Screening of CYP1B1 and MYOC in Moroccan families with primary congenital glaucoma: three novel mutations in CYP1B1 - PubMed (original) (raw)

Screening of CYP1B1 and MYOC in Moroccan families with primary congenital glaucoma: three novel mutations in CYP1B1

Latifa Hilal et al. Mol Vis. 2010.

Abstract

Purpose: To investigate the contribution of cytochrome P4501B1 (CYP1B1) and myocillin (MYOC) mutations to primary congenital glaucoma (PCG) in Moroccan families.

Methods: This study included 90 unrelated families with PCG and 100 normal control individuals. Two previously reported CYP1B1 mutations (g.4339delG and p.G61E) were first screened by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The coding exons of CYP1B1 were sequenced in g.4339delG- and p.G61E-negative or heterozygous probands. Then the coding exons of MYOC were sequenced in patients who had no mutation in CYP1B1 or carried heterozygous CYP1B1 mutation.

Results: Twelve CYP1B1 mutations were identified in 43 PCG pedigrees. Three of them were novel (p.R163C, p.C470Y, and g.4330-4331delTG) and associated with moderate to severe phenotypes. Two novel intronic polymorphisms in CYP1B1 were identified in addition to those previously described. The g.4339delG was the most frequent mutation detected in 31 families (34.44%), followed by the p.G61E in seven families (7.77%). The remaining mutations (p.R163C, p.E173K, g.4330-4331delTG, p.E229K, p.R390S, p.R368H, p.R469W, p.C470Y, and g.7901-7913del13bp) were infrequent. One family with the p.R390S mutation showed both PCG and primary open angle glaucoma (POAG) phenotypes. One proband was heterozygous for p.T193K mutation in MYOC. This mutation has been initially associated with POAG, but never with PCG.

Conclusions: Our results support that mutations in CYP1B1 are a major cause for PCG in the Moroccan population with a predominance of the g.4339delG mutation. Furthermore, these results demonstrate the diversity of CYP1B1 mutations, while suggesting a modest role of MYOC in Moroccan PCG.

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Figures

Figure 1

Figure 1

Pedigrees of PCG families with CYP1B1 or MYOC mutations. A: Families with the CYP1B1 novel mutation (p.R163C, p.C470Y, and g.4330–4331delTG) identified in this study. B: Family PCG-40 with the CYP1B1 p.R390S mutation showing variable expression of the PCG phenotype. The proband (PCG-40-IV.6) was affected with PCG, while his uncle (PCG-40-III.1; gray symbol) developed POAG at the age of 45. C: Family PCG-9 with MYOC mutation. Deceased individuals are denoted by diagonal slashes, and consanguineous marriages by double lines. Asterisks indicate probands. Genotypes in available subjects are indicated below the symbols. delG: g.4339delG, delTG: g.4430–4431delTG, w: normal allele.

Figure 2

Figure 2

Detection of three novel CYP1B1 mutations in Moroccan PCG families by direct DNA sequencing. Sequencing results of probands from families PCG-101 (A), PCG-100, and PCG-64 (B) and PCG-84 (C). Chromatogram of a heterozygous subject for g.4330–4331delG is shown in C. The names of the mutations and their corresponding amino-acid change are indicated above each chromatogram. Control sequences are shown for comparison purposes. Arrows indicate the changed nucleotides and curley bracket the deleted nucleotides in the g.4330–4331delTG allele. Because of the presence of a three GT repeat in this region, it is not possible to determine exactly which of the positions is deleted. Therefore, the position of this deletion was arbitrarily indicated. Htr: heterozygous mutation and Hmz: homozygous mutation.

Figure 3

Figure 3

Multiple amino-acid sequence alignment of CYP1B1 from different species. Sequence alignment was generated by

ClustalW

. The positions of mutated amino-acids newly reported in this study are indicated by arrows and red letters. The COOH-terminal amino-acids of C-helix, NH2-terminal amino-acids of D-helix and heme binding loop (HBL) are indicated below the sequence alignment, by a line.

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