1. MCM complex members MCM3 and MCM7 are associated with a phenotypic spectrum from Meier-Gorlin syndrome to lipodystrophy and adrenal insufficiency.
- Author
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Knapp KM, Jenkins DE, Sullivan R, Harms FL, von Elsner L, Ockeloen CW, de Munnik S, Bongers EMHF, Murray J, Pachter N, Denecke J, Kutsche K, and Bicknell LS
- Subjects
- Adolescent, Alleles, Amino Acid Sequence, Cell Cycle genetics, Child, Child, Preschool, Facies, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Infant, Male, Minichromosome Maintenance Complex Component 3 chemistry, Minichromosome Maintenance Complex Component 7 chemistry, Models, Molecular, New Zealand, Phenotype, Protein Conformation, Adrenal Insufficiency diagnosis, Adrenal Insufficiency genetics, Congenital Microtia diagnosis, Congenital Microtia genetics, Growth Disorders diagnosis, Growth Disorders genetics, Lipodystrophy diagnosis, Lipodystrophy genetics, Micrognathism diagnosis, Micrognathism genetics, Minichromosome Maintenance Complex Component 3 genetics, Minichromosome Maintenance Complex Component 7 genetics, Patella abnormalities
- Abstract
The MCM2-7 helicase is a heterohexameric complex with essential roles as part of both the pre-replication and pre-initiation complexes in the early stages of DNA replication. Meier-Gorlin syndrome, a rare primordial dwarfism, is strongly associated with disruption to the pre-replication complex, including a single case described with variants in MCM5. Conversely, a biallelic pathogenic variant in MCM4 underlies immune deficiency with growth retardation, features also seen in individuals with pathogenic variants in other pre-initiation complex encoding genes such as GINS1, MCM10, and POLE. Through exome and chromium genome sequencing, supported by functional studies, we identify biallelic pathogenic variants in MCM7 and a strong candidate biallelic pathogenic variant in MCM3. We confirm variants in MCM7 are deleterious and through interfering with MCM complex formation, impact efficiency of S phase progression. The associated phenotypes are striking; one patient has typical Meier-Gorlin syndrome, whereas the second case has a multi-system disorder with neonatal progeroid appearance, lipodystrophy and adrenal insufficiency. We provide further insight into the developmental complexity of disrupted MCM function, highlighted by two patients with a similar variant profile in MCM7 but disparate clinical features. Our results build on other genetic findings linked to disruption of the pre-replication and pre-initiation complexes, and the replisome, and expand the complex clinical genetics landscape emerging due to disruption of DNA replication., (© 2021. The Author(s), under exclusive licence to European Society of Human Genetics.)
- Published
- 2021
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