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Identification of a novel mutation in the NTF4 gene that causes primary open-angle glaucoma in a Chinese population.

Vithana EN, Nongpiur ME, Venkataraman D, Chan SH, Mavinahalli J, Aung T - Mol. Vis. (2010)

Bottom Line: Neurotrophin-4 protein (NT-4) plays a role in the protection of retinal ganglion cells by activating tyrosine kinase B (TrkB) receptors.The single coding exon of NTF4 was PCR amplified and subjected to bidirectional sequencing in all subjects.Structural analysis indicated that the Leu113Ser mutation is likely to alter the NT-4 protein structure near the TrkB binding site and disrupts the formation of the NT-4-TrkB complex required for the activation of TrkB.

View Article: PubMed Central - PubMed

Affiliation: Singapore Eye Research Institute, 11 Third Hospital Avenue, Singapore. eranga.n.v@seri.com.sg

ABSTRACT

Purpose: Neurotrophin-4 protein (NT-4) plays a role in the protection of retinal ganglion cells by activating tyrosine kinase B (TrkB) receptors. A recent study identified mutations within the neurotrophin-4 (NTF4) gene to account for 1.7% of primary open-angle glaucoma (POAG) in Europeans. The aim of this study was to investigate the frequency of NTF4 mutations in Chinese POAG patients.

Methods: One hundred-seventy-four Chinese subjects with POAG and 91 normal Chinese subjects were recruited. POAG was defined by the presence of glaucomatous optic neuropathy, open angles on gonioscopy, and absence of secondary causes of glaucoma. The single coding exon of NTF4 was PCR amplified and subjected to bidirectional sequencing in all subjects.

Results: The mean age of POAG patients was 66.0+/-13.0 years (range 25-96 years) and that of controls was 67.1+/-4.6 years (range 60-85 years). We identified a novel NTF4 missense mutation substituting leucine by serine at codon 113 (Leu113Ser) caused by a c.338T>C mutation in a single patient with unilateral POAG, who presented with a baseline intraocular pressure of 25 mmHg, a vertical cup-to-disc ratio of 0.9 and an inferior hemifield defect in the affected eye. Structural analysis indicated that the Leu113Ser mutation is likely to alter the NT-4 protein structure near the TrkB binding site and disrupts the formation of the NT-4-TrkB complex required for the activation of TrkB.

Conclusions: Identification of a single mutation in our study suggests that NTF4 mutations are a rare cause of POAG (0.6%, 95%CI 0.02%-3.16%) in Chinese people.

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Related in: MedlinePlus

Location of the Leu113Ser mutation in the crystal structure of the NT-4-TrkB complex. The two chains of the dimeric NT-4 are in cyan and blue, respectively. The alpha carbon of the mutated residue is shown as a magenta sphere, with the prime symbol denoting the residue of the second subunit. TrkB domains are shown in orange and red color. The Leu113 residue is located close to the TrkB binding site.
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f2: Location of the Leu113Ser mutation in the crystal structure of the NT-4-TrkB complex. The two chains of the dimeric NT-4 are in cyan and blue, respectively. The alpha carbon of the mutated residue is shown as a magenta sphere, with the prime symbol denoting the residue of the second subunit. TrkB domains are shown in orange and red color. The Leu113 residue is located close to the TrkB binding site.

Mentions: According to the known crystal structure of the NT-4-TrkB complex Leu113 is located near the surface of NT-4 (Figure 2 and Figure 3A) but in the hydrophobic core comprising residues from both the chains of NT-4 and a chain of TrkB. The modeled structure of Leu113Ser showed a gap (Figure 3B) compared to the wild type structure due to the substitution with the much smaller polar amino acid. The hydrophilic nature of the serine residue is also likely to cause destabilization of the hydrophobic core due to its orientation towards the solvent. As a result, it is highly likely that Leu113Ser disrupt the integrity of both tertiary and quaternary structure of the protein complex leading to disruption of the binding with TrkB and thus its activation.


