In this study, we demonstrated that a similar disease complex can be caused by mutations in the CRB1 gene.

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Related in: MedlinePlus

Identification of a novel crumbs homolog 1 mutation in a family with retinitis pigmentosa, nanophthalmos, and optic disc drusen. A: Crumbs homolog 1 sequence analysis demonstrated a homozygous mutation (c.2498G>A) in exon 7. B: At the protein level, the mutation (p.Gly833Asp) alters a highly conserved amino acid residue.
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f3: Identification of a novel crumbs homolog 1 mutation in a family with retinitis pigmentosa, nanophthalmos, and optic disc drusen. A: Crumbs homolog 1 sequence analysis demonstrated a homozygous mutation (c.2498G>A) in exon 7. B: At the protein level, the mutation (p.Gly833Asp) alters a highly conserved amino acid residue.

Mentions: Sequence analysis of CRB1 revealed a novel homozygous missense mutation in exon 7 (c.2498G>A; p.Gly833Asp), which affects a highly conserved amino acid residue (Figure 3). The mutation was found homozygously in both affected siblings, and heterozygously in the unaffected father. Restriction enzyme digestion did not reveal the mutation in 100 Turkish controls. Bioinformatic analyses confirmed pathogenicity of the mutation (Grantham score: 94, Sorting Intolerant From Tolerant [SIFT]: deleterious, Polymorphism Phenotyping v2 [PolyPHen-2]: probably damaging with a score of 1.000, PhyloP: 5.3).


A novel crumbs homolog 1 mutation in a family with retinitis pigmentosa, nanophthalmos, and optic disc drusen.

Paun CC, Pijl BJ, Siemiatkowska AM, Collin RW, Cremers FP, Hoyng CB, den Hollander AI - Mol. Vis. (2012)

Identification of a novel crumbs homolog 1 mutation in a family with retinitis pigmentosa, nanophthalmos, and optic disc drusen. A: Crumbs homolog 1 sequence analysis demonstrated a homozygous mutation (c.2498G>A) in exon 7. B: At the protein level, the mutation (p.Gly833Asp) alters a highly conserved amino acid residue.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472923&req=5

f3: Identification of a novel crumbs homolog 1 mutation in a family with retinitis pigmentosa, nanophthalmos, and optic disc drusen. A: Crumbs homolog 1 sequence analysis demonstrated a homozygous mutation (c.2498G>A) in exon 7. B: At the protein level, the mutation (p.Gly833Asp) alters a highly conserved amino acid residue.
Mentions: Sequence analysis of CRB1 revealed a novel homozygous missense mutation in exon 7 (c.2498G>A; p.Gly833Asp), which affects a highly conserved amino acid residue (Figure 3). The mutation was found homozygously in both affected siblings, and heterozygously in the unaffected father. Restriction enzyme digestion did not reveal the mutation in 100 Turkish controls. Bioinformatic analyses confirmed pathogenicity of the mutation (Grantham score: 94, Sorting Intolerant From Tolerant [SIFT]: deleterious, Polymorphism Phenotyping v2 [PolyPHen-2]: probably damaging with a score of 1.000, PhyloP: 5.3).

Bottom Line: After MFRP was excluded, genome-wide homozygosity mapping was performed with 250 K single nucleotide polymorphism (SNP) microarrays.Ophthalmological evaluation of both affected individuals in the family revealed a decreased axial length (18-19 mm), retinal dystrophy, macular edema, and hyperopia of >+8.0 diopters.In this study, we demonstrated that a similar disease complex can be caused by mutations in the CRB1 gene.

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 is to identify the genetic defect in a Turkish family with autosomal recessive retinitis pigmentosa, nanophthalmos, and optic disc drusen.

Methods: Ophthalmological examinations consisted of measuring the best-corrected visual acuity and the refractive error, electroretinography, optical coherence tomography, B-mode ultrasonography, and fundus photography. The involvement of the membrane frizzled-related protein (MFRP) gene in this family was studied with direct DNA sequencing of the coding exons of MFRP and with linkage analysis with microsatellite markers. After MFRP was excluded, genome-wide homozygosity mapping was performed with 250 K single nucleotide polymorphism (SNP) microarrays. Mutation analysis of the crumbs homolog 1 (CRB1) gene was performed with direct sequencing.

Results: Ophthalmological evaluation of both affected individuals in the family revealed a decreased axial length (18-19 mm), retinal dystrophy, macular edema, and hyperopia of >+8.0 diopters. Sequencing of MFRP did not reveal any pathogenic changes, and microsatellite marker analysis showed that the chromosomal region did not segregate within the disease in this family. Genome-wide homozygosity mapping using single nucleotide polymorphism microarrays revealed a 28-Mb homozygous region encompassing the CRB1 gene, and direct sequencing disclosed a novel homozygous missense mutation (p.Gly833Asp) in CRB1.

Conclusions: Previous studies associated mutations in the MFRP gene with the syndrome nanophthalmos-retinitis pigmentosa-foveoschisis-optic disc drusen. In this study, we demonstrated that a similar disease complex can be caused by mutations in the CRB1 gene.

Show MeSH
Related in: MedlinePlus