학술논문
Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome.
Document Type
Article
Author
Riestra, Maria Rodrigo; Pillay, Bethany A.; Willemsen, Mathijs; Kienapfel, Verena; Ehlers, Lisa; Delafontaine, Selket; Pinton, Antoine; Wouters, Marjon; Hombrouck, Anneleen; Sauer, Kate; Bossuyt, Xavier; Voet, Arnout; Soenen, Stefaan J.; Conde, Cecilia Dominguez; Bucciol, Giorgia; Boztug, Kaan; Humblet-Baron, Stephanie; Touzart, Aurore; Rieux-Laucat, Frédéric; Notarangelo, Luigi D.
Source
Subject
*SEVERE combined immunodeficiency
*DNA polymerases
*HEMATOPOIETIC stem cell transplantation
*GLYCOGEN storage disease type II
*DNA synthesis
*CELL cycle
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Language
ISSN
0271-9142
Abstract
The DNA polymerase δ complex (PolD), comprising catalytic subunit POLD1 and accessory subunits POLD2, POLD3, and POLD4, is essential for DNA synthesis and is central to genome integrity. We identified, by whole exome sequencing, a homozygous missense mutation (c.1118A > C; p.K373T) in POLD3 in a patient with Omenn syndrome. The patient exhibited severely decreased numbers of naïve T cells associated with a restricted T-cell receptor repertoire and a defect in the early stages of TCR recombination. The patient received hematopoietic stem cell transplantation at age 6 months. He manifested progressive neurological regression and ultimately died at age 4 years. We performed molecular and functional analysis of the mutant POLD3 and assessed cell cycle progression as well as replication-associated DNA damage. Patient fibroblasts showed a marked defect in S-phase entry and an enhanced number of double-stranded DNA break-associated foci despite normal expression levels of PolD components. The cell cycle defect was rescued by transduction with WT POLD3. This study validates autosomal recessive POLD3 deficiency as a novel cause of profound T-cell deficiency and Omenn syndrome. [ABSTRACT FROM AUTHOR]