DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency
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2018-12-06
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American Journal of Human Genetics
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CELL PRESS
Melbourne Authors
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Paediatrics (RCH)
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Journal Article
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Logan, C. V., Murray, J. E., Parry, D. A., Robertson, A., Bellelli, R., Tarnauskaitė, Ž., Challis, R., Cleal, L., Borel, V., Fluteau, A., Santoyo-Lopez, J., Aitman, T., Biankin, A. V., Cooke, S. L., Humphrey, W. I., Martin, S., Mennie, L., Meynert, A., Miedzybrodzka, Z. ,... Jackson, A. P. (2018). DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency. American Journal of Human Genetics, 103 (6), pp.1038-1044. https://doi.org/10.1016/j.ajhg.2018.10.024.
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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.