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Expanding the spectrum of PEX16 mutations and novel insights into disease mechanisms

机译：扩大PEX16突变的范围和对疾病机制的新见解

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Zellweger syndrome spectrum disorders are caused by mutations in any of at least 12 different PEX genes. This includes PEX16 , an important regulator of peroxisome biogenesis. Using whole genome sequencing, we detected previously unreported, biallelic variants in PEX16 [NM_004813.2:c.658GA, p.(Ala220Thr) and NM_004813.2:c.830GA, p.(Arg277Gln)] in an individual with leukodystrophy, spastic paraplegia, cerebellar ataxia, and craniocervical dystonia with normal plasma very long chain fatty acids. Using olfactory-neurosphere derived cells, a population of neural stem cells, we showed patient cells had reduced peroxisome density and increased peroxisome size, replicating previously reported findings in PEX16 cell lines. Along with alterations in peroxisome morphology, patient cells also had impaired peroxisome function with reduced catalase activity. Furthermore, patient cells had reduced oxidative stress levels after exposure to hydrogen-peroxide (Hsub2/subOsub2/sub), which may be a result of compensation by Hsub2/subOsub2/sub metabolising enzymes other than catalase to preserve peroxisome-related cell functions. Our findings of impaired catalase activity and altered oxidative stress response are novel. Our study expands the phenotype of PEX16 mutations by including dystonia and provides further insights into the pathological mechanisms underlying PEX16 -associated disorders. Additional studies of the full spectrum of peroxisomal dysfunction could improve our understanding of the mechanism underlying PEX16-associated disorders.
机译：Zellweger综合征谱异常是由至少12种不同的PEX基因中的任何一种突变引起的。其中包括PEX16，过氧化物酶体生物合成的重要调节剂。使用全基因组测序，我们在个体中检测到PEX16中先前未报道的双等位基因变异[NM_004813.2：c.658G> A，p。（Ala220Thr）和NM_004813.2：c.830G> A，p。（Arg277Gln）]患有血浆营养不良，痉挛性截瘫，小脑性共济失调和颅颈肌张力障碍，血浆中的长链脂肪酸含量正常。使用嗅觉神经球来源的细胞，一组神经干细胞，我们显示患者细胞的过氧化物酶体密度降低且过氧化物酶体大小增加，从而复制了以前在PEX16细胞系中报道的发现。除过氧化物酶体形态改变外，患者细胞还具有过氧化物酶体功能受损，过氧化氢酶活性降低的特点。此外，患者细胞暴露于过氧化氢（H 2 O 2 ）后具有降低的氧化应激水平，这可能是由于H 2 <过氧化氢酶以外的/ sub> O 2 代谢酶来保持与过氧化物酶体相关的细胞功能。我们对过氧化氢酶活性受损和氧化应激反应改变的发现是新颖的。我们的研究通过包括肌张力障碍扩大了PEX16突变的表型，并提供了对与PEX16相关的疾病的病理机制的进一步认识。关于过氧化物酶体功能障碍全谱的其他研究可以增进我们对与PEX16相关疾病潜在机制的了解。

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