DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency

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.

Biallelic variants in DNA2 cause microcephalic primordial dwarfism

“…Proteins encoded by MPD disease genes participate in essential cellular processes, including DNA replication (Bicknell, Bongers, et al, ; Bicknell, Walker, et al, ; Burrage et al, ; Fenwick et al, ; Guernsey et al, ; Logan et al, ; Vetro et al, ), DNA damage response signalling and DNA repair (Harley et al, ; Murray et al, , ; O'Driscoll, Ruiz‐Perez, Woods, Jeggo, & Goodship, ; Ogi et al, ; Qvist et al, ; Reynolds et al, ). Collectively, variants in these genes are thought to cause disease by prolonging the cell cycle, with reduced cell proliferation resulting in a smaller number of cells throughout the body and brain, and therefore a smaller person (Klingseisen & Jackson, ).…”

Defective DNA Polymerase α-Primase Leads to X-Linked Intellectual Disability Associated with Severe Growth Retardation, Microcephaly, and Hypogonadism

“…[48][49][50][51] Fascinatingly, differing mutations in POLE underlie a clinical spectrum that includes FILS syndrome (facial dysmorphism, immunodeficiency, livedo reticularis, and short stature; MIM: 615083) 52 and IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia, and congenital and genitourinary anomalies in males; MIM: 614732), and both diseases are associated with variable immunodeficiency. 36,53 Additionally, a POLE2 (MIM: 602670) mutation has been identified in an individual with combined immunodeficiency, facial dysmorphism, and autoimmunity associated with compromised lymphocyte proliferation. 54 Germline mutations in POLD1 have been described to underlie a range of congenital disorders, including MDP syndrome (mandibular hypoplasia, deafness, and progeroid; MIM: 615381), lipodystrophy, and atypical Werner's syndrome with short stature (MIM: 277700).…”

Compensation for the absence of the catalytically active half of DNA polymerase ε in yeast by positively selected mutations inCDC28gene

“…In humans, homozygous mutations severely decreasing levels of pol ε are surprisingly not lethal but cause immunodeficiency, facial dysmorphism, livedo, and short stature [81]. Bi-allelic mutations in POLE cause IMAGe syndrome [82]. Mutations in POLE cause the same conditions as some DNA breakage/instability syndromes [83].…”