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Biallelic mutation of protocadherin-21 (PCDH21) causes retinal degeneration in humans.

Henderson RH, Li Z, Abd El Aziz MM, Mackay DS, Eljinini MA, Zeidan M, Moore AT, Bhattacharya SS, Webster AR - Mol. Vis. (2010)

Bottom Line: No color vision was detected in any proband.The fundus appearance included the later development of characteristic circular patches of pigment epithelial atrophy at the macula and in the peripheral retina.Biallelic mutations in the photoreceptor-specific gene PCDH21 cause recessive retinal degeneration in humans.

View Article: PubMed Central - PubMed

Affiliation: Moorfields Eye Hospital, London, UK.

ABSTRACT

Purpose: To describe the clinical findings and mutations in affected members of two families with an autosomal recessive retinal dystrophy associated with mutations in the protocadherin-21 (PCDH21) gene.

Methods: A full genome scan of members of two consanguineous families segregating an autosomal recessive retinal dystrophy was performed and regions identical by descent identified. Positional candidate genes were identified and sequenced. All patients had a detailed ophthalmic examination, including electroretinography and retinal imaging.

Results: Affected members of both families showed identical homozygosity for an overlapping region of chromosome 10q. Sequencing of a candidate gene, PCDH21, showed two separate homozygous single-base deletions, c.337delG (p.G113AfsX1) and c.1459delG (p.G487GfsX20), which were not detected in 282 control chromosomes. Affected members of the two families first reported nyctalopia in late teenage years and retained good central vision until their late 30s. No color vision was detected in any proband. The fundus appearance included the later development of characteristic circular patches of pigment epithelial atrophy at the macula and in the peripheral retina.

Conclusions: Biallelic mutations in the photoreceptor-specific gene PCDH21 cause recessive retinal degeneration in humans.

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Related in: MedlinePlus

These are illustrations of both the exon structure and a schematic of the Protocadherin-21 (PCDH21) protein with indications of the location of the two deletions. Sequence alignments demonstrate the conservation of both amino-acid positions across several species. Panel A: PCDH21 exon structure as derived from ensembl: the exons are colored according to domain structure, and, as illustrated in Panel B, with asterisks to denote the location of the novel deletions. Panel B is a schematic of the cellular domain structure derived from UniProt (created using Adobe Illustrator-Adobe Systems Inc.) with the protein numbers corresponding to each of the structural domains. Panel C is an sequence alignment created using PipeAlign for PCDH21 mutation p.G113fsX1, that was identified in family 1, and shows that there is a high level of conservation at this amino acid position-except for species Danio rerio. Panel D is a further alignment around the site of the PCDH21 deletion p.G487fsX20, identified in family 2, demonstrating a high level of conservation at this amino acid position and therefore providing evidence of the likely deleterious effect of this variant.
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f4: These are illustrations of both the exon structure and a schematic of the Protocadherin-21 (PCDH21) protein with indications of the location of the two deletions. Sequence alignments demonstrate the conservation of both amino-acid positions across several species. Panel A: PCDH21 exon structure as derived from ensembl: the exons are colored according to domain structure, and, as illustrated in Panel B, with asterisks to denote the location of the novel deletions. Panel B is a schematic of the cellular domain structure derived from UniProt (created using Adobe Illustrator-Adobe Systems Inc.) with the protein numbers corresponding to each of the structural domains. Panel C is an sequence alignment created using PipeAlign for PCDH21 mutation p.G113fsX1, that was identified in family 1, and shows that there is a high level of conservation at this amino acid position-except for species Danio rerio. Panel D is a further alignment around the site of the PCDH21 deletion p.G487fsX20, identified in family 2, demonstrating a high level of conservation at this amino acid position and therefore providing evidence of the likely deleterious effect of this variant.

Mentions: In family 2, the largest region of autozygosity, which contained 195 contiguous homozygous SNPs, was on chromosome 10q. Direct sequencing of PCDH21 revealed a homozygous single-base deletion in exon 13, c.1459delG, p.G487GfsX20 (Figure 2B). This is predicted to lead to truncation of the protein through a premature stop codon, 19 codons downstream of the deletion. This deletion segregated as a recessive allele in family 2 and was not found in 292 control chromosomes or in our LCA and arRP panel. Both deletions reside within the cadherin domains of the protein and occur at amino-acid positions that are highly conserved across species (Figure 4A-D).


