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MCM complex members MCM3 and MCM7 are associated with a phenotypic spectrum from Meier-Gorlin syndrome to lipodystrophy and adrenal insufficiency

European Journal of Human Genetics volume 29, pages 1110–1120 (2021)Cite this article

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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.

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Fig. 1: Individuals with biallelic variants in MCM3 and MCM7.
Fig. 2: Consequences of MCM3 and MCM7 variants on transcript and protein.
Fig. 3: Cellular consequences of variants in MCM3 and MCM7.

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Acknowledgements

The authors thank the families for their involvement in this study. Thank you to Katie Young for assistance with flow cytometry and Anna Pawluchin for assistance with Sanger sequencing.

Funding

KK is supported by the Deutsche Forschungsgemeinschaft (KU 1240/6-2 and KU 1240/10-1). This research, KMK and LSB are supported by the Marsden Fund; LSB is supported by a Rutherford Discovery Fellowship, both administered by the Royal Society of New Zealand. DEJ is supported by the Neurological Foundation of New Zealand and RS is supported by the Health Research Council of New Zealand; both awarded to LSB.

Sources of support

Deutsche Forschungsgemeinschaft (KU 1240/6-2 and KU 1240/10-1). Marsden Fund; Rutherford Discovery Fellowship, both administered by the Royal Society of New Zealand; Neurological Foundation of New Zealand; Health Research Council of New Zealand.

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Authors and Affiliations

  1. Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

    Karen M. Knapp, Danielle E. Jenkins, Rosie Sullivan & Louise S. Bicknell

  2. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Frederike L. Harms, Leonie von Elsner & Kerstin Kutsche

  3. Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands

    Charlotte W. Ockeloen, Sonja de Munnik & Ernie M. H. F. Bongers

  4. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

    Jennie Murray

  5. South East Scotland Clinical Genetics Service, NHS Lothian, Western General Hospital, Edinburgh, UK

    Jennie Murray

  6. Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, WA, Australia

    Nicholas Pachter

  7. Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia

    Nicholas Pachter

  8. Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Jonas Denecke

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Correspondence to Louise S. Bicknell.

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Knapp, K.M., Jenkins, D.E., Sullivan, R. et al. MCM complex members MCM3 and MCM7 are associated with a phenotypic spectrum from Meier-Gorlin syndrome to lipodystrophy and adrenal insufficiency. Eur J Hum Genet 29, 1110–1120 (2021). https://doi.org/10.1038/s41431-021-00839-4

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