Developmental delay with hypotrophy associated with homozygous functionally relevant REV3L variant
| Autor: | Miroslaw Bik-Multanowski, Agnieszka Pollak, Ewa Sledziewska-Gojska, Aneta Kaniak-Golik, Jolanta Fijak-Moskal, Jarosław Poznański, Rafał Płoski, Victor Murcia Pienkowski, Renata Kuberska, Małgorzata Rydzanicz, Agnieszka Halas |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Models Molecular Proband Mitochondrial DNA Saccharomyces cerevisiae Proteins Skin Neoplasms Protein Conformation Ultraviolet Rays Developmental Disabilities Mutation Missense DNA-Directed DNA Polymerase Saccharomyces cerevisiae Biology medicine.disease_cause DNA Mitochondrial Neoplasms Multiple Primary Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine REV3L Neoplastic Syndromes Hereditary Catalytic Domain Exome Sequencing Drug Discovery medicine Humans Point Mutation DNA Fungal Gene Aldose-Ketose Isomerases Genetics (clinical) Exome sequencing Genetics Nevus Pigmented Mutation Homozygote Mutagenesis DNA Mobius Syndrome Pedigree Nuclear DNA DNA-Binding Proteins Phenotype Child Preschool Molecular Medicine Female 030215 immunology |
| Popis: | REV3L encodes a catalytic subunit of DNA polymerase zeta (Pol zeta) which is essential for the tolerance of DNA damage by inducing translesion synthesis (TLS). So far, the only Mendelian disease associated with REV3L was Moebius syndrome (3 patients with dominant REV3L mutations causing monoallelic loss-of-function were reported). We describe a homozygous ultra-rare REV3L variant (T2753R) identified with whole exome sequencing in a child without Moebius syndrome but with developmental delay, hypotrophy, and dysmorphic features who was born to healthy parents (heterozygous carriers of the variant). The variant affects the amino acid adjacent to functionally important KKRY motif. By introducing an equivalent mutation (S1192R) into the REV3 gene in yeasts, we showed that, whereas it retained residual function, it caused clear dysfunction of TLS in the nucleus and instability of mitochondrial genetic information. In particular, the mutation increased UV sensitivity measured by cell survival, decreased both the spontaneous (P < 0.005) and UV-induced (P < 0.0001) mutagenesis rates of nuclear DNA and increased the UV-induced mutagenesis rates of mitochondrial DNA (P < 0.0005). We propose that our proband is the first reported case of a REV3L associated disease different from Moebius syndrome both in terms of clinical manifestations and inheritance (autosomal recessive rather than dominant). KEY MESSAGES: First description of a human recessive disorder associated with a REV3L variant. A study in yeast showed that the variant affected the enzymatic function of the protein. In particular, it caused increased UV sensitivity and abnormal mutagenesis rates. |
| Databáze: | OpenAIRE |
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