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Mutations in the β-subunit of rod phosphodiesterase identified in consanguineous Pakistani families with autosomal recessive retinitis pigmentosa.

Ali S, Riazuddin SA, Shahzadi A, Nasir IA, Khan SN, Husnain T, Akram J, Sieving PA, Hejtmancik JF, Riazuddin S - Mol. Vis. (2011)

Bottom Line: During exclusion analyses both families localized to chromosome 4p, harboring PDE6β, a gene previously associated with autosomal recessive RP.Bioinformatic analyses suggested that both mutations are deleterious for the native three-dimensional structure of the PDE6β protein.These results strongly suggest that mutations in PDE6β are responsible for the disease phenotype in the consanguineous Pakistani families.

View Article: PubMed Central - PubMed

Affiliation: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.

ABSTRACT

Purpose: This study was designed to identify pathogenic mutations causing autosomal recessive retinitis pigmentosa (RP) in consanguineous Pakistani families.

Methods: Two consanguineous families affected with autosomal recessive RP were identified from the Punjab Province of Pakistan. All affected individuals underwent a thorough ophthalmologic examination. Blood samples were collected, and genomic DNAs were extracted. Exclusion analysis was completed, and two-point LOD scores were calculated. Bidirectional sequencing of the β subunit of phosphodiesterase 6 (PDE6β) was completed.

Results: During exclusion analyses both families localized to chromosome 4p, harboring PDE6β, a gene previously associated with autosomal recessive RP. Sequencing of PDE6β identified missense mutations: c.1655G>A (p.R552Q) and c.1160C>T (p.P387L) in families PKRP161 and PKRP183, respectively. Bioinformatic analyses suggested that both mutations are deleterious for the native three-dimensional structure of the PDE6β protein.

Conclusions: These results strongly suggest that mutations in PDE6β are responsible for the disease phenotype in the consanguineous Pakistani families.

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Related in: MedlinePlus

Amino Acid conservation of the P387 and R552 residues in other PDE6β orthologs. The arrows point to the amino acid residues P387 and R552, which are mutated in the affected individuals of families PKRP183 and PKRP161, respectively. Primates are colored green, placental mammals are blue, and vertebrates are purple.
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f5: Amino Acid conservation of the P387 and R552 residues in other PDE6β orthologs. The arrows point to the amino acid residues P387 and R552, which are mutated in the affected individuals of families PKRP183 and PKRP161, respectively. Primates are colored green, placental mammals are blue, and vertebrates are purple.

Mentions: As shown in Figure 5, both amino acid residues P387 and R552 are highly conserved among other PDE6β orthologs; therefore we next examined the possible impact of these two variations on PDE6β with SIFT and PolyPhen algorithms. SIFT predictions suggested that both p.P387L and p.R552Q substitutions will not be tolerated by the native three dimensional structure of PDE6β. The affected protein function score for p.P387L and p.R552Q were 0.01 and 0.02, respectively (scores <0.05 are predicted to be damaging). Likewise, position-specific score differences obtained from Polyphen suggested that both p.P387L and p.R552Q substitutions could potentially have deleterious effect on the PDE6β structure, with a position- specific independent count scores of 3.09 and 2.24, respectively (scores >1 are predicted to be damaging).


Mutations in the β-subunit of rod phosphodiesterase identified in consanguineous Pakistani families with autosomal recessive retinitis pigmentosa.

Ali S, Riazuddin SA, Shahzadi A, Nasir IA, Khan SN, Husnain T, Akram J, Sieving PA, Hejtmancik JF, Riazuddin S - Mol. Vis. (2011)

Amino Acid conservation of the P387 and R552 residues in other PDE6β orthologs. The arrows point to the amino acid residues P387 and R552, which are mutated in the affected individuals of families PKRP183 and PKRP161, respectively. Primates are colored green, placental mammals are blue, and vertebrates are purple.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108895&req=5

f5: Amino Acid conservation of the P387 and R552 residues in other PDE6β orthologs. The arrows point to the amino acid residues P387 and R552, which are mutated in the affected individuals of families PKRP183 and PKRP161, respectively. Primates are colored green, placental mammals are blue, and vertebrates are purple.
Mentions: As shown in Figure 5, both amino acid residues P387 and R552 are highly conserved among other PDE6β orthologs; therefore we next examined the possible impact of these two variations on PDE6β with SIFT and PolyPhen algorithms. SIFT predictions suggested that both p.P387L and p.R552Q substitutions will not be tolerated by the native three dimensional structure of PDE6β. The affected protein function score for p.P387L and p.R552Q were 0.01 and 0.02, respectively (scores <0.05 are predicted to be damaging). Likewise, position-specific score differences obtained from Polyphen suggested that both p.P387L and p.R552Q substitutions could potentially have deleterious effect on the PDE6β structure, with a position- specific independent count scores of 3.09 and 2.24, respectively (scores >1 are predicted to be damaging).

Bottom Line: During exclusion analyses both families localized to chromosome 4p, harboring PDE6β, a gene previously associated with autosomal recessive RP.Bioinformatic analyses suggested that both mutations are deleterious for the native three-dimensional structure of the PDE6β protein.These results strongly suggest that mutations in PDE6β are responsible for the disease phenotype in the consanguineous Pakistani families.

View Article: PubMed Central - PubMed

Affiliation: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.

ABSTRACT

Purpose: This study was designed to identify pathogenic mutations causing autosomal recessive retinitis pigmentosa (RP) in consanguineous Pakistani families.

Methods: Two consanguineous families affected with autosomal recessive RP were identified from the Punjab Province of Pakistan. All affected individuals underwent a thorough ophthalmologic examination. Blood samples were collected, and genomic DNAs were extracted. Exclusion analysis was completed, and two-point LOD scores were calculated. Bidirectional sequencing of the β subunit of phosphodiesterase 6 (PDE6β) was completed.

Results: During exclusion analyses both families localized to chromosome 4p, harboring PDE6β, a gene previously associated with autosomal recessive RP. Sequencing of PDE6β identified missense mutations: c.1655G>A (p.R552Q) and c.1160C>T (p.P387L) in families PKRP161 and PKRP183, respectively. Bioinformatic analyses suggested that both mutations are deleterious for the native three-dimensional structure of the PDE6β protein.

Conclusions: These results strongly suggest that mutations in PDE6β are responsible for the disease phenotype in the consanguineous Pakistani families.

Show MeSH
Related in: MedlinePlus