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Am J Hum Genet. 2018 Dec 6;103(6):1038-1044. doi: 10.1016/j.ajhg.2018.10.024. Epub 2018 Nov 29.

DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.

Author information

1
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
2
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK; South East Scotland Clinical Genetics Service, Western General Hospital, Edinburgh EH4 2XU, UK. Electronic address: jennie.murray@igmm.ed.ac.uk.
3
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
4
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK; South East Scotland Clinical Genetics Service, Western General Hospital, Edinburgh EH4 2XU, UK.
5
Edinburgh Genomics Clinical Division, University of Edinburgh, The Roslin Institute, Edinburgh EH25 9RG, UK.
6
MRC Centre for Genomic & Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
7
Wellcome Sanger Institute, Cambridge CB10 1SA, UK.
8
Medical College of Wisconsin from Children's Hospital of Wisconsin, Milwaukee, WI 53226, USA.
9
Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
10
Hunter Genetics, Waratah, NSW 2305, Australia; University of Newcastle, Callaghan, NSW 2308, Australia.
11
Department of Epidemiology, MD Anderson Cancer Center, Houston, TX 77030, USA.
12
Department of Pediatrics, University of Arkansas, Little Rock, AR 72205, USA.
13
Department of Clinical Biochemistry, Cork University Hospital, Cork, Ireland.
14
MRC Metabolic Diseases Unit, University of Cambridge, Cambridge CB2 0QQ, UK.
15
University of Nebraska Medical Centre, Omaha, NE 68918, USA.
16
Department of Medical Genetics, The University of British Columbia, Vancouver, BC V6H 3N1, Canada.
17
Pediatric Genetics, UH Cleveland Medical Center, Cleveland, OH 44106, USA.
18
Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust and Institute of Human Development, University of Manchester, Manchester M13 9WL, UK.
19
Department of Paediatrics and Child Health, Cork University Hospital, Cork, Ireland.
20
UCD School of Medicine, Children's University Hospital, Temple St, Dublin, Ireland.
21
Sorbonne Université, INSERM, UMR_S 938, APHP, Hospital Trousseau, 75012 Paris, France.
22
Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA.
23
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
24
Department of Endocrinology, Beaumont Hospital, Dublin, Ireland.
25
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
26
Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
27
Division of Medicine, Royal Children's Hospital, Melbourne, VIC 3052, Australia.
28
Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester Academic Health Science Centre, Manchester M13 9WU, UK.
29
Nemours-Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA.
30
MRC Metabolic Diseases Unit, University of Cambridge, Cambridge CB2 0QQ, UK; Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, UK.
31
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. Electronic address: andrew.jackson@igmm.ed.ac.uk.

Abstract

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins.

KEYWORDS:

DNA replication; IMAGe syndrome; adrenal failure; cell cycle; growth; immunodeficiency; microcephaly; polymerase epsilon

PMID:
30503519
PMCID:
PMC6288413
DOI:
10.1016/j.ajhg.2018.10.024
[Indexed for MEDLINE]
Free PMC Article

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