- Title
- DNA polymerase epsilon deficiency causes IMAGe syndrome with variable immunodeficiency
- Creator
- 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, Timothy J.; Biankin, Andrew V.; Cooke, Susanna L.; Humphrey, Wendy Inglis; Martin, Sacha; Mennie, Lynne; Meynert, Alison; Miedzybrodzka, Zosia; Murphy, Fiona; Goel, Himanshu
- Relation
- American Journal of Human Genetics Vol. 103, Issue 6, p. 1038-1044
- Publisher Link
- http://dx.doi.org/10.1016/j.ajhg.2018.10.024
- Publisher
- Cell Press
- Resource Type
- journal article
- Date
- 2018
- Description
- 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.
- Subject
- DNA replication; growth; adrenal failure; immunodeficiency; cell cycle; ploymerase epsilon; IMAGe syndrome; microcephaly
- Identifier
- http://hdl.handle.net/1959.13/1409156
- Identifier
- uon:35953
- Identifier
- ISSN:0002-9297
- Rights
- © 2018 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
- Language
- eng
- Full Text
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