학술논문
DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.
Document Type
Article
Author
Logan, Clare V.; Murray, Jennie E.; Parry, David A.; Robertson, Andrea; Bellelli, Roberto; Tarnauskaitė, Žygimantė; Challis, Rachel; Cleal, Louise; Borel, Valerie; Fluteau, Adeline; Santoyo-Lopez, Javier; Aitman, Tim; Barroso, Inês; Basel, Donald; Bicknell, Louise S.; Goel, Himanshu; Hu, Hao; Huff, Chad; Hutchison, Michele; Joyce, Caroline
Source
Subject
*DNA polymerases
*EPSILON meson
*IMMUNODEFICIENCY
*DYSPLASIA
*LYMPHOCYTES
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Language
ISSN
0002-9297
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. [ABSTRACT FROM AUTHOR]