Congenital coenzyme Q5-linked pathology: causal genetic association, core phenotype, and molecular mechanism

• Published in: Journal of applied genetics 2023-09, Vol.64 (3), p.507-514
• Main Authors: Dawidziuk, Mateusz, Podwysocka, Aleksandra, Jurek, Marta, Obersztyn, Ewa, Bekiesinska-Figatowska, Monika, Goszczanska-Ciuchta, Alicja, Bukowska-Olech, Ewelina, Rygiel, Agnieszka Magdalena, Guilbride, Dorothy Lys, Wiszniewski, Wojciech, Gawlinski, Pawel
• Format: Article
• Language: English
• Subjects: Animal Genetics and Genomics; Ataxia; Atrophy; Biomedical and Life Sciences; Biosynthesis; Cerebellar ataxia; Cerebellum; Coenzyme Q10; Comparative analysis; Encephalopathy; Enzymes; Genetic aspects; Genetic disorders; Human Genetics; Human Genetics • Short Communication; Intellectual disabilities; Life Sciences; Methyltransferase; Microbial Genetics and Genomics; Molecular modelling; mRNA; Pathology; Phenotypes; Physiological aspects; Plant Genetics and Genomics; Zinc finger proteins
• ISSN: 1234-1983; 2190-3883
• DOI: 10.1007/s13353-023-00773-9

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.