title: The novel heterozygous Thr377Arg MYOC mutation causes severe Juvenile Open Angle Glaucoma in a large Pakistani family.
abstract: Glaucoma is one of the major causes of blindness worldwide with characteristic optic disc changes and elevated intraocular pressure. It is subcategorized into Primary Open Angle Glaucoma (POAG) and Juvenile Open Angle Glaucoma (JOAG) depending upon age of the disease onset. Myocilin (MYOC) is the frequently mutated gene in familial cases of glaucoma. MYOC mutations show variable phenotype and penetrance. This study was aimed to identify disease causing mutation in 8 affected of a consanguineous family diagnosed with severe form of Juvenile Open Angle Glaucoma. Homozygosity mapping with four microsatellite markers and subsequent direct sequencing of MYOC revealed a novel heterozygous transition c.1130 C>G, substituting Threonine in to Arginine at codon 377 (p.Thr377Arg) of MYOC. This mutation was segregating with phenotype in all affected and was not found in control subjects. Ophthalmological findings revealed JOAG with severe and rapidly progressive phenotype. The age of onset was in the first decade of life and maximum Intra Ocular Pressure (IOP) recorded was 25mmHg. Bioinformatic tools predicted C to G transition at c.1130 as pathogenic and no structural changes were predicted in protein. This is the first report of novel MYOC mutation from Pakistan; segregating as autosomal dominant trait in large family diagnosed with JOAG. Identification of novel disease causing allele in MYOC indicates genetic heterogeneity of the population. This finding will help to provide genetic counseling to the affected family and carriers of this mutation may be advised for early therapeutic intervention to avoid irreversible visual loss.
authors.affiliation: Molecular Biology & Genetics Department, Medical Research Center, Liaquat University of Medical & Health Sciences, Jamshoro, Pakistan. aliwaryah@lumhs.edu.pk
authors.forename: Ali Muhammad
authors.initials: AM
authors.lastname: Waryah
authors.forename: Ashok Kumar
authors.initials: AK
authors.lastname: Narsani
authors.forename: Shakeel Ahmad
authors.initials: SA
authors.lastname: Sheikh
authors.forename: Hina
authors.initials: H
authors.lastname: Shaikh
authors.forename: Muhammad Yaqoob
authors.initials: MY
authors.lastname: Shahani
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D003241:Consanguinity; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005902:Glaucoma, Open-Angle / Q000235:genetics* / Q000473:pathology; D006023:Glycoproteins / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010154:Pakistan; D010375:Pedigree; D055815:Young Adult; D000099179:Myocilin
chemical_list: D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D006023:Glycoproteins; D000099179:Myocilin
keywords: Arg; Arginine; JOAG; Juvenile Open Angle Glaucoma; Lys; Lysine; MYOC; Met; Methionine; Myocilin gene; PCR; POAG; Pakistan; Polymerase Chain Reaction; Primary Open Angle Glaucoma; STR; Short Tandem Repeats; Thr; Thr377Arg; Threonine