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.

中文翻译：

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在纯合子显性急性间歇性卟啉症小鼠模型中，严重的羟甲基胆烷合酶缺乏症会导致抑郁样行为和线粒体功能障碍。

急性间歇性卟啉症（AIP）是血红素生物合成的常染色体显性先天性错误，归因于Hmbs基因的致病性突变，导致羟甲基胆碱合酶的半正常活性。诱导肝血红素生物合成的因素在杂合性患者中诱发发作性发作。急性发作的临床表现涉及特征性神经内脏疼痛，并且可能包括精神病症状。在这里，我们使用了一种双等位基因敲除小鼠系，用于Hmbs c.500G> A（p.R167Q）突变，具有约5％的正常羟甲基胆烷合酶活性，以揭示严重的HMBS缺乏对情感行为和脑生理的影响。Hmbs敲入小鼠（KI小鼠）模拟了AIP的罕见纯合显性形式，并用作阐明该疾病行为表现及其神经基础的迄今未知的病理生理学的工具。广泛的行为分析表明，Hmbs KI小鼠具有选择性的抑郁样表型。转录组和免疫组化分析显示异常髓鞘形成。在敲入小鼠海马中发现的线粒体功能受损及其随之而来的神经原性和神经塑性缺陷，使我们提出了在严重HMBS缺乏及其在大脑中的神经病理后遗症的行为后果的发病机理中，线粒体能量产生受阻的机制作用。广泛的行为分析表明，Hmbs KI小鼠具有选择性的抑郁样表型。转录组和免疫组化分析显示异常髓鞘形成。在敲入小鼠海马中发现的线粒体功能受损及其随之而来的神经原性和神经塑性缺陷，使我们提出了在严重HMBS缺乏及其在大脑中的神经病理后遗症的行为后果的发病机理中，线粒体能量产生受阻的机制作用。广泛的行为分析表明，Hmbs KI小鼠具有选择性的抑郁样表型。转录组和免疫组化分析显示异常髓鞘形成。在敲入小鼠海马中发现的受损线粒体功能及其随之而来的神经原性和神经塑性缺陷，使我们提出了在严重HMBS缺乏及其脑后神经病理后遗症的行为后果的发病机理中，线粒体能量产生受阻的机制作用。