Publikationsdatum:
2012-12-18
Beschreibung:
DNA polymerase (Pol) is a large, four-subunit polymerase that is conserved throughout the eukaryotes. Its primary function is to synthesize DNA at the leading strand during replication. It is also involved in a wide variety of fundamental cellular processes, including cell cycle progression and DNA repair/recombination. Here, we report that a homozygous single base pair substitution in POLE1 ( polymerase 1 ), encoding the catalytic subunit of