DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency. Am J Hum Genet 2018 Dec 06;103(6):1038-1044
Date
12/07/2018Pubmed ID
30503519Pubmed Central ID
PMC6288413DOI
10.1016/j.ajhg.2018.10.024Scopus ID
2-s2.0-85058605364 (requires institutional sign-in at Scopus site) 64 CitationsAbstract
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.
Author List
Logan CV, Murray JE, Parry DA, Robertson A, Bellelli R, Tarnauskaitė Ž, Challis R, Cleal L, Borel V, Fluteau A, Santoyo-Lopez J, SGP Consortium, Aitman T, Barroso I, Basel D, Bicknell LS, Goel H, Hu H, Huff C, Hutchison M, Joyce C, Knox R, Lacroix AE, Langlois S, McCandless S, McCarrier J, Metcalfe KA, Morrissey R, Murphy N, Netchine I, O'Connell SM, Olney AH, Paria N, Rosenfeld JA, Sherlock M, Syverson E, White PC, Wise C, Yu Y, Zacharin M, Banerjee I, Reijns M, Bober MB, Semple RK, Boulton SJ, Rios JJ, Jackson APAuthors
Donald Basel MD Chief, Professor in the Pediatrics department at Medical College of WisconsinErin Syverson MGC Director, Assistant Professor in the Institute for Health and Equity department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdolescentAdrenal Insufficiency
Adult
Alleles
Child
Child, Preschool
Cyclin-Dependent Kinase Inhibitor p57
DNA Polymerase II
DNA Replication
Female
Fetal Growth Retardation
Humans
Infant
Male
Middle Aged
Mutation
Osteochondrodysplasias
Phenotype
Poly-ADP-Ribose Binding Proteins
Urogenital Abnormalities
Young Adult