The Francis Crick Institute
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DNA polymerase epsilon deficiency causes IMAGe syndrome with variable immunodeficiency

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journal contribution
posted on 2020-08-27, 15:31 authored by Clare V Logan, Jennie E Murray, David A Parry, Andrea Robertson, Roberto Bellelli, Žygimantė Tarnauskaitė, Rachel Challis, Louise Cleal, Valerie Borel, Adeline Fluteau, Javier Santoyo-Lopez, SGP Consortium, Tim Aitman, Inês Barroso, Donald Basel, Louise S Bicknell, Himanshu Goel, Hao Hu, Chad Huff, Michele Hutchison, Caroline Joyce, Rachel Knox, Amy E Lacroix, Sylvie Langlois, Shawn McCandless, Julie McCarrier, Kay A Metcalfe, Rose Morrissey, Nuala Murphy, Irène Netchine, Susan M O'Connell, Ann Haskins Olney, Nandina Paria, Jill A Rosenfeld, Mark Sherlock, Erin Syverson, Perrin C White, Carol Wise, Yao Yu, Margaret Zacharin, Indraneel Banerjee, Martin Reijns, Michael B Bober, Robert K Semple, Simon J Boulton, Jonathan J Rios, Andrew P Jackson
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.