DNA polymerase epsilon deficiency causes IMAGe syndrome with variable immunodeficiencyMore about Open Access at the Crick
Authors listClare 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 Boulton Jonathan J Rios Andrew P Jackson
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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.
Issue number 6