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Analysis of CYP1B1 Gene Mutations in Patients
Analysis of CYP1B1 Gene Mutations in Patients
1 Department of Medicine and Pharmacy, Hassan II University of Address for correspondence Sellama Nadifi, MD, PhD, Laboratory of
Casablanca, Casablanca, Morocco Medical Genetics and Molecular Pathology, Department of Medicine
2 Laboratory of Medical Genetics and Molecular Pathology, and Pharmacy, Hassan II University of Casablanca, 19 Rue Tarik Ibou
Department of Medicine and Pharmacy, Hassan II University of Ziad, B.P: 9154, Morocco (e-mail: nadifisel@yahoo.fr).
Casablanca, Casablanca, Morocco
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
geographic area. ►Table 3 lists some examples of these the c.868_869insC, p.Glu229Lys, and Ala115Pro have each
founder mutations. been found only once in three families.
In Lebanon, the most common mutation was p.Gly61Glu.
Middle East CYP1B1 mutations in Lebanese patients are rarer compared
In the Iranian population, the most common mutation was with the Middle East and other Arab populations. This is
p.Gly61Glu. It was found in two homozygous patients and in probably because the Lebanese originated from a mix of
one heterozygous patient, followed by p.Arg390His identi- European and Asian populations, providing a wider genetic
fied in two homozygous patients. heterogeneity in Lebanese families, whereas homozygosity is
In Saudi Arabia, the p.Gly61Glu mutation is considered as more common in the Arab population.9
the major mutation, found 17 times in the homozygous state
and once in the heterozygous state.7 Findings from Saudi Maghreb
Arabia suggest that novel PCG genes are more likely to arise In Morocco, among the mutation carriers, 62.7% (32/51) had
in their population. However, in other case reports, not any frameshift truncating mutations (g.4339delG, g.4330–
CYP1B1 mutations were found, where the glaucoma was 4331delTG, and g.79016–7913del13bp) in both alleles, and
probably related to novel CNVs (copy number variations).8 37.3% (19/51) had at least one missense mutation (nine patients
Another example of Saudi Arabian children, affected by were homozygous for p.Arg390Ser, p.Arg469Trp, p.Cys470Tyr,
unilateral PCG, where no CYP1B1 mutation was detected, or p.Gly61Glu; eight patients were compound heterozygous,
suggests that the pathogenesis of unilateral glaucoma differs including (5) p.Glu173Lys, (2) p.Gly61Glu, (1) p.V364M ,and two
from the bilateral form. heterozygous for p.Arg163Cys and p.Arg368His, respectively).
In Pakistan, the p.Arg390His mutation was the most In Tunisia, the CYP1B1 mutations were present in 55%
common, identified in five families (50%, 5/10), whereas of the patient’s alleles. Two mutations p.Gly61Glu and
Population Location genomic DNA Amino acid change Type of N Homozygote Heterozygote
scheduled change mutation
Vietnamese Exon 2 c.836A > T p.His279Leu NM 1 þ
Vietnamese Exon 2 c.847C > T p.Leu283Phe NM 1 þ
Lebanese NM 1793delC p.Ser464 Frameshift 1 þ
Iranian NM NM p.Tyr81 NM 1 þ
Iranian NM NM p.Arg390His NM 2 þ
Iranian-Saudi Exon 2 c.685G > A p.Glu229Lys Missense 1 þ þ
1
Iranian NM NM p.Pro289fs NM 1 þ
Iranian NM NM p.Gly329Val NM 1 þ
Iranian NM NM p.Arg368Cys NM 1 þ
Spanish NM NM p.Thr404fsX38 NM NM NM
Moroccan NM g.4339delG NM Frameshift þ
Table 2 (Continued)
Population Location genomic DNA Amino acid change Type of N Homozygote Heterozygote
scheduled change mutation
Chinese NM g.G4322A p.Glu173Lys Missense NM þ ch
Tunisian NM 691T > A p.Phe231Ile NM 1 þ
Tunisian NM c.1309C > G p.Pro437Ala NM 1 þ
European Exon 1 c.337G > T NM NM NM NM
European Exon 2 NM p.Phe123Leu NM NM þ
European Exon 2 I399_P400del NM NM NM ch
European NM NM p.Ala237Glu NM NM NM
United States NM c.1063C > T p.Arg355 Nonsense NM 1þ
United States NM c.171G > A p.Trp57 Nonsense NM þ
United States NM c.1209_1210insTCATGCCACC 10-bp insertion Frameshift NM NM
United States NM c.1064_1076delGAGTGCAGGCAGA 13-bp deletion Frameshift frame NM NM
Korean NM c.970_971dupAT p.Thr325SerfsX104 NM NM þ
Abbreviations: (þ), present; ch, compound heterozygous; N, number; NM, not mentioned.
Location Genomic DNA Amino acid change/scheduled change Type mutations Country Consanguinity
Exon 2 3987G > A p.Gly61Glu Missense Lebanon þ
Morocco þ
Tunisia þ
Saudi Arabia þ
Exon 2 958G > T p.Val320Leu Missense Vietnam
South Korea
Exon 3 8242C > T p.Arg469Trp Missense Lebanon þ
Morocco þ
Saudi Arabia þ
Exon 2 182G > A p.Gly61Glu Missense Iran þ
Portugal NM
Saudi Arabia þ
Exon 2 4322G > A p.Glu173Lys Missense China NM
Morocco þ
Exon 3 7927G > A p.Val364Met Missense South Korea
p.Arg368His, p.Pro437Leu, p.Ala443Gly, p.Ala106Asp, p. This review also revealed a nonsignificant difference in
Glu387Lys, p.Arg390His, p.Glu229Lys, p.Glu229Lys, p. the sex ratio between different ethnic groups and CYP1B1
Arg444Gln, p.Ala179fs, p.Glu387Lys), 47.1% locate in exon mutation carriers.
