Analysis of CYP1B1 Gene Mutations in Patients with Primary Congenital Glaucoma

Abstract

Primary congenital glaucoma (PCG) is the most common type of infantile glaucoma, yet it remains a relatively rare disease, because the disease is often transmitted in an autosomal recessive pattern. However, PCG occurs up to 10 times more frequently in certain ethnic and geographical groups where consanguineous relationships are common. The aim of this study was to investigate the distribution of mutations in the cytochrome P450 1B1 gene ( ) in patients with PCG among different populations around the world from 2011 until May 2016. We referred to the electronic databases, such as Medline, Clinicalkey, Scopus, and ScienceDirect, to search for articles that were published in this area. Nineteen records were included in this qualitative synthesis. mutations were assessed in 1,220 patients with PCG and identified in 41.6% of them. According to these studies, 99 mutations including 60 novel mutations were found. Nonsignificant difference in the sex ratio has been reported. This current review shows that consanguinity plays an important role in the PCG pathogenesis and transmission; however, sporadic mutations have been found in some cases. A difference in penetrance was highlighted by some mutations. The mutations were mostly found in the Middle East and the Maghreb with a rate of 64.8 and 54.4%, respectively, followed by Europe (34.7%), Asia (21.3%), and finally the United States (14.9%). Founder mutations in different geographical areas have been discovered. For instance, the p.Gly61Glu, p.Arg390His, p.Gly61Glu, c.4,339delG, p.E387Lys, and p.Val320Leu were considered founder mutations for Iran/Saudi Arabia, Pakistan, Lebanon, Morocco, Europe, and Vietnam/South Korea, respectively. Many common mutations in different countries were found, such as in Morocco, where its mutations were similar to seven other countries. These findings suggest that the ethnic differences and the geographical distribution of PCG give us a large mutation pattern. Genetic tests looking for founder and common mutations should be the first step in genetic screening for patients with PCG.

CYP1B1 gene: Implications in glaucoma and cancer

“…Therefore, variability in prevalence indicates that other main genetic factors for PCG have not been identified yet. PCG is usually inherited as an autosomal recessive disease with incomplete penetrance [33]. This form is considered a rare form of glaucoma.…”

“…It is characterised by isolated angle anomalies, possibly involve mild congenital iris anomalies, ocular hypertension, buphthalmos (enlargement of the eye), oedema, corneal opacification (scarring or clouding of the cornea), descemet's membrane herniation, lower density of the anterior sclera, iris atrophy and increased depth of the anterior chamber. Patients with PCG manifest variable symptoms include photophobia (intolerance to visual observation of light), blepharospasm (involuntary closing of the eyelids), and increased lacrimation (tear discharge) [33]. Optic neuropathy is not the sole contributor to PCG; glial cells are also considered major players in disease pathogenicity [34].…”

“…Multiple PCG loci have been mapped; however, only CYP1B1 has been identified to date as the leading cause of PCG. Interestingly, more than 150 mutations in CYP1B1, including missense, nonsense, regulatory, insertions, or deletions, have been associated with PCG [33]. In glaucoma, most scientists focus on the optic nerve.…”

Risk factors for primary congenital glaucoma in the National Birth Defects Prevention Study

“…The most consistently identified mutated gene in PCG is CYP1B1 , a member of the cytochrome P450 family of genes (Li, Zhou, Du, Wei, & Chen, ; Vasiliou & Gonzalez, ). The frequencies of specific CYP1B1 mutations vary among ethnic groups (Chouiter & Nadifi, ; Li, Zhou, et al, ). Within the U.S., an ethnically heterogeneous population, CYP1B1 mutations are much rarer and are found in less than 15% of families with PCG (Lim et al, ).…”

Exome Sequencing in a Swiss Childhood Glaucoma Cohort Reveals CYP1B1 and FOXC1 Variants as Most Frequent Causes

“…The prevalence of CYP1B1 pathogenic variants in our cohort was comparable to other European populations. 17 , 19 , 38 Previous studies investigated the prevalence of FOXC1 pathogenic variants among childhood glaucoma patients. 34 , 39 , 40 Siggs et al 34 recently analyzed a large Italian-Australian cohort of PCG patients without CYP1B1 variants, and found 6.1% of disease-causing FOXC1 variants among these patients.…”