Abstract
Purpose: Congenital glaucoma (CG) results from poorly understood developmental abnormalities of the aqueous drainage structures and is clinically characterized by high intraocular pressure (IOP), epiphora, corneal oedema, photophobia, blepharospasm and ocular enlargement. To date, more than 50 pathogenic mutations in the CYP1B1 gene, a member of the cytochrome P450 gene family, have been reported in CG patients. The aim of this paper was to determine the genetic defects underlying CG in Italian patients. Methods: Molecular analysis of CYP1B1 was performed on the DNA of 120 patients and the transcript region of the MYOC/TIGR gene was also studied in all the patients bearing only one mutation in CYP1B1 gene. Previously described CYP1B1 polymorphisms (R48G, A119S, L432V, D449D and N453S) were also analyzed in our patients. Results: Seventeen different variations of CYP1B1 were found in 30 of the 120 (25.0%) CG patients. Twelve of these changes had been identified in previous reports as disease-causing mutations, while L26R, P52L, A106D, A237E and F440L are described here for the first time. F440L has always been found in cis with P52L, both in patients and healthy carriers, suggesting its role as a rare polymorphism linked to the P52L, while the other new variations we found could possibly play a pathogenetic role. G61E and 1775-1801dup27 are the most frequent mutations in our patients. Two amino acid variations (A447V and R76K) were identified in MYOC/TIGR analysis. Conclusions: Our results confirm the major role of the CYP1B1 gene in congenital glaucoma and also suggest an autosomal recessive role of MYOC/TIGR in a digenic inheritance model.
Highlights
Glaucoma is a heterogeneous group of optic neuropathies which can lead to optic nerve loss of optic nerve fibers and permanent loss of vision
Four of these variations (L26R, P52L, A106D, A237E) are reported here for the first time and produced a non synonymous aminoacidic change. Their pathological role in congenital glaucoma (CG) development could be an explanation for the significant changes in the protein caused by the aminoacidic substitutions in Eukariota and cytochrome P450 family conserved regions
The conservative aminoacid change F440L always found in cis with the P52L in 4 subjects, both in patients and in healthy carriers, could be classified as a rare polymorphism linked to the pathological P52L
Summary
Glaucoma is a heterogeneous group of optic neuropathies which can lead to optic nerve loss of optic nerve fibers and permanent loss of vision. CG may be associated with ocular malformation, such as aniridia (Lee et al, 2003) or congenital hydrocephalus and anterior segment dysgenesis (Mandal et al, 2002) It results from poorly understood developmental abnormalities of the ocular drainage structures and is clinically characterized by high intraocular pressure (IOP), epiphora, corneal oedema, photophobia, blepharospasm and ocular enlargement (Libby et al, 2003). Different CYP1B1 mutations together with a common MYOC/TIGR mutation (Gln48His) have been reported in CG patients (Ming and Muenke, 2002, Chakrabarti et al, 2005), suggesting a role for the MYOC gene in congenital glaucoma via digenic interactions with CYP1B1. In 22 Saudi Arabian families, 40 apparently unaffected individuals had mutations in CYP1B1 and haplotypes identical to their affected siblings Analysis of these relatives suggested the presence of a dominant modifier locus that is not linked genetically to CYP1B1. We describe here the pathogenic mutations found, some of which are not published, and the haplotype for five intragenic SNPs (Single Nucleotide Polymorphisms) associated with the mutations identified
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