Abstract
Acute intermittent porphyria (AIP) is an autosomal dominant inborn error of heme biosynthesis due to a pathogenic mutation in the Hmbs gene, resulting in half-normal activity of hydroxymethylbilane synthase. Factors that induce hepatic heme biosynthesis induce episodic attacks in heterozygous patients. The clinical presentation of acute attacks involves the signature neurovisceral pain and may include psychiatric symptoms. Here we used a knock-in mouse line that is biallelic for the Hmbs c.500G > A (p.R167Q) mutation with ~ 5% of normal hydroxymethylbilane synthase activity to unravel the consequences of severe HMBS deficiency on affective behavior and brain physiology. Hmbs knock-in mice (KI mice) model the rare homozygous dominant form of AIP and were used as tool to elucidate the hitherto unknown pathophysiology of the behavioral manifestations of the disease and its neural underpinnings. Extensive behavioral analyses revealed a selective depression-like phenotype in Hmbs KI mice; transcriptomic and immunohistochemical analyses demonstrated aberrant myelination. The uncovered compromised mitochondrial function in the hippocampus of knock-in mice and its ensuing neurogenic and neuroplastic deficits lead us to propose a mechanistic role for disrupted mitochondrial energy production in the pathogenesis of the behavioral consequences of severe HMBS deficiency and its neuropathological sequelae in the brain.
Highlights
Acute intermittent porphyria (AIP), an autosomal dominant inborn error of heme biosynthesis, is due to pathogenic mutations in the hydroxymethylbilane synthase (Hmbs) gene which reduce the activity of its encoded enzyme (HMBS or porphobilinogen deaminase) by approximately 50% [1, 2]
Characterization of emotional behavior in knock-in mice (KI mice) We initially analyzed the behavioral phenotype of Homozygous dominant (HD)-AIP mice comparing adult male and female KI animals to wildtype littermate controls, focusing on depression- and anxiety-like displays, in light of the symptoms reported in AIP patients
No alterations in anxiety-like behavior were detected in the KI mice in comparison to WT controls in the Light/dark box (LD) or the Elevated plus maze (EPM)
Summary
Acute intermittent porphyria (AIP), an autosomal dominant inborn error of heme biosynthesis, is due to pathogenic mutations in the hydroxymethylbilane synthase (Hmbs) gene which reduce the activity of its encoded enzyme (HMBS or porphobilinogen deaminase) by approximately 50% [1, 2]. AIP heterozygotes are at risk of having life-threatening acute neurovisceral attacks that may be accompanied by psychiatric manifestations [3,4,5,6,7]. These episodic attacks are triggered by endogenous (e.g. hormones) or exogenous (e.g. drugs) precipitating factors that induce the hepatic expression of δaminolevulinic acid synthase 1, the first and rate-limiting enzyme of heme biosynthesis [8,9,10,11] resulting in the massive accumulation of the putatively neurotoxic porphyrin precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) in the liver plasma and urine. As the clinical and biochemical phenotype in these animals is only apparent after induction with a porphyrinogenic agent, namely phenobarbital [18] which has strong sedative effects, the possibilities for behavioral examinations in this model have been limited
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