title: GLYOXALASE I A111E, PARAOXONASE 1 Q192R AND L55M POLYMORPHISMS IN ITALIAN PATIENTS WITH SPORADIC CEREBRAL CAVERNOUS MALFORMATIONS: A PILOT STUDY.
abstract: It is already known that the conditions of increased oxidative stress are associated to a greater susceptibility to vascular malformations including cerebral cavernous malformations (CCMs). These are vascular lesions of the CNS characterized by abnormally enlarged capillary cavities that can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes: CCM1(Krit1), CCM2 (MGC4607) and CCM3 (PDCD10). Polymorphisms in the genes encoding for enzymes involved in the antioxidant systems such as glyoxalase I (GLO I) and paraoxonase I (PON I) could influence individual susceptibility to the vascular malformations. A single nucleotide polymorphism was identified in the exon 4 of GLO 1 gene that causes an amino acid substitution of Ala for Glu (Ala111Glu). Two common polymorphisms have been described in the coding region of PON1, which lead to glutamine → arginine substitution at 192 (Q192R) and a leucine → methionine substitution at 55 (L55M). The polymorphisms were characterized in 59 patients without mutations in the CCM genes versus 213 healthy controls by PCR/RFLP methods using DNA from lymphocytes. We found that the frequency of patients carrying the GLO1 A/E genotype among the case group (56%) was four-fold higher than among the controls (14.1%). In the cohort of CCM patients, an increase in the frequency of PON192 Q/R genotype was observed (39% in the CCM group versus 3.7% in the healthy controls). Similarly, an increase was observed in the proportion of individuals with the genotype R/R in the disease group (5%) in respect to the normal healthy cohort (0.5%). Finally, the frequency of the PON55 heterozygotes L/M genotype was 29% in patients with CCMs and 4% in the healthy controls. The same trend was observed in PON55 homozygous M/M genotype frequency (CCMs 20% vs controls 10%). The present study aimed to investigate the possible association of GLO1 A111E, PON1 Q192R and L55M polymorphisms with the risk of CCMs. We found that individuals with the GLO1 A /E genotype, PON192/QR-RR genotypes and PON55/LM-MM genotypes had a significantly higher risk of CCMs compared with the other genotypes. However, because CCM is a heterogeneous disease, other additional factors might be involved in the initiation and progression of CCM disease.
authors.affiliation: Department of Biomedical Sciences and Morphological and Functional Images, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Rinaldi
authors.affiliation: IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Bramanti
authors.affiliation: Department of Biomedical Sciences and Morphological and Functional Images, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Famà
authors.affiliation: Department of Biomedical Sciences and Morphological and Functional Images, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Scimone
authors.affiliation: Department of Biomedical Sciences and Morphological and Functional Images, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Donato
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Antognelli
authors.affiliation: Department of Neurosciences, University of Messina, Messina, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Alafaci
authors.affiliation: Department of Neurosciences, University of Messina, Messina, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Tomasello
authors.affiliation: Department of Biomedical Sciences and Morphological and Functional Images, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, Italy.
authors.forename: R
authors.initials: R
authors.lastname: D'Angelo
authors.affiliation: Department of Biomedical Sciences and Morphological and Functional Images, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Sidoti
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D019943:Amino Acid Substitution; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D020786:Hemangioma, Cavernous, Central Nervous System / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D007558:Italy / Q000453:epidemiology; D007791:Lactoylglutathione Lyase / Q000235:genetics*; D008214:Lymphocytes / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: C000597196:GLO1 protein, human; D007791:Lactoylglutathione Lyase