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Molecular analysis of CHX10 and MFRP in Chinese subjects with primary angle closure glaucoma and short axial length eyes.

Aung T, Lim MC, Wong TT, Thalamuthu A, Yong VH, Venkataraman D, Venkatraman A, Chew PT, Vithana EN - Mol. Vis. (2008)

Bottom Line: We identified a possible disease-causing variant in CHX10 (c.728G>A) resulting in Gly243Asp substitution in one patient.This variant was not found in 215 normal controls.Our results do not support a significant role for CHX10 or MFRP mutations in PACG.

View Article: PubMed Central - PubMed

Affiliation: Singapore National Eye Centre, Singapore; 2Singapore Eye Research Institute, Singapore. tin11@pacific.net.sg

ABSTRACT

Purpose: The genetic basis of primary angle closure glaucoma (PACG) has yet to be elucidated. Ocular characteristics related to PACG such as short hyperopic eyes with shallow anterior chambers suggest the involvement of genes that regulate ocular size. CHX10, a retinal homeobox gene associated with microphthalmia, and MFRP, the membrane-type frizzled-related protein gene underlying recessive nanophthalmos, represent good candidate genes for PACG due to the association with small eyes. To investigate the possible involvement of CHX10 and MFRP in PACG, we sequenced both genes in PACG patients with small ocular dimensions.

Methods: One hundred and eight Chinese patients with axial lengths measuring 22.50 mm or less were selected for analysis. Ninety-three age- and ethnically-matched control subjects were also screened. Genomic DNA was extracted from leukocytes of peripheral blood samples, and the exons of CHX10 and MFRP were amplified by polymerase chain reaction (PCR) and subjected to bidirectional sequencing and analysis.

Results: All study patients were Chinese with a mean age of 66.2+/-9.1 years (range 46-86). There were 77 females (71.3%). Forty-nine out of the one hundred and eight subjects had previous symptomatic PACG, and 59 had asymptomatic PACG. The mean axial length was 21.90+/-0.50 mm (range 19.98-22.50 mm). We identified a possible disease-causing variant in CHX10 (c.728G>A) resulting in Gly243Asp substitution in one patient. This variant was not found in 215 normal controls. Several CHX10 and MFRP polymorphisms were also identified.

Conclusions: Our results do not support a significant role for CHX10 or MFRP mutations in PACG.

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Related in: MedlinePlus

The c.728G>A (Gly243Asp) variation in CHX10. A: The wild type sequence is shown on the left to compare with the variant CHX10 sequence on the right. The comparison depicts the G>A transition that changed codon 243 from glycine (GGC) in the wild type sequence to aspartic acid (GAC) in the variant CHX10 sequence. B: Protein alignment of human (Homo sapiens) CHX10 (residues 215-261) is compared to other CHX10-like proteins from other species, i.e., chimp (P. troglodytes), mouse (M. musculus), rat (R.norvegicus), chick (G. gallus), puffer fish (T. nigroviridis), and worm (C. elegans). This comparison shows the conservation of the glycine 243 residue in CHX10.
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f1: The c.728G>A (Gly243Asp) variation in CHX10. A: The wild type sequence is shown on the left to compare with the variant CHX10 sequence on the right. The comparison depicts the G>A transition that changed codon 243 from glycine (GGC) in the wild type sequence to aspartic acid (GAC) in the variant CHX10 sequence. B: Protein alignment of human (Homo sapiens) CHX10 (residues 215-261) is compared to other CHX10-like proteins from other species, i.e., chimp (P. troglodytes), mouse (M. musculus), rat (R.norvegicus), chick (G. gallus), puffer fish (T. nigroviridis), and worm (C. elegans). This comparison shows the conservation of the glycine 243 residue in CHX10.

Mentions: Four CHX10 sequence alterations consisting of two heterozygous missense and two synonymous changes were identified in our study subjects (Table 2). The two synonymous variations, Ser157Ser and Pro250Pro, were both found in control subjects. The missense sequence alteration, Asp291Asn (D291N), identified in seven PACG cases, was also detected in eight normal controls. The Gly243Asp (728G>A) missense change was found in one patient with previous acute PACG (who also had the Arg257His mutation in MFRP, see below) but not in a total of 215 controls of Chinese ethnicity (Figure 1A). We analyzed an additional 122 control subjects for this particular sequence variant apart from the initial 93 control subjects enrolled in the study. The Gly243Asp (728G>A) missense change also involved a residue that is conserved across several species (Figure 1B). The patient concerned was an 82-year-old lady with chronic PACG first diagnosed at age 75. At presentation, the vertical cup:disc ratio was 0.8 in both eyes, and gonioscopy revealed 360 degrees of closed angles with extensive peripheral anterior synechiae. The axial length was 21.05 mm, and anterior chamber depth was 2.09 mm in the affected eye.


