Our results provide genetic evidence that Hfe and Hjv operate in the same pathway for the regulation of hepcidin expression and iron metabolism. Disclosures: The following people have nothing to disclose: Patricia Kent, Nicole Wilkinson, Marco Constante, Konstantinos Gkouvatsos, John Wagner, Manuela M. Santos, Kostas Pantopoulos Acute Intermittent Porphyria (AIP) is an autosomal dominant hepatic porphyria
due to the half-normal activity of the heme biosynthetic enzyme, hydroxymethlbilane synthase MG-132 (HMBS). The disease is characterized by life threatening acute neurovisceral attacks, which are triggered by factors that induce the up-regulation of hepatic 5′-aminolevulinic acid synthase. To date, over 360 HMBS mutations that lead to acute attacks of AIP have been reported in the Human Genome Mutation Database (HGMD). The disease prevalence in Western Europe, based on newly diagnosed patients with acute attacks (Elder et al. J Inherit Metab Dis, 2013), ranges from 1 in 158,000 to 222,000. It is estimated that only 10% of AIP heterozygotes have acute attacks. However, neither the frequency of pathogenic HMBS mutations
that markedly reduce enzyme activity nor selleck kinase inhibitor the actual disease penetrance is known. To estimate the incidence of known and likely pathogenic HMBS mutations, we searched the databases of the 1K Human Genome Project and the NHLBI Exome Sequencing Project to identify nsSNPs in various racial/ethnic populations. Thirteen nsSNPs were identified in
Caucasians with allele frequencies from <0.001 to 0.28%, for a surprisingly high combined frequency of 0.73% (1 in 137). Four (combined frequency of 0.44% or 1 in 230) have been reported in HGMD as causing AIP acute attacks. The remaining nine are novel, accounting for a combined frequency of 0.28% (1 in 360). To determine their potential pathogenicity, the novel mutations were analyzed by 18 in silico programs. Of these, three nsSNPs were predicted as deleterious (D65H, I71T, A122P), for a combined allele frequency of 0.15% (1 in 670). Four nsSNPs (V237M, R246C, I54L, S45L) were predicted to be tolerated, benign or likely polymorphisms, while two nsSNPs (R246H and R355Q) had equivocal predictions. All nsSNPs are being expressed Cyclooxygenase (COX) in vitro to determine which encode enzymes with markedly reduced HMBS activity. In addition, efforts are directed to identify in the dbGaP database possible disease phenotypes associated with the pathogenic HMBS nsSNPs. Thus, the incidence of the four known and three predicted pathogenic HMBS mutations in Caucasians may be as high as 0.59% (1 in 170). The penetrance of this hepatic porphyria may be unusually low, even if the frequency of pathogenic alleles is 1 in 103. As the prevalence of patients who have had acute attacks is ∼ 1 in 20,000 in Sweden to ∼1 in 200,000 in Western Europe, our results suggest the importance of modifying genes and environmental triggering factors causing the acute attacks.