Distribution study of the frequent pG111R mutation in the Argentinean population

CERBINO G; GEREZ, E; PARERA VE; BATLLE A; ROSSETTI MV

Cardiff

Congreso; International Porphyrins and Porphyrias Meeting; 2011

British Society of Dermatologists

Acute intermittent porphyria (AIP) is an autosomal dominant disorder caused by a reduction in the activity of porphobilinogen deaminase. Its clinical expression is variable, determined by environmental, metabolic and hormonal factors. In Argentina, AIP has a prevalence of 1 : 100 000 and while most of the 300 different mutations described worldwide are present in a few families, p.G111R is present in 52% of Argentine families. The aim of this study was to investigate the origin of the high frequency of this mutation in our population. Routine biochemical assays and genetic studies by polymerase chain reaction and automatic sequencing were performed. In CIPYP, 172 AIP families have been diagnosed biochemically; 88 of them were analysed at the molecular level, and 46 carried the mutation p.G111R. We present results of the last 22 p.G111R families tested: 61 of 103 individuals studied carry the mutation (59%) and 65% of mutation carriers are women. Sixty-eight per cent of AIP p.G111R families come from the Northwest of Argentina, 50% of them from the province of Tucuma´n. Forty-five per cent of all patients with the mutation are symptomatic and 85% are women. Among the latent carriers, there is no significant difference between genders. We analysed 13 single nucleotide polymorphisms (SNPs) distributed throughout the gene sequence and found variability in six of them: 3119G>T, 3581A>G, 3982T>C, 6479G>T, 7064C>A, 7539C>T. All mutation carriers have p.G111R haplotype (GATGAC). In the remaining SNPs analysed (3651C>T, 4679C>T, 6589A>G, 6761A>G, 7052A>G, 7998A>G, 8003G>A) variability (CCAAAGG) was not observed. These data reflect a higher penetrance of the mutation p.G111R and a common haplotype associated with this mutation in the Argentinian population. Taking into account that the frequency of this mutation is extremely low worldwide (<5%), we suggest that it would have appeared as a de novo mutation in our Northwest region.