Our findings demonstrate the great potential of these hits for the development of a pharmacological chaperone-based corrective treatment of AIP by enhancing wild-type HMBS function independently of the patients' specific mutation.
To investigate the dramatically different manifestations, knock-in mice with human HD-AIP missense mutations c.500G>A (p.Arg167Glu) or c.518_519GC>AG (p.Arg173Glu), designated R167Q or R173Q mice, respectively, were generated and compared with the previously established T1/T2 mice with ~30% residual HMBS activity and the heterozygous AIP phenotype.
In a recent study published in Nature Medicine (Published online October 8, 2018. doi.org/10.1038/s41591-018-0199-z), the intravenous delivery of human porphobilinogen deaminase (PBGD) mRNA, targeting the liver, demonstrated its efficacy and safety to replace the defective PBGD protein in preclinical models of acute intermittent porphyria.
Acute intermittent porphyria (AIP) is a low-penetrant genetic metabolic disease caused by a deficiency of hydroxymethylbilane synthase (HMBS) in the haem biosynthesis.
Here, we characterized the reactivity of mesenteric arteries from male and female AIP mice with ~30% of normal PBGD activity and wild type C57BL/6 mice.
Mice with severe HMBS deficiency, which clinically and biochemically mimic the early-onset homozygous dominant AIP (HD-AIP) patients, have been generated and were used to elucidate the striking phenotypic differences between AIP and HD-AIP.
To better interpret the underlying mechanism of clinical phenotypes, we collected 117 <i>HMBS</i> gene mutations from reported individuals with AIP and evaluated the mutations' impacts on the corresponding protein structure and function.
Acute intermittent porphyria (AIP) is an inherited metabolic disease with low clinical penetrance caused by mutations in the hydroxymethylbilane (HMBS) gene.
Acute intermittent porphyria (AIP) is an inherited disorder of haem metabolism characterized by life-threatening acute neurovisceral attacks due to the induction of hepatic δ-aminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency.
Molecular characterization, by digital PCR analysis of four HMBS gene mutations affecting the ubiquitous isoform of Porphobilinogen Deaminase (PBGD) in patients with Acute Intermittent Porphyria (AIP).
A novel 55-basepair deletion of hydroxymethylbilane synthase gene found in a Chinese patient with acute intermittent porphyria and her family: A case report.
Acute intermittent porphyria (AIP) results from haploinsufficiency of porphobilinogen deaminase (PBGD), the third enzyme in the heme biosynthesis pathway.
The three groups of subjects were used to establish the best cut-off of PBGD activity for identifying symptomatic AIP patients by using area under receiver operating characteristic curve analysis.
In conclusion, the striking difference in the penetrance of HMBS mutations between the general population and the French AIP families suggests that AIP inheritance does not follow the classical autosomal dominant model, instead of being modulated by strong environmental and genetic factors independent from HMBS.
Mutations in human <i>HMBS</i> (<i>hHMBS</i>) cause acute intermittent porphyria (AIP), an autosomal-dominant disorder characterized by life-threatening neurovisceral attacks.
Finally, full protection against a phenobarbital-induced attack was achieved in AIP mice after the administration of 1 × 1011 gc/kg of rAAV2/8-PBGD-I291M/N340S vector; three times lower than the dose required to achieve full protection with the control rAAV2/8-hPBGD vector.
Acute intermittent porphyria (AIP) is a rare metabolic disorder due to a deficiency of porphobilinogen deaminase, the third enzyme of the heme biosynthetic pathway.
Acute intermittent porphyria (AIP) is a disorder of the haem biosynthetic pathway caused by mutations in the hydroxymethylbilane synthase (<i>HMBS</i>) gene.