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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 paired domain of PAX6. A: Sketch of the PAX6 paired domain–DNA complex. Cylinders represent α helices; arrows represent β strands. Helices 1–6 are labeled; residue numbers indicate termini of the corresponding secondary structure elements. B: Cn3D display for the paired domain of PAX6. The yellow segment represents the mutation region (COOH-terminal region in PAX6 paired domain).
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f5: The paired domain of PAX6. A: Sketch of the PAX6 paired domain–DNA complex. Cylinders represent α helices; arrows represent β strands. Helices 1–6 are labeled; residue numbers indicate termini of the corresponding secondary structure elements. B: Cn3D display for the paired domain of PAX6. The yellow segment represents the mutation region (COOH-terminal region in PAX6 paired domain).

Mentions: PAX6 may regulate the expression of other genes during embryogenesis as a transcription factor [4,10]. PAX6 expresses two isoforms by alternative splicing, PAX6 (−5a; 422 amino acids) and PAX6 (+5a; 436 amino acids) [14,17]. The paired domain (PD) and homeodomain (HD) are two DNA-binding domains of PAX6 and the paired domain consists of 128 amino acids and contains two globular subdomains (NH2-subdomain and COOH-subdomain) linked by an extended polypeptide chain [18,19]. This novel p.P118Q mutation was in the COOH-terminal region of the paired domain. The p.P118Q mutation turned a hydrophobic amino acid (proline) into a hydrophilic amino acid (glutamine), and since it is located in the hydrophobic core of the COOH-subdomain, it may disrupt the folding and stability of the whole protein (Figure 5). The proline at codon 118 is highly conserved in PAX6 paired-domains of all species, including Mus musculus, Rattus norvegicus, Macaca mulatta, Bos taurus, Gorilla gorilla, Gallus gallus, Danio rerio, and Xenopus tropicalis (Figure 4). Such a high degree of conservation argues for a functional importance of the relevant amino acid residue.


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 paired domain of PAX6. A: Sketch of the PAX6 paired domain–DNA complex. Cylinders represent α helices; arrows represent β strands. Helices 1–6 are labeled; residue numbers indicate termini of the corresponding secondary structure elements. B: Cn3D display for the paired domain of PAX6. The yellow segment represents the mutation region (COOH-terminal region in PAX6 paired domain).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: The paired domain of PAX6. A: Sketch of the PAX6 paired domain–DNA complex. Cylinders represent α helices; arrows represent β strands. Helices 1–6 are labeled; residue numbers indicate termini of the corresponding secondary structure elements. B: Cn3D display for the paired domain of PAX6. The yellow segment represents the mutation region (COOH-terminal region in PAX6 paired domain).
Mentions: PAX6 may regulate the expression of other genes during embryogenesis as a transcription factor [4,10]. PAX6 expresses two isoforms by alternative splicing, PAX6 (−5a; 422 amino acids) and PAX6 (+5a; 436 amino acids) [14,17]. The paired domain (PD) and homeodomain (HD) are two DNA-binding domains of PAX6 and the paired domain consists of 128 amino acids and contains two globular subdomains (NH2-subdomain and COOH-subdomain) linked by an extended polypeptide chain [18,19]. This novel p.P118Q mutation was in the COOH-terminal region of the paired domain. The p.P118Q mutation turned a hydrophobic amino acid (proline) into a hydrophilic amino acid (glutamine), and since it is located in the hydrophobic core of the COOH-subdomain, it may disrupt the folding and stability of the whole protein (Figure 5). The proline at codon 118 is highly conserved in PAX6 paired-domains of all species, including Mus musculus, Rattus norvegicus, Macaca mulatta, Bos taurus, Gorilla gorilla, Gallus gallus, Danio rerio, and Xenopus tropicalis (Figure 4). Such a high degree of conservation argues for a functional importance of the relevant amino acid residue.

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