A spectrum of CYP1B1 mutations associated with primary congenital glaucoma in families of Pakistani descent

Bushra Rauf; Bushra Irum; Firoz Kabir; Sabika Firasat; Muhammad Asif Naeem; Shaheen N Khan; Tayyab Husnain; Sheikh Riazuddin; Javed Akram; S Amer Riazuddin

doi:10.1038/hgv.2016.21

A spectrum of CYP1B1 mutations associated with primary congenital glaucoma in families of Pakistani descent

Hum Genome Var. 2016 Aug 4:3:16021. doi: 10.1038/hgv.2016.21. eCollection 2016.

Authors

Affiliations

¹ 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.
² The Wilmer Eye Institute, Johns Hopkins University School of Medicine , Baltimore, MD, USA.
³ National Centre of Excellence in Molecular Biology, University of the Punjab , Lahore, Pakistan.
⁴ 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.
⁵ Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan; National Centre for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.

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.