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.

Mutational analysis of the CYP1B1 gene in Pakistani primary congenital glaucoma patients: Identification of four known and a novel causative variant at the 3′ splice acceptor site of intron 2

“…Some previous studies conducted on PCG patients from the Pakistani population have shown variable percentages of mutations such as 47.8%, 30%, and 23.1%. 10,12,13 The possible reason behind the identification of low percentage of mutations in our study could be analysis of 32 isolated cases (Figure 1) that may have disease due to nongenetic factors.…”

Cytochrome P450 1B1: role in health and disease and effect of nutrition on its expression

“…33 Until now, more than 150 mutations in CYP1B1 have been determined linked with PCG that account a signicant fraction of the genetic load of familial and sporadic cases of PCG. 34 Previous studies have shown that there are two chromosomal locations for PCG on 2p21 (GLC3A, MIM 231300) and 1p36 (GLC3B), where GLC3A locus colocalizes to the CYP1B1 gene (MIM 601771 or MYOC) on chromosome 2p21. 35 Basically MYOC encodes a 504-amino-acid glycoprotein that contains an olfactomedin domain (residues 246-501) and is known to be the site where the majority (42/46 [91.3%]) of the mutations documented have been identied.…”

“…They stated that all of these mutations segregated with the disease phenotype in their respective families. 34 Researchers from Germany investigated 12 rare heterozygous missense mutations in TEK by targeted sequencing. Among them four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) cooccurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and p.R368H) in ve families.…”

CYP1B1 variants have low contribution to Pakistani patients with Primary Open Angle Glaucoma Page

“…It is noteworthy that CYP1B1 mutations are population specific and have been detected in patients with diverse ethnic backgrounds. (Sheikh et al, 2014, Rauf et al, 2016 The Pakistani population is genetically heterogeneous with combination of several ethnicities.…”