2 and 52.9% in exon 3, respectively.
All the common mutations had almost the same mutation In the Middle-East
type in missense except for the frameshift mutation p. According to Li et al,6 the 3987G > A (p.Gly61Glu) seemed to
Ala179fs. be the most common mutation in Middle Easterners, ac-
Morocco had similar mutations to other countries such as counting for 45.52% (183 out of 402) of CYP1B1 mutations.
Lebanon, Tunisia, Saudi Arabia, China, South Korea, Brazil, The other common mutations were 8006G > A (p.Ar-
and India. g390His) (8.71%), 8242C > T (p.Arg469Trp) (8.21%), and
Asian patients such as South Korean have no consangui- 4339delG (5.72%).
nity status, yet they showed the same mutations as countries In comparison with this current review, the p.Gly61Glu
where the consanguinity is quite high as: 7927G > A/p. mutation was also prominent. It was discovered in four
Val364Met, 7940G > A/p.Afg368His, 8006G > A/Arg390His, different countries with a high rate of consanguinity, such
and 8168G > A/p.Arg444Gln. as Morocco, Tunisia, Lebanon, and Saudi Arabia. According to
Nevertheless, the 958G > T/p.Val320Leu remains the mu- the literature, this mutation was also found in other coun-
tation observed only in Asia (Vietnam and South Korea). tries such as Ecuador, Spain, India, Iran, Oman, Kuwait,
g.4339delG was never described before and was considered identified in an Egyptian family and later reported among
the most frequent (25.8% of alleles). Nevertheless, it had been Iranian patients.18,33 It has also been found in Morocco.
found in Algerian descendants (E. Colomb and HJ Garchon,
unpublished data). Therefore, this should be closely related Europe
to the presence of the Berber people, representing a major The p.Glu387Lys is considered the most common mutation.
part of the Algerian and Moroccan population. The other This mutation was also found in a Hungarian patient in the
mutation, p.Gly61Glu, had already been identified in Turkish homozygous state where both parents were heterozygous. It
and Saudi patients.27 was also demonstrated that this mutation was the most
Since the myocilin (MYOC) gene has also been found to be frequent in Gypsy population.9
involved in the etiology of the PCG, another Moroccan study
was conducted to assess the mutation spectrum of both, the United States
CYP1B1 and MYOC gene. The CYP1B1 gene was the major In the United States study, two novel combinations of
cause of GCP with a frequency of 48%, while MYOC played compound heterozygous mutations have been found with
only a modest role in Moroccan patients. The g.4339delG whole exome sequencing. Whole exome sequencing,
mutation was the most frequent followed by p.Gly61Glu. coupled with Sanger sequencing, may identify novel genes
These two mutations were present in 37.21% (30.55% and for PCG patients who do not harbor mutations in known
6.66%, respectively) of the Moroccan alleles. The g.4339delG PCG genes.
was also the most common mutation in Brazil23 with a lower
Conclusion
Asia
According to the study conducted by Li et al, the three most In this meta-analysis, 99 CYP1B1 gene mutations causing PCG
common mutations in Asian patients were p.Val364Met, p. from 2011 until May 2016 were identified. Moreover, 60 new
Arg390His, and p.Leu385Phe.9 mutations, not listed in the reference study of Li et al,6 were
In this meta-analysis, both p.Val364Met and p.Arg390His reported.
mutations were identified in South Korea, but also in Mor- CYP1B1 mutations were identified in 41.6% of the pa-
occo and in some Middle East countries (Saudi Arabia, and tients, which underlines the importance of CYP1B1 muta-
Pakistan). tional analysis. Therefore, other possibilities may cause the
On the other hand, the p.Leu385Phe was not found either PCG for the remaining 58.2% patients.
in Asian population or in other ethnic groups. It could be a Nonsignificant difference in the sex prevalence between
mutation that had stopped being transmitted through gen- different ethnic groups has been reported.
erations or not found in our sample of patients. Consanguinity plays an important role in the pathogen-
The p.Val320Leu mutation appeared only in Asian coun- esis and the transmission of PCG; however, some sporadic
tries including Vietnam and South Korea, where the con- mutations were also found. A difference in the penetrance for
sanguinity rate is low. This mutation has also been reported the same mutation was also highlighted in affected and
previously in the Chinese and Japanese population30,31 nonaffected Chinese individuals in this review.
suggesting that she could be a specific mutation for the The mutations distribution and frequency vary consider-
Asian population. ably between different ethnic and geographic locations.
The mutation p.Glu173Lys was detected in two Chinese The G61E was the most frequent mutation and was
patients and also in a nonaffected patient, which could be discovered in four different countries where the consangui-
explained by an incomplete penetrance. It suggested the nity rate is high.
presence of a dominant modifier locus that is not genetically Some mutations may be considered as founder mutations
linked to CYP1B1. Further studies of a possible regulation of for different populations. For example, the Gly61Glu, R390H,
other factors or other genes (e.g., LTBP2) should be performed G61E, 4339delG, E387K, and V320L were estimated as foun-
to explore the pathogenesis of PCG.32 This mutation was first der mutations for these countries: Iran/Saudi Arabia,
Pakistan, Lebanon, Morocco, Europe, and Vietnam/South 13 Stoilov I, Akarsu AN, Sarfarazi M. Identification of three different
Korea, respectively. truncating mutations in cytochrome P4501B1 (CYP1B1) as the
In addition, many common mutations in different coun- principal cause of primary congenital glaucoma (Buphthalmos) in
families linked to the GLC3A locus on chromosome 2p21. Hum
tries were found, such as Morocco where its mutations were
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