Short Communication The novel heterozygous Thr377Arg MYOC mutation causes severe Juvenile Open Angle Glaucoma in a large Pakistani family Ali Muhammad Waryah a, ⁎, Ashok Kumar Narsani b , Shakeel Ahmad Sheikh a,1 , Hina Shaikh a,1 , Muhammad Yaqoob Shahani a a Molecular Biology & Genetics Department, Medical Research Center, Liaquat University of Medical & Health Sciences, Jamshoro, Pakistan b Department of Ophthalmology, Liaquat University of Medical & Health Sciences, Jamshoro, Pakistan abstract article info Article history: Accepted 10 July 2013 Available online 23 July 2013 Keywords: Pakistan MYOC JOAG Thr377Arg 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 CNG, substituting Threonine in to Ar- ginine 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 25 mm Hg. 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 autoso- mal 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 af- fected family and carriers of this mutation may be advised for early therapeutic intervention to avoid irreversible visual loss. © 2013 Elsevier B.V. All rights reserved. 1. Introduction Primary Open Angle Glaucoma (POAG) is one of the leading causes of irreversible blindness in the world, characterized by elevated intraoc- ular pressure (IOP), optic disc damage and loss of visual field (Wiggs et al., 1996). Based upon the age of diagnosis, POAG is subcategorized into adult onset POAG and Juvenile onset Open Angle Glaucoma (JOAG). Adult onset POAG is diagnosed after the age of 40 years (Cai et al., 2012; Goldwyn et al., 1970), while JOAG onset may occur between the age of 3 and 30 (Cai et al., 2012). POAG is genetically heterogeneous and more than 20 loci have been associated with JOAG and adult onset POAG (Allingham et al., 2009). Typically JOAG is inherited as an autoso- mal dominant trait, while adult onset POAG shows complex inheritance (Wiggs, 2007). MYOC (OMIM 601652) gene at GLC1A locus on chromosome 1q23 is the most frequently mutated gene in familial glaucoma cases, account- ing for 4% of adult onset POAG and 10% JOAG (Fingert et al., 2002). MYOC consists of 3 exons and encodes 57 kD myocilin protein. Over 80 different mutations have been identified in MYOC. Majority of these mutations are clustered in exon 3, which constitute the olfactomedin domain of myocilin (Kubota et al., 1998). MYOC mutations show vari- able penetrance, resulting in mild to severe phenotypes (Cai et al., 2012; Gong et al., 2004). POAG is one of the common types of glaucoma in Pakistan (Qureshi et al., 2006). But there is no information about molecular basis of POAG in the patients. Here, we investigated the molecular basis of the early onset glaucoma in a large Pakistani family with 8 affected individuals in 3 generations and the related clinical findings. 2. Methods 2.1. Study subject recruitment and clinical examination This study was approved by the Ethical Review Committee of Liaquat University of Medical and Health Sciences, Jamshoro. After obtaining informed consent, the family (POG 05) was enrolled from Liaquat Gene 528 (2013) 356–359 Abbreviations: POAG, Primary Open Angle Glaucoma; JOAG, Juvenile Open Angle Glaucoma; STR, Short Tandem Repeats; MYOC, Myocilin gene; Thr, Threonine; Lys, Lysine; Met, Methionine; Arg, Arginine; PCR, Polymerase Chain Reaction. ⁎ Corresponding author. Tel.: +92 229213317. E-mail address: aliwaryah@lumhs.edu.pk (A.M. Waryah). 1 These authors have equal contribution. 0378-1119/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.gene.2013.07.016 Contents lists available at ScienceDirect Gene journal homepage: www.elsevier.com/locate/gene