Distinguishing PEX2 and PEX16 gene variant severity for mild, severe and atypical peroxisome biogenesis disorders.

IF 3.3 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2025-07-01 Epub Date: 2025-07-28 DOI:10.1242/dmm.052258
Vanessa A Gomez, Oguz Kanca, Sharayu V Jangam, Saurabh Srivastav, Jonathan C Andrews, Michael F Wangler
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引用次数: 0

Abstract

Peroxisomal biogenesis disorders (PBD) are autosomal recessive diseases caused by mutations in specific PEX genes that impair peroxisome formation, leading to multi-systemic failure. Symptoms vary, even in patients with variants in the same PEX gene. Our goal is to select PEX mutations and use Drosophila to model a severity spectrum based on genotype-phenotype correlations. Utilizing KozakGAL4 (KZ) cassettes, we replaced the coding sequence of Pex with a GAL4 driver, ideal for making 'humanized' flies in which human PEX can replace the fly loss. We generated Pex2KZ and Pex16KZ lines and assessed them in various behavior assays, confirming their severe phenotypes. We performed rescue with human reference, variant PEX2 and PEX16 alleles, and phenotypic rescue was observed when human PEX2Ref or PEX16Ref were expressed in Pex2KZ or Pex16KZ flies, respectively. We identified a severity spectrum for PEX2 and PEX16 alleles, with some missense mutations exhibiting severity comparable to truncations. Alleles linked to mild PBD showed partial rescue, while variants associated with atypical ataxia could fully rescue. Drosophila humanization is an effective method to study the range of severity of PBD.

区分果蝇轻度、重度和非典型过氧化物酶体生物发生障碍的PEX2和PEX16基因变异严重程度。
过氧化物酶体生物发生障碍(PBD)是一种常染色体隐性遗传病,由特定PEX基因突变引起的过氧化物酶体形成障碍,导致多系统功能衰竭。即使在同一PEX基因变异的患者中,症状也各不相同。我们的目标是选择PEX突变,并利用果蝇建立基于基因型-表型相关性的严重程度谱。利用KozakGAL4 (KZ)盒式磁带,我们用GAL4驱动器替换Pex的编码序列,这是制造“人性化”苍蝇的理想选择,其中人类Pex可以取代苍蝇的损失。我们生成了Pex2KZ和Pex16KZ系,并在各种行为分析中对它们进行了评估,证实了它们的严重表型。我们使用人类参考基因和变体PEX2和PEX16等位基因进行拯救,分别在Pex2KZ或Pex16KZ果蝇中表达人类PEX2Ref或PEX16Ref时观察到表型拯救。我们确定了PEX2和PEX16等位基因的严重性谱,其中一些错义突变表现出与截断相当的严重性。与轻度PBD相关的等位基因显示部分拯救,而与非典型共济失调相关的变异可以完全拯救。果蝇人源化是研究PBD严重程度范围的有效方法。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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