Duration 5min, Q&A 3min
A Novel Thr377Arg MYOC Mutation in a Large Pakistani Pedigree with Autosomal Dominant Juvenile Open Angle Glaucoma
To identify disease causing mutations in 8 affected of a consanguineous family diagnosed with severe form of Juvenile Open Angle Glaucoma
This study was approved by Ethical Review Committee of Liaquat University of Medical and Health Sciences, Jamshoro. After obtaining informed consent, Pedigree was drawn and detailed family history was recorded. Total 17 members including 8 affected in 3 generations participated in the study.
After detail clinical assessment including visual acuity, IOP measurement, Slit-lamp biomicroscopy, gonioscopy, and fundus examination of all affected and two normal siblings. Blood samples were obtained to extract DNA. Homozygousity mapping was performed by using four STR markers. Three exons of myocilin gene (OMIM 601652) were sequenced in all recruited family members. Bioinformatics analysis was performed by using Polyphen and SIFT to predict pathogenecity of novel variant and GORV method was used to predict structural changes in protein.
Results and Conclusion
Juvenile Open Angle Glaucoma was found segregating as an autosomal dominant trait in all affected family members. Linkage analysis showed a linkage to GLCA1 locus on chromosome 1q24-25, harboring myocilin gene (OMIM 601652). Mutation screening revealed a novel heterozygous transition C to G at position c.1130, substituting Threonine in to Arginine at codon 377 of MYOC. This mutation was segregating with phenotype in all eight affected and was not found in normal subjects of the family and 120 ethically matched normal chromosomes. Ophthalmological findings revealed juvenile open angle glaucoma with severe and rapidly progressive phenotype. The age of onset was in first decade of life and maximum recorded IOP was 25mmHg. Bioinformatics tools predicted C to G transition at c.1130 as pathogenic and no structural changes was predicted in protein.
This is the first report of novel MYOC mutation from Pakistan; segregating as an autosomal dominant trait in large family diagnosed with JOAG. Identification of novel disease causing allele in MYOC indicates genetic heterogeneity of our population. Juvenile onset of the glaucoma with rapidly progressive clinical presentations suggests early molecular diagnosis of mutation carriers. This will help to intervene and control disease by providing appropriate therapy.
[ Keyword ]
Pakistan, MYOC, JOAG
[ Conflict of Interest ]