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Am J Hum Genet ; 103(6): 1038-1044, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30503519

RESUMO

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.


Assuntos
Insuficiência Adrenal/genética , DNA Polimerase II/genética , Retardo do Crescimento Fetal/genética , Mutação/genética , Osteocondrodisplasias/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Anormalidades Urogenitais/genética , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Inibidor de Quinase Dependente de Ciclina p57/genética , Replicação do DNA/genética , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
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