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Identification a novel MYOC gene mutation in a Chinese family with juvenile-onset open angle glaucoma.

Zhao X, Yang C, Tong Y, Zhang X, Xu L, Li Y - Mol. Vis. (2010)

Bottom Line: Bioinformatics analysis by the Garnier-Osguthorpe-Robson (GOR) method predicted the effects of variants detected on secondary structures of the MYOC protein.This missense mutation co-segregated with the disease phenotype of the family, but was not found in 100 normal controls.The finding provides pre-symptomatic molecular diagnosis for the members of this family and is useful for further genetic consultation.

View Article: PubMed Central - PubMed

Affiliation: Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing, China.

ABSTRACT

Purpose: To describe the clinical and genetic findings in one Chinese family with juvenile-onset open angle glaucoma (JOAG).

Methods: One family was examined clinically and a follow-up took place 5 years later. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. Linkage analysis was performed with three microsatellite markers around the MYOC gene (D1S196, D1S2815, and D1S218) in the family. Mutation screening of all coding exons of MYOC was performed by direct sequencing of PCR-amplified DNA fragments and restriction fragment length polymorphism (RFLP) analysis. Bioinformatics analysis by the Garnier-Osguthorpe-Robson (GOR) method predicted the effects of variants detected on secondary structures of the MYOC protein.

Results: Clinical examination and pedigree analysis revealed a three- generation family with seven members diagnosed with JOAG, three with ocular hypertension, and five normal individuals. Through genotyping, the pedigree showed a linkage to the MYOC on chromosome 1q24-25. Mutation screening of MYOC in this family revealed an A-->T transition at position 1348 (p. N450Y) of the cDNA sequence. This missense mutation co-segregated with the disease phenotype of the family, but was not found in 100 normal controls. Secondary structure prediction of the p.N450Y by the GOR method revealed the replacement of a coil with a beta sheet at the amino acid 447.

Conclusions: Early onset JOAG, with incomplete penetrance, is consistent with a novel mutation in MYOC. The finding provides pre-symptomatic molecular diagnosis for the members of this family and is useful for further genetic consultation.

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Related in: MedlinePlus

Family structure and haplotype analysis of a Chinese family with JOAG. Pedigree and haplotype analysis of the family with JOAG showed segregation with three microsatellite markers on chromosome 1, listed in descending order from the centromeric end. Squares indicate males; circles indicate females; slashed symbols indicate deceased; solid symbols indicate affected; open symbols indicate unaffected; symbols with upper left filled-in quadrant indicate members with ocular hypertension; symbols with dot in the center indicate carriers.
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f1: Family structure and haplotype analysis of a Chinese family with JOAG. Pedigree and haplotype analysis of the family with JOAG showed segregation with three microsatellite markers on chromosome 1, listed in descending order from the centromeric end. Squares indicate males; circles indicate females; slashed symbols indicate deceased; solid symbols indicate affected; open symbols indicate unaffected; symbols with upper left filled-in quadrant indicate members with ocular hypertension; symbols with dot in the center indicate carriers.

Mentions: We have identified a three- generation family diagnosed with JOAG. The inheritance pattern in this family appeared to be autosomal dominant (Figure 1). After clinical examinations and hospital records reviewing, six individuals of this pedigree were found to have glaucoma in 2004. The patient in the first generation had not received any treatment and totally lost her sight before the age of 35. The remaining five patients underwent trabeculectomies in both eyes. The mean onset age of these patients was 27.42 years (ranging from 20 to 31 years old), which was consistent with juvenile glaucoma. All patients experienced elevated IOP (32–50 mmHg) and most of them presented typical late stage glaucoma changes in the optic disc and in the visual field (Figure 2A). In 2004, six members were diagnosed with ocular hypertension (IOPs were higher than 22 mmHg) but without optic disc or visual field changes. A five-year follow-up was conducted with fifteen of the seventeen individuals and their blood samples were collected for further genetic analysis. At the 5-year follow-up, two ocular hypertension patients (Figure 1; III:2 and III:7) were newly diagnosed with glaucoma due to their elevated IOP, enlarged cup/disc ratio of the optic disc, and early visual field changes in 2009 (Figure 2B) . Detailed clinical information of the pedigree is summarized in Table 2.


