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Molecular genetics of familial nystagmus complicated with cataract and iris anomalies.

Yan N, Zhao Y, Wang Y, Xie A, Huang H, Yu W, Liu X, Cai SP - Mol. Vis. (2011)

Bottom Line: All coding exons of PAX6 were amplified by polymerase chain reaction (PCR), sequenced and compared with reference database.Such a change may cause structural and functional changes of the protein based on bioinformatics analysis.This study added a novel mutation to the existing spectrum of PAX6 mutations, suggesting that a mutation in PAX6 correlated with anterior segment disorders observed in this family.

View Article: PubMed Central - PubMed

Affiliation: Ophthalmic Laboratories & Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, PR China.

ABSTRACT

Purpose: Familial nystagmus complicated with cataract and iris anomalies are genetically heterogeneous, and the pathophysiological mechanisms remain unclear. It is anticipated that mutations in the paired box 6 (PAX6) gene play a major role in pathogenesis of malformations in anterior segment of the eye. In this study, we analyzed PAX6 in a Chinese pedigree of nystagmus, cataract and iris anomalies. This study will provide insights into the genetic basis of this disease.

Methods: Complete ophthalmologic examinations were performed on four patients (excluding one dead patient) and four unaffected individuals in this four-generation family. All coding exons of PAX6 were amplified by polymerase chain reaction (PCR), sequenced and compared with reference database. The variations detected were evaluated in available family members as well as 110 normal controls. Possible changes in structure and function of the protein induced by amino acid variance were predicted by bioinformatics analysis.

Results: Nystagmus, cataract or iris anomalies were found in all patients of this family, but the severity was different among these patients. A novel missense mutation in PAX6 was identified in all affected individuals but not in asymptomatic members and 110 normal controls. This mutation causes an amino acid substitution of proline to glutamine at position 118 (p.P118Q) of the paired domain of the PAX6 protein. Such a change may cause structural and functional changes of the protein based on bioinformatics analysis.

Conclusions: This study added a novel mutation to the existing spectrum of PAX6 mutations, suggesting that a mutation in PAX6 correlated with anterior segment disorders observed in this family.

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Related in: MedlinePlus

The mutation involved a highly conserved residue. The proline at position 118 is highly conserved for PAX6, which was demonstrated by analysis of orthologs from eight different species.
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f4: The mutation involved a highly conserved residue. The proline at position 118 is highly conserved for PAX6, which was demonstrated by analysis of orthologs from eight different species.

Mentions: PAX6 has two DNA-binding domains, a paired domain (PD) and a homeodomain (HD) and this mutation is in a paired domain. PAX6 with the c.353 C>A mutation would result in replacement of proline by glutamine, leading to a change of a hydrophobic amino acid to a hydrophilic amino acid. Proline in this position was found highly conserved for PAX6 by analyzing orthologs from eight different species using Clustalw tool on line (Figure 4). The p.P118Q mutation was predicted to be “probably damaging” by Polyphen with a score of 2.736, and “affect protein function” by SIFT with a score of 0.00. The theoretical pI of mutant PAX6 was 9.45 and no change compared with wild type PAX6. The Mw of the mutant PAX6 was slightly increased to 46714.39 Da from the wild type PAX6 of 46683.37 Da. Cn3D tool analysis also showed that p.P118Q mutation was located in the COOH-terminal region of PAX6 paired domain (Figure 5) [14].


Molecular genetics of familial nystagmus complicated with cataract and iris anomalies.

Yan N, Zhao Y, Wang Y, Xie A, Huang H, Yu W, Liu X, Cai SP - Mol. Vis. (2011)

The mutation involved a highly conserved residue. The proline at position 118 is highly conserved for PAX6, which was demonstrated by analysis of orthologs from eight different species.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198497&req=5

f4: The mutation involved a highly conserved residue. The proline at position 118 is highly conserved for PAX6, which was demonstrated by analysis of orthologs from eight different species.
Mentions: PAX6 has two DNA-binding domains, a paired domain (PD) and a homeodomain (HD) and this mutation is in a paired domain. PAX6 with the c.353 C>A mutation would result in replacement of proline by glutamine, leading to a change of a hydrophobic amino acid to a hydrophilic amino acid. Proline in this position was found highly conserved for PAX6 by analyzing orthologs from eight different species using Clustalw tool on line (Figure 4). The p.P118Q mutation was predicted to be “probably damaging” by Polyphen with a score of 2.736, and “affect protein function” by SIFT with a score of 0.00. The theoretical pI of mutant PAX6 was 9.45 and no change compared with wild type PAX6. The Mw of the mutant PAX6 was slightly increased to 46714.39 Da from the wild type PAX6 of 46683.37 Da. Cn3D tool analysis also showed that p.P118Q mutation was located in the COOH-terminal region of PAX6 paired domain (Figure 5) [14].

Bottom Line: All coding exons of PAX6 were amplified by polymerase chain reaction (PCR), sequenced and compared with reference database.Such a change may cause structural and functional changes of the protein based on bioinformatics analysis.This study added a novel mutation to the existing spectrum of PAX6 mutations, suggesting that a mutation in PAX6 correlated with anterior segment disorders observed in this family.

View Article: PubMed Central - PubMed

Affiliation: Ophthalmic Laboratories & Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, PR China.

ABSTRACT

Purpose: Familial nystagmus complicated with cataract and iris anomalies are genetically heterogeneous, and the pathophysiological mechanisms remain unclear. It is anticipated that mutations in the paired box 6 (PAX6) gene play a major role in pathogenesis of malformations in anterior segment of the eye. In this study, we analyzed PAX6 in a Chinese pedigree of nystagmus, cataract and iris anomalies. This study will provide insights into the genetic basis of this disease.

Methods: Complete ophthalmologic examinations were performed on four patients (excluding one dead patient) and four unaffected individuals in this four-generation family. All coding exons of PAX6 were amplified by polymerase chain reaction (PCR), sequenced and compared with reference database. The variations detected were evaluated in available family members as well as 110 normal controls. Possible changes in structure and function of the protein induced by amino acid variance were predicted by bioinformatics analysis.

Results: Nystagmus, cataract or iris anomalies were found in all patients of this family, but the severity was different among these patients. A novel missense mutation in PAX6 was identified in all affected individuals but not in asymptomatic members and 110 normal controls. This mutation causes an amino acid substitution of proline to glutamine at position 118 (p.P118Q) of the paired domain of the PAX6 protein. Such a change may cause structural and functional changes of the protein based on bioinformatics analysis.

Conclusions: This study added a novel mutation to the existing spectrum of PAX6 mutations, suggesting that a mutation in PAX6 correlated with anterior segment disorders observed in this family.

Show MeSH
Related in: MedlinePlus