Identification of a novel mutation in the NTF4 gene that causes primary open-angle glaucoma in a Chinese population.

Vithana EN, Nongpiur ME, Venkataraman D, Chan SH, Mavinahalli J, Aung T - Mol. Vis. (2010)

Location of the Leu113Ser mutation in the crystal structure of the NT-4-TrkB complex. The two chains of the dimeric NT-4 are in cyan and blue, respectively. The alpha carbon of the mutated residue is shown as a magenta sphere, with the prime symbol denoting the residue of the second subunit. TrkB domains are shown in orange and red color. The Leu113 residue is located close to the TrkB binding site.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2927376&req=5

f2: Location of the Leu113Ser mutation in the crystal structure of the NT-4-TrkB complex. The two chains of the dimeric NT-4 are in cyan and blue, respectively. The alpha carbon of the mutated residue is shown as a magenta sphere, with the prime symbol denoting the residue of the second subunit. TrkB domains are shown in orange and red color. The Leu113 residue is located close to the TrkB binding site.
Mentions: According to the known crystal structure of the NT-4-TrkB complex Leu113 is located near the surface of NT-4 (Figure 2 and Figure 3A) but in the hydrophobic core comprising residues from both the chains of NT-4 and a chain of TrkB. The modeled structure of Leu113Ser showed a gap (Figure 3B) compared to the wild type structure due to the substitution with the much smaller polar amino acid. The hydrophilic nature of the serine residue is also likely to cause destabilization of the hydrophobic core due to its orientation towards the solvent. As a result, it is highly likely that Leu113Ser disrupt the integrity of both tertiary and quaternary structure of the protein complex leading to disruption of the binding with TrkB and thus its activation.

Bottom Line: Neurotrophin-4 protein (NT-4) plays a role in the protection of retinal ganglion cells by activating tyrosine kinase B (TrkB) receptors.The single coding exon of NTF4 was PCR amplified and subjected to bidirectional sequencing in all subjects.Structural analysis indicated that the Leu113Ser mutation is likely to alter the NT-4 protein structure near the TrkB binding site and disrupts the formation of the NT-4-TrkB complex required for the activation of TrkB.

View Article: PubMed Central - PubMed

Affiliation: Singapore Eye Research Institute, 11 Third Hospital Avenue, Singapore. eranga.n.v@seri.com.sg

ABSTRACT

Purpose: Neurotrophin-4 protein (NT-4) plays a role in the protection of retinal ganglion cells by activating tyrosine kinase B (TrkB) receptors. A recent study identified mutations within the neurotrophin-4 (NTF4) gene to account for 1.7% of primary open-angle glaucoma (POAG) in Europeans. The aim of this study was to investigate the frequency of NTF4 mutations in Chinese POAG patients.

Methods: One hundred-seventy-four Chinese subjects with POAG and 91 normal Chinese subjects were recruited. POAG was defined by the presence of glaucomatous optic neuropathy, open angles on gonioscopy, and absence of secondary causes of glaucoma. The single coding exon of NTF4 was PCR amplified and subjected to bidirectional sequencing in all subjects.

Results: The mean age of POAG patients was 66.0+/-13.0 years (range 25-96 years) and that of controls was 67.1+/-4.6 years (range 60-85 years). We identified a novel NTF4 missense mutation substituting leucine by serine at codon 113 (Leu113Ser) caused by a c.338T>C mutation in a single patient with unilateral POAG, who presented with a baseline intraocular pressure of 25 mmHg, a vertical cup-to-disc ratio of 0.9 and an inferior hemifield defect in the affected eye. Structural analysis indicated that the Leu113Ser mutation is likely to alter the NT-4 protein structure near the TrkB binding site and disrupts the formation of the NT-4-TrkB complex required for the activation of TrkB.

Conclusions: Identification of a single mutation in our study suggests that NTF4 mutations are a rare cause of POAG (0.6%, 95%CI 0.02%-3.16%) in Chinese people.

Show MeSH
Related in: MedlinePlus