DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency

SGP Consortium

Research output: Contribution to journalArticle

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1038-1044
Number of pages7
JournalAmerican Journal of Human Genetics
Volume103
Issue number6
DOIs
StatePublished - Dec 6 2018

Keywords

  • DNA replication
  • IMAGe syndrome
  • adrenal failure
  • cell cycle
  • growth
  • immunodeficiency
  • microcephaly
  • polymerase epsilon

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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