Molecular analysis of CHX10 and MFRP in Chinese subjects with primary angle closure glaucoma and short axial length eyes.

Aung T, Lim MC, Wong TT, Thalamuthu A, Yong VH, Venkataraman D, Venkatraman A, Chew PT, Vithana EN - Mol. Vis. (2008)

The c.728G>A (Gly243Asp) variation in CHX10. A: The wild type sequence is shown on the left to compare with the variant CHX10 sequence on the right. The comparison depicts the G>A transition that changed codon 243 from glycine (GGC) in the wild type sequence to aspartic acid (GAC) in the variant CHX10 sequence. B: Protein alignment of human (Homo sapiens) CHX10 (residues 215-261) is compared to other CHX10-like proteins from other species, i.e., chimp (P. troglodytes), mouse (M. musculus), rat (R.norvegicus), chick (G. gallus), puffer fish (T. nigroviridis), and worm (C. elegans). This comparison shows the conservation of the glycine 243 residue in CHX10.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2480479&req=5

f1: The c.728G>A (Gly243Asp) variation in CHX10. A: The wild type sequence is shown on the left to compare with the variant CHX10 sequence on the right. The comparison depicts the G>A transition that changed codon 243 from glycine (GGC) in the wild type sequence to aspartic acid (GAC) in the variant CHX10 sequence. B: Protein alignment of human (Homo sapiens) CHX10 (residues 215-261) is compared to other CHX10-like proteins from other species, i.e., chimp (P. troglodytes), mouse (M. musculus), rat (R.norvegicus), chick (G. gallus), puffer fish (T. nigroviridis), and worm (C. elegans). This comparison shows the conservation of the glycine 243 residue in CHX10.
Mentions: Four CHX10 sequence alterations consisting of two heterozygous missense and two synonymous changes were identified in our study subjects (Table 2). The two synonymous variations, Ser157Ser and Pro250Pro, were both found in control subjects. The missense sequence alteration, Asp291Asn (D291N), identified in seven PACG cases, was also detected in eight normal controls. The Gly243Asp (728G>A) missense change was found in one patient with previous acute PACG (who also had the Arg257His mutation in MFRP, see below) but not in a total of 215 controls of Chinese ethnicity (Figure 1A). We analyzed an additional 122 control subjects for this particular sequence variant apart from the initial 93 control subjects enrolled in the study. The Gly243Asp (728G>A) missense change also involved a residue that is conserved across several species (Figure 1B). The patient concerned was an 82-year-old lady with chronic PACG first diagnosed at age 75. At presentation, the vertical cup:disc ratio was 0.8 in both eyes, and gonioscopy revealed 360 degrees of closed angles with extensive peripheral anterior synechiae. The axial length was 21.05 mm, and anterior chamber depth was 2.09 mm in the affected eye.

Bottom Line: We identified a possible disease-causing variant in CHX10 (c.728G>A) resulting in Gly243Asp substitution in one patient.This variant was not found in 215 normal controls.Our results do not support a significant role for CHX10 or MFRP mutations in PACG.

View Article: PubMed Central - PubMed

Affiliation: Singapore National Eye Centre, Singapore; 2Singapore Eye Research Institute, Singapore. tin11@pacific.net.sg

ABSTRACT

Purpose: The genetic basis of primary angle closure glaucoma (PACG) has yet to be elucidated. Ocular characteristics related to PACG such as short hyperopic eyes with shallow anterior chambers suggest the involvement of genes that regulate ocular size. CHX10, a retinal homeobox gene associated with microphthalmia, and MFRP, the membrane-type frizzled-related protein gene underlying recessive nanophthalmos, represent good candidate genes for PACG due to the association with small eyes. To investigate the possible involvement of CHX10 and MFRP in PACG, we sequenced both genes in PACG patients with small ocular dimensions.

Methods: One hundred and eight Chinese patients with axial lengths measuring 22.50 mm or less were selected for analysis. Ninety-three age- and ethnically-matched control subjects were also screened. Genomic DNA was extracted from leukocytes of peripheral blood samples, and the exons of CHX10 and MFRP were amplified by polymerase chain reaction (PCR) and subjected to bidirectional sequencing and analysis.

Results: All study patients were Chinese with a mean age of 66.2+/-9.1 years (range 46-86). There were 77 females (71.3%). Forty-nine out of the one hundred and eight subjects had previous symptomatic PACG, and 59 had asymptomatic PACG. The mean axial length was 21.90+/-0.50 mm (range 19.98-22.50 mm). We identified a possible disease-causing variant in CHX10 (c.728G>A) resulting in Gly243Asp substitution in one patient. This variant was not found in 215 normal controls. Several CHX10 and MFRP polymorphisms were also identified.

Conclusions: Our results do not support a significant role for CHX10 or MFRP mutations in PACG.

Show MeSH
Related in: MedlinePlus