Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
Department of Diagnostic Imaging, Institute of Mother and Child, Warsaw, Poland.
J Appl Genet. 2023 Sep;64(3):507-514. doi: 10.1007/s13353-023-00773-9. Epub 2023 Aug 21.
Coenzyme Q5 (COQ5), a C-methyltransferase, modifies coenzyme Q10 (COQ10) during biosynthesis and interacts with polyA-tail regulating zinc-finger protein ZC3H14 in neural development. Here, we present a fifth patient (a third family) worldwide with neurodevelopmental and physiological symptoms including COQ10 deficiency. Our patient harbors one novel c.681+1G>A and one recurrent p.Gly118Ser variant within COQ5. The patient's mRNA profile reveals multiple COQ5 splice-variants. Subsequently, we comprehensively described patient's clinical features as compared to phenotype and symptoms of other known congenital coenzyme Q5-linked cases. A core spectrum of COQ5-associated symptoms includes reduced COQ10 levels, intellectual disability, encephalopathy, cerebellar ataxia, cerebellar atrophy speech regression/dysarthria, short stature, and developmental delays. Our patient additionally displays dysmorphia, microcephaly, and regressive social faculties. These results formally establish causal association of biallelic COQ5 mutation with pathology, outline a core COQ5-linked phenotype, and identify mRNA mis-splicing as the molecular mechanism underlying all COQ5 variant-linked pathology to date.
辅酶 Q5（COQ5）是一种 C-甲基转移酶，在生物合成过程中修饰辅酶 Q10（COQ10），并与 polyA-尾相互作用，调节神经发育中的锌指蛋白 ZC3H14。在这里，我们报告了全球第五例（第三家系）具有神经发育和生理症状的患者，包括辅酶 Q10 缺乏。我们的患者携带一个新的 c.681+1G>A 和一个反复出现的 p.Gly118Ser 变体在内的 COQ5 中。患者的 mRNA 谱显示出多种 COQ5 剪接变体。随后，我们全面描述了患者的临床特征，与其他已知先天性辅酶 Q5 相关病例的表型和症状进行了比较。COQ5 相关症状的核心谱包括辅酶 Q10 水平降低、智力障碍、脑病、小脑共济失调、小脑萎缩、言语退化/构音障碍、身材矮小和发育迟缓。我们的患者还表现出畸形、小头症和社会功能倒退。这些结果正式确立了 COQ5 双等位基因突变与病理学的因果关系，概述了 COQ5 相关表型的核心，并确定了 mRNA 错剪接是迄今为止所有 COQ5 变体相关病理学的分子机制。
