A novel frameshift founder mutation in the cytochrome P450 1B1 (CYP1B1) gene is associated with primary congenital glaucoma in Morocco

Abstract

Primary congenital glaucoma (PCG) is a heterogeneous autosomal recessive disorder caused by unknown developmental defect(s) of the anterior chamber of the eye. A member of the cytochrome P450 gene family, CYP1B1, was found to be mutated in PCG patients in different populations, albeit to a variable extent. In this study, CYP1B1 mutations were searched for in 32 unrelated PCG patients from Morocco. Two mutations were detected in 11 (34%) patients. One, 4339delG, is novel and causes a frameshift at residue 179. The other, G61E, was previously found in patients from Turkey and Saudi Arabia. Seven patients were homozygous for 4339delG and two other patients for G61E, whereas the two remaining patients were compound heterozygotes. The close association of 4339delG with a rare allele of D2S177, a microsatellite marker located 270 kb upstream of CYP1B1, strongly suggested a founder effect for 4339delG. The occurrence of this mutation was tentatively dated at between 900 and 1700 years ago. Typing 4339delG and G61E mutations should help to prevent blindness resulting from a delayed diagnosis of PCG in Morocco.

Novel cytochrome P450 1B1 (CYP1B1) mutations in patients with primary congenital glaucoma in France

“…The four patients with the g.4340delG mutation and the patient with the p.269S_271Fdel mutation carried the same homozygous SNP haplotype, g.3793C-g3947C-g.4160G-g.8131G-g.8184T-g.8195A. This haplotype was previously associated with the two mutations (Bejjani et al, 2000;Belmouden et al, 2002). However, it is also the most frequent one in Morrocco and in Saudi Arabia.…”

“…However, the parents of the patients who carried g.4340delG (4 cases) and p.269S_271Fdel (1 case) came from Algeria. The g.4340delG mutation has been previously described in patients from Morocco and from Brazil (Belmouden et al, 2002;Stoilov et al, 2002). In Morocco, this mutation is largely predominant among PCG patients and has been associated with a founding effect.…”

“…Numerous mutations of this gene have been characterized in PCG patients from different populations (Sarfarazi and Stoilov, 2000). In some ethnic groups, however, the diversity of mutations is restricted and founding effects are apparent (Bejjani et al, 1998;Plasilova et al, 1999;Belmouden et al, 2002;Sitorus et al, 2003). In the present study, we have investigated mutations of the CYP1B1 gene in 31 unrelated French PCG patients.…”

Molecular analysis of Italian patients with congenital glaucoma

“…The most frequent haplotype in individuals with CYP1B1 mutations is 5'-C-G-G-T-A-3', as already described in other populations (Belmouden et al,2002, Bejjani et al, 1998, Stoilov et al, 2001). This haplotype is present in 41 of the 44 mutated alleles (93%), and in only 20 of the remaining 100 wild type alleles (20%); the difference is statistically significant (Q2= 22.23, p < 0.0001, CI95% 0.555-0.905).…”

“…(Online Mendelian Inheritance in Man, OMIM 231300). An increase in IOP, untreated either with surgery or pharmacological therapy, results in ocular enlargement (buphthalmos) and rapidly progressive cupping of the optic nerve with severe and irreversible alteration of the visual field (Belmouden et al, 2002, Bruttini et al, 2003. Early recognition and therapy can significantly improve the child's visual function.…”