Biallelic mutation of protocadherin-21 (PCDH21) causes retinal degeneration in humans.

Henderson RH, Li Z, Abd El Aziz MM, Mackay DS, Eljinini MA, Zeidan M, Moore AT, Bhattacharya SS, Webster AR - Mol. Vis. (2010)

These are illustrations of both the exon structure and a schematic of the Protocadherin-21 (PCDH21) protein with indications of the location of the two deletions. Sequence alignments demonstrate the conservation of both amino-acid positions across several species. Panel A: PCDH21 exon structure as derived from ensembl: the exons are colored according to domain structure, and, as illustrated in Panel B, with asterisks to denote the location of the novel deletions. Panel B is a schematic of the cellular domain structure derived from UniProt (created using Adobe Illustrator-Adobe Systems Inc.) with the protein numbers corresponding to each of the structural domains. Panel C is an sequence alignment created using PipeAlign for PCDH21 mutation p.G113fsX1, that was identified in family 1, and shows that there is a high level of conservation at this amino acid position-except for species Danio rerio. Panel D is a further alignment around the site of the PCDH21 deletion p.G487fsX20, identified in family 2, demonstrating a high level of conservation at this amino acid position and therefore providing evidence of the likely deleterious effect of this variant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2806159&req=5

f4: These are illustrations of both the exon structure and a schematic of the Protocadherin-21 (PCDH21) protein with indications of the location of the two deletions. Sequence alignments demonstrate the conservation of both amino-acid positions across several species. Panel A: PCDH21 exon structure as derived from ensembl: the exons are colored according to domain structure, and, as illustrated in Panel B, with asterisks to denote the location of the novel deletions. Panel B is a schematic of the cellular domain structure derived from UniProt (created using Adobe Illustrator-Adobe Systems Inc.) with the protein numbers corresponding to each of the structural domains. Panel C is an sequence alignment created using PipeAlign for PCDH21 mutation p.G113fsX1, that was identified in family 1, and shows that there is a high level of conservation at this amino acid position-except for species Danio rerio. Panel D is a further alignment around the site of the PCDH21 deletion p.G487fsX20, identified in family 2, demonstrating a high level of conservation at this amino acid position and therefore providing evidence of the likely deleterious effect of this variant.
Mentions: In family 2, the largest region of autozygosity, which contained 195 contiguous homozygous SNPs, was on chromosome 10q. Direct sequencing of PCDH21 revealed a homozygous single-base deletion in exon 13, c.1459delG, p.G487GfsX20 (Figure 2B). This is predicted to lead to truncation of the protein through a premature stop codon, 19 codons downstream of the deletion. This deletion segregated as a recessive allele in family 2 and was not found in 292 control chromosomes or in our LCA and arRP panel. Both deletions reside within the cadherin domains of the protein and occur at amino-acid positions that are highly conserved across species (Figure 4A-D).

Bottom Line: No color vision was detected in any proband.The fundus appearance included the later development of characteristic circular patches of pigment epithelial atrophy at the macula and in the peripheral retina.Biallelic mutations in the photoreceptor-specific gene PCDH21 cause recessive retinal degeneration in humans.

View Article: PubMed Central - PubMed

Affiliation: Moorfields Eye Hospital, London, UK.

ABSTRACT

Purpose: To describe the clinical findings and mutations in affected members of two families with an autosomal recessive retinal dystrophy associated with mutations in the protocadherin-21 (PCDH21) gene.

Methods: A full genome scan of members of two consanguineous families segregating an autosomal recessive retinal dystrophy was performed and regions identical by descent identified. Positional candidate genes were identified and sequenced. All patients had a detailed ophthalmic examination, including electroretinography and retinal imaging.

Results: Affected members of both families showed identical homozygosity for an overlapping region of chromosome 10q. Sequencing of a candidate gene, PCDH21, showed two separate homozygous single-base deletions, c.337delG (p.G113AfsX1) and c.1459delG (p.G487GfsX20), which were not detected in 282 control chromosomes. Affected members of the two families first reported nyctalopia in late teenage years and retained good central vision until their late 30s. No color vision was detected in any proband. The fundus appearance included the later development of characteristic circular patches of pigment epithelial atrophy at the macula and in the peripheral retina.

Conclusions: Biallelic mutations in the photoreceptor-specific gene PCDH21 cause recessive retinal degeneration in humans.

Show MeSH
Related in: MedlinePlus