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| Status |
Public on Mar 03, 2020 |
| Title |
Severe hydroxymethylbilane synthase deficiency causes depression-like behavior and mitochondrial dysfunction in a mouse model of homozygous dominant acute intermittent porphyria |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
The aim of this study was to examine the consequences of severe HMBS deficiency on affective behavior and to examine the underlying pathophysiological principles in a mouse model of homozygous AIP. KI mice harboring a point mutation in the HMBS gene were compared to WT littermate controls in behavioral, molecular and biochemical studies. In-vivo and ex-vivo experiments were further investigated using primary neuronal cultures of KI and WT mice.
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| Contributor(s) |
Berger S, Stattmann M, Cicvaric A, Monje FJ, Coiro P, Hotka M, Ricken G, Hainfellner J, Greber-Platzer S, Yasuda M, Desnick RJ, Pollak DD |
| Citation(s) |
32197664 |
| Submission date |
Mar 02, 2020 |
| Last update date |
Jun 02, 2020 |
| Contact name |
Stefanie Berger |
| Organization name |
Medical University Vienna
|
| Street address |
Schwarzspanierstraße 17
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| City |
Vienna |
| ZIP/Postal code |
1090 |
| Country |
Austria |
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| Platforms (1) |
| GPL21493 |
Illumina HiSeq 3000 (Mus musculus) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA609709 |
| SRA |
SRP251269 |
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