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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严重的羟甲基胆烷合酶缺乏会导致纯合显性急性间歇性卟啉症小鼠模型出现抑郁样行为和线粒体功能障碍。


急性间歇性卟啉症 (AIP) 是一种常染色体显性遗传性血红素生物合成缺陷，由于 Hmbs 基因致病性突变导致羟甲基联苯合酶活性半正常。诱导肝血红素生物合成的因素会导致杂合子患者出现阵发性发作。急性发作的临床表现包括典型的神经内脏疼痛，并可能包括精神症状。在这里，我们使用了具有 Hmbs c.500G > A (p.R167Q) 突变双等位基因的敲入小鼠品系，其羟甲基双烷合酶活性约为正常的 5%，以揭示严重 HMBS 缺乏对情感行为和大脑生理学的影响。 Hmbs 敲入小鼠（KI 小鼠）模拟了罕见的 AIP 纯合显性形式，并被用作阐明该疾病的行为表现及其神经基础的迄今为止未知的病理生理学的工具。广泛的行为分析揭示了 Hmbs KI 小鼠的选择性抑郁样表型；转录组学和免疫组织化学分析表明髓鞘形成异常。敲入小鼠海马体中发现的线粒体功能受损及其随之而来的神经源性和神经可塑性缺陷使我们提出线粒体能量产生破坏在严重 HMBS 缺乏的行为后果及其大脑神经病理学后遗症的发病机制中的机制作用。