DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency

SGP Consortium

Research output: Contribution to journalArticle

8 Citations (Scopus)

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

Fingerprint

DNA Polymerase II
Mutation
DNA-Directed DNA Polymerase
Growth
DNA Replication
S Phase
Haplotypes
Genes
Catalytic Domain
Variable Immunodeficiency syndrome
Genome
Lymphocytes
Phenotype
Proteins

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency. / SGP Consortium.

In: American Journal of Human Genetics, Vol. 103, No. 6, 06.12.2018, p. 1038-1044.

Research output: Contribution to journalArticle

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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.",
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author = "{SGP Consortium} and Logan, {Clare V.} and Murray, {Jennie E.} and Parry, {David A.} and Andrea Robertson and Roberto Bellelli and Žygimantė Tarnauskaitė and Rachel Challis and Louise Cleal and Valerie Borel and Adeline Fluteau and Javier Santoyo-Lopez and Aitman, {Timothy J.} and Biankin, {Andrew V.} and Cooke, {Susanna L.} and Humphrey, {Wendy Inglis} and Sancha Martin and Lynne Mennie and Alison Meynert and Zosia Miedzybrodzka and Fiona Murphy and Craig Nourse and Semple, {Colin A.} and Nicola Williams and Tim Aitman and In{\^e}s Barroso and Donald Basel and Bicknell, {Louise S.} and Himanshu Goel and Hao Hu and Chad Huff and Michele Hutchison and Caroline Joyce and Rachel Knox and Lacroix, {Amy E.} and Sylvie Langlois and Shawn McCandless and Julie McCarrier and Metcalfe, {Kay A.} and Rose Morrissey and Nuala Murphy and Ir{\`e}ne Netchine and O'Connell, {Susan M.} and Olney, {Ann Haskins} and Nandina Paria and Rosenfeld, {Jill A.} and Mark Sherlock and Erin Syverson and White, {Perrin C} and Wise, {Carol A} and Rios, {Jonathan J}",
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AU - Cooke, Susanna L.

AU - Humphrey, Wendy Inglis

AU - Martin, Sancha

AU - Mennie, Lynne

AU - Meynert, Alison

AU - Miedzybrodzka, Zosia

AU - Murphy, Fiona

AU - Nourse, Craig

AU - Semple, Colin A.

AU - Williams, Nicola

AU - Aitman, Tim

AU - Barroso, Inês

AU - Basel, Donald

AU - Bicknell, Louise S.

AU - Goel, Himanshu

AU - Hu, Hao

AU - Huff, Chad

AU - Hutchison, Michele

AU - Joyce, Caroline

AU - Knox, Rachel

AU - Lacroix, Amy E.

AU - Langlois, Sylvie

AU - McCandless, Shawn

AU - McCarrier, Julie

AU - Metcalfe, Kay A.

AU - Morrissey, Rose

AU - Murphy, Nuala

AU - Netchine, Irène

AU - O'Connell, Susan M.

AU - Olney, Ann Haskins

AU - Paria, Nandina

AU - Rosenfeld, Jill A.

AU - Sherlock, Mark

AU - Syverson, Erin

AU - White, Perrin C

AU - Wise, Carol A

AU - Rios, Jonathan J

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N2 - 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.

AB - 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.

KW - adrenal failure

KW - cell cycle

KW - DNA replication

KW - growth

KW - IMAGe syndrome

KW - immunodeficiency

KW - microcephaly

KW - polymerase epsilon

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