Identification a novel MYOC gene mutation in a Chinese family with juvenile-onset open angle glaucoma.

Zhao X, Yang C, Tong Y, Zhang X, Xu L, Li Y - Mol. Vis. (2010)

Family structure and haplotype analysis of a Chinese family with JOAG. Pedigree and haplotype analysis of the family with JOAG showed segregation with three microsatellite markers on chromosome 1, listed in descending order from the centromeric end. Squares indicate males; circles indicate females; slashed symbols indicate deceased; solid symbols indicate affected; open symbols indicate unaffected; symbols with upper left filled-in quadrant indicate members with ocular hypertension; symbols with dot in the center indicate carriers.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2927375&req=5

f1: Family structure and haplotype analysis of a Chinese family with JOAG. Pedigree and haplotype analysis of the family with JOAG showed segregation with three microsatellite markers on chromosome 1, listed in descending order from the centromeric end. Squares indicate males; circles indicate females; slashed symbols indicate deceased; solid symbols indicate affected; open symbols indicate unaffected; symbols with upper left filled-in quadrant indicate members with ocular hypertension; symbols with dot in the center indicate carriers.
Mentions: We have identified a three- generation family diagnosed with JOAG. The inheritance pattern in this family appeared to be autosomal dominant (Figure 1). After clinical examinations and hospital records reviewing, six individuals of this pedigree were found to have glaucoma in 2004. The patient in the first generation had not received any treatment and totally lost her sight before the age of 35. The remaining five patients underwent trabeculectomies in both eyes. The mean onset age of these patients was 27.42 years (ranging from 20 to 31 years old), which was consistent with juvenile glaucoma. All patients experienced elevated IOP (32–50 mmHg) and most of them presented typical late stage glaucoma changes in the optic disc and in the visual field (Figure 2A). In 2004, six members were diagnosed with ocular hypertension (IOPs were higher than 22 mmHg) but without optic disc or visual field changes. A five-year follow-up was conducted with fifteen of the seventeen individuals and their blood samples were collected for further genetic analysis. At the 5-year follow-up, two ocular hypertension patients (Figure 1; III:2 and III:7) were newly diagnosed with glaucoma due to their elevated IOP, enlarged cup/disc ratio of the optic disc, and early visual field changes in 2009 (Figure 2B) . Detailed clinical information of the pedigree is summarized in Table 2.

Bottom Line: Bioinformatics analysis by the Garnier-Osguthorpe-Robson (GOR) method predicted the effects of variants detected on secondary structures of the MYOC protein.This missense mutation co-segregated with the disease phenotype of the family, but was not found in 100 normal controls.The finding provides pre-symptomatic molecular diagnosis for the members of this family and is useful for further genetic consultation.

View Article: PubMed Central - PubMed

Affiliation: Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing, China.

ABSTRACT

Purpose: To describe the clinical and genetic findings in one Chinese family with juvenile-onset open angle glaucoma (JOAG).

Methods: One family was examined clinically and a follow-up took place 5 years later. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. Linkage analysis was performed with three microsatellite markers around the MYOC gene (D1S196, D1S2815, and D1S218) in the family. Mutation screening of all coding exons of MYOC was performed by direct sequencing of PCR-amplified DNA fragments and restriction fragment length polymorphism (RFLP) analysis. Bioinformatics analysis by the Garnier-Osguthorpe-Robson (GOR) method predicted the effects of variants detected on secondary structures of the MYOC protein.

Results: Clinical examination and pedigree analysis revealed a three- generation family with seven members diagnosed with JOAG, three with ocular hypertension, and five normal individuals. Through genotyping, the pedigree showed a linkage to the MYOC on chromosome 1q24-25. Mutation screening of MYOC in this family revealed an A-->T transition at position 1348 (p. N450Y) of the cDNA sequence. This missense mutation co-segregated with the disease phenotype of the family, but was not found in 100 normal controls. Secondary structure prediction of the p.N450Y by the GOR method revealed the replacement of a coil with a beta sheet at the amino acid 447.

Conclusions: Early onset JOAG, with incomplete penetrance, is consistent with a novel mutation in MYOC. The finding provides pre-symptomatic molecular diagnosis for the members of this family and is useful for further genetic consultation.

Show MeSH
Related in: MedlinePlus