Distribution study of the frequent pG111R mutation in the Argentinean population

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

Cardiff

Congreso; Porphyrins and Porphyrias 2011; 2011

British Association of Dermatologists

Acute intermittent porphyria (AIP) is an autosomal dominant disorder caused by a reduction in the activity of porphobilinogen deaminase (PBG-D). Its clinical expression is variable, determined by environmental, metabolic and hormonal factors. In Argentina, the AIP has a prevalence of 1:100000 and while most of the 300 different mutations described worldwide are present in a few families, the 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 PCR and automatic sequencing were performed. In CIPYP, 172 PAI families have been diagnosed biochemically, 88 of them were analyzed at the molecular level, 46 of which carry the mutation p.G111R. We present results of the last 22 p.G111R families tested: 61 out of the 103 individuals studied carry the mutation (59%) and 65% of mutation carriers are women. Sixty-eight percent of PAI p.G111R families belong to the Northwest of Argentina and 50% of them belong to the province of Tucumán. Fourty-five percent of all patients with the mutation are symptomatic and 85% of them are women. Among the latent carriers, there is no significant differences between genders. We analyzed 13 SNPs distributed throughout the gene sequence and we found variability in 6 of them (3119 G> T, 3581 A> G, 3982 T> C, 6479 G> T, 7064 C> A, 7539 C> T). All mutation carriers have p.G111R haplotype (GATGAC). In the rest of the analyzed SNPs (3651 C> T, 4679 C> T, 6589 A> G, 6761 A> G, 7052 A> G, 7998 A> G, 8003 G> 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 Argentinean population. Taking into account that  the frequency of this mutation  is extremely low worldwide (< 5%), we suggest that it would have appeared as de novo mutation in our Norwest region.                                                                         .