title: A spectrum of CYP1B1 mutations associated with primary congenital glaucoma in families of Pakistani descent.
abstract: Glaucoma is the second leading cause of blindness, affecting ~65 million people worldwide. We identified and ascertained a large cohort of inbred families with multiple individuals manifesting cardinal symptoms of primary congenital glaucoma (PCG) to investigate the etiology of the disease at a molecular level. Ophthalmic examinations, including slit-lamp microscopy and applanation tonometry, were performed to characterize the causal phenotype and confirm that affected individuals fulfilled the diagnostic criteria for PCG. Subsequently, exclusion analysis was completed with fluorescently labeled short tandem repeat markers, followed by Sanger sequencing to identify pathogenic variants. Exclusion analysis suggested linkage to the CYP1B1 locus, with positive two-point logarithm of odds scores in 23 families, while Sanger sequencing identified a total of 11 variants, including two novel mutations, in 23 families. All mutations segregated with the disease phenotype in their respective families. These included the following seven missense mutations: p.Y81N, p.E229K, p.R368H, p.R390H, p.W434R, p.R444Q and p.R469W, as well as one nonsense mutation, p.Q37*, and three frameshift mutations, p.W246Lfs81*, p.T404Sfs30* and p.P442Qfs15*. In conclusion, we identified a total of 11 mutations, reconfirming the genetic heterogeneity of CYP1B1 in the pathogenesis of PCG. To the best of our knowledge, this is the largest study investigating the contribution of CYP1B1 to the pathogenesis of PCG in the Pakistani population.
authors: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
authors: Bushra
authors: B
authors: Rauf
authors: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
authors: Bushra
authors: B
authors: Irum
authors: The Wilmer Eye Institute, Johns Hopkins University School of Medicine , Baltimore, MD, USA.
authors: Firoz
authors: F
authors: Kabir
authors: National Centre of Excellence in Molecular Biology, University of the Punjab , Lahore, Pakistan.
authors: Sabika
authors: S
authors: Firasat
authors: National Centre of Excellence in Molecular Biology, University of the Punjab , Lahore, Pakistan.
authors: Muhammad Asif
authors: MA
authors: Naeem
authors: National Centre of Excellence in Molecular Biology, University of the Punjab , Lahore, Pakistan.
authors: Shaheen N
authors: SN
authors: Khan
authors: National Centre of Excellence in Molecular Biology, University of the Punjab , Lahore, Pakistan.
authors: Tayyab
authors: T
authors: Husnain
authors: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan; Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan; National Centre for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.
authors: Sheikh
authors: S
authors: Riazuddin
authors: Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan; National Centre for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.
authors: Javed
authors: J
authors: Akram
authors: The Wilmer Eye Institute, Johns Hopkins University School of Medicine , Baltimore, MD, USA.
authors: S Amer
authors: SA
authors: Riazuddin