A Pex7 Deficient Mouse Series Correlates Biochemical and Neurobehavioral Markers to Genotype Severity-Implications for the Disease Spectrum of Rhizomelic Chondrodysplasia Punctata Type 1.
A Pex7 Deficient Mouse Series Correlates Biochemical and Neurobehavioral Markers to Genotype Severity-Implications for the Disease Spectrum of Rhizomelic Chondrodysplasia Punctata Type 1.
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DOI：
10.3389/fcell.2022.886316
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发表时间：
2022
影响因子：
5.5
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根茎样点状软骨发育不良1型（RCDP1）是一种过氧化物酶体生物发生障碍，由PEX7缺陷引起，导致plasmalogen （Pls）生物合成和植酸（PA）氧化受损。Pls缺乏是决定RCDP严重程度的主要致病因素。重度（典型）RCDP患者在脑MRI上可忽略Pls水平、先天性白内障、骨骼发育不良、生长和神经发育缺陷、脑髓鞘过低和小脑萎缩。轻度或非典型RCDP患者的Pls水平较高，生长和认知结果更好。为了更好地了解RCDP疾病的病理生理，我们生成了一个等位基因系列的Pex7小鼠，这些等位基因要么是次形等位基因的纯合，要么是次形等位基因和零等位基因的复合杂合，要么是零等位基因的纯合。Pex7转录物和蛋白在半胚模型中几乎检测不到，在复合杂合和阴性小鼠中可以忽略不计。Pex7缺陷小鼠的血浆和脑组织中Pls呈分级降低，C26:0-LPC和PA呈升高趋势。神经病理学评估显示，随着时间的推移，Pex7缺陷模型的小脑浦肯野细胞显著减少，脑髓鞘碱性蛋白（MBP）含量下降，且与Pex7基因型相关的影响更严重。所有缺乏Pex7的小鼠在开阔的野外环境中表现出过度活跃的行为。对Pex7缺陷小鼠的脑神经递质分析显示，多巴胺、去甲肾上腺素、血清素和GABA的水平显著降低。此外，脑神经递质水平、多动症表型、Pls水平与Pex7基因型严重程度之间存在显著相关性。总之，我们的研究表明，在RCDP1小鼠模型中，Pex7缺乏的严重程度与几种临床和神经生化表型之间存在基因型-表型相关性。我们提出PA积累可能是老年RCDP1患者小脑萎缩的基础，因为在小鼠模型中，即使相对较低的组织水平也与浦肯野细胞随时间的损失密切相关。此外，我们的数据证明了Pls、脑神经递质缺乏和神经行为表型之间的相互关系，这可以进一步用作治疗干预的有价值的临床终点。最后，这些模型表明，Pex7水平的增加会导致表型的显著改善。
Rhizomelic chondrodysplasia punctata type 1 (RCDP1) is a peroxisome biogenesis disorder caused by defects in PEX7 leading to impairment in plasmalogen (Pls) biosynthesis and phytanic acid (PA) oxidation. Pls deficiency is the main pathogenic factor that determines the severity of RCDP. Severe (classic) RCDP patients have negligible Pls levels, congenital cataracts, skeletal dysplasia, growth and neurodevelopmental deficits, and cerebral hypomyelination and cerebellar atrophy on brain MRI. Individuals with milder or nonclassic RCDP have higher Pls levels, better growth and cognitive outcomes. To better understand the pathophysiology of RCDP disorders, we generated an allelic series of Pex7 mice either homozygous for the hypomorphic allele, compound heterozygous for the hypomorphic and null alleles or homozygous for the null allele. Pex7 transcript and protein were almost undetectable in the hypomorphic model, and negligible in the compound heterozygous and null mice. Pex7 deficient mice showed a graded reduction in Pls and increases in C26:0-LPC and PA in plasma and brain according to genotype. Neuropathological evaluation showed significant loss of cerebellar Purkinje cells over time and a decrease in brain myelin basic protein (MBP) content in Pex7 deficient models, with more severe effects correlating with Pex7 genotype. All Pex7 deficient mice exhibited a hyperactive behavior in the open field environment. Brain neurotransmitters analysis of Pex7 deficient mice showed a significant reduction in levels of dopamine, norepinephrine, serotonin and GABA. Also, a significant correlation was found between brain neurotransmitter levels, the hyperactivity phenotype, Pls level and the severity of Pex7 genotype. In conclusion, our study showed evidence of a genotype-phenotype correlation between the severity of Pex7 deficiency and several clinical and neurobiochemical phenotypes in RCDP1 mouse models. We propose that PA accumulation may underlie the cerebellar atrophy seen in older RCDP1 patients, as even relatively low tissue levels were strongly associated with Purkinje cells loss over time in the murine models. Also, our data demonstrate the interrelation between Pls, brain neurotransmitter deficiencies and the neurobehavioral phenotype, which could be further used as a valuable clinical endpoint for therapeutic interventions. Finally, these models show that incremental increases in Pex7 levels result in dramatic improvements in phenotype.