A Pex7 hypomorphic mouse model for plasmalogen deficiency affecting the lens and skeleton.
A Pex7 hypomorphic mouse model for plasmalogen deficiency affecting the lens and skeleton.
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DOI：
10.1016/j.ymgme.2009.12.005
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发表时间：
2010-04
影响因子：
3.8
通讯作者：
Steinberg, Steven
中科院分区：
文献类型：
--
作者：
Braverman, Nancy;Zhang, Rui;Chen, Li;Nimmo, Graeme;Scheper, Sarah;Tran, Tammy;Chaudhury, Rupsa;Moser, Ann;Steinberg, Steven
关键词：
点状根状软骨发育不良 1 型是一种过氧化物酶体生物发生障碍，临床特征为根状软骨脱落、骨骺钙化异常、先天性白内障以及严重的生长和发育迟缓。它是一种罕见的常染色体隐性遗传疾病，由过氧化物酶体受体 Pex7 缺陷引起。这种病理学是由缩醛磷脂缺乏引起的，缩醛磷脂是一类关键的醚磷脂，其功能很大程度上未知。为了在动物模型中研究缩醛磷脂、避免早期死亡并促进该疾病的治疗研究，我们设计了一种亚效型小鼠模型，其中 Pex7 转录水平降低至野生型的 5% 以下。这些小鼠以预期的比例出生，具有生育能力并且具有正常的寿命。然而，他们身材娇小，并且患有早期白内障。进一步的研究显示软骨内骨化延迟和晶状体纤维异常。该模型再现了 Pex7 功能降低的生化特征，包括组织缩醛磷脂缺乏、植烷酸积累、Pex7 配体输入减少以及随之而来的缩醛磷脂生物合成和植烷酸氧化缺陷。膳食补充蝙蝠醇（一种缩醛磷脂前体）可恢复血液中的醚磷脂，但不会改变临床表型。这些小鼠相对较轻的表型模仿了具有较轻 pex7 缺陷的患者，并强调骨骼和晶状体是缩醛磷脂缺乏的敏感标记。现在可以研究缩醛磷脂在不同年龄的这些组织的正常功能中的作用，并在该模型中测试其他治疗干预措施。
Rhizomelic chondrodysplasia punctata type 1 is a peroxisome biogenesis disorder with the clinical features of rhizomelia, abnormal epiphyseal calcifications, congenital cataracts, and profound growth and developmental delays. It is a rare autosomal recessive disorder, caused by defects in the peroxisome receptor, Pex7. The pathology results from a deficiency of plasmalogens, a critical class of ether phospholipids whose functions are largely unknown. To study plasmalogens in an animal model, avoid early mortality and facilitate therapeutic investigations in this disease, we engineered a hypomorphic mouse model in which Pex7 transcript levels are reduced to less than 5% of wild type. These mice are born in expected ratios, are fertile and have a normal life span. However, they are petite and develop early cataracts. Further investigations showed delayed endochondral ossification and abnormalities in lens fibers. The biochemical features of reduced Pex7 function were reproduced in this model, including tissue plasmalogen deficiency, phytanic acid accumulation, reduced import of Pex7 ligands and consequent defects in plasmalogen biosynthesis and phytanic acid oxidation. Dietary supplementation with batyl alcohol, a plasmalogen precursor, recovered ether phospholipids in blood, but did not alter the clinical phenotype. The relatively mild phenotype of these mice mimics patients with milder pex7 defects, and highlights the skeleton and lens as sensitive markers of plasmalogen deficiency. The role of plasmalogens in the normal function of these tissues at various ages can now be studied and additional therapeutic interventions tested in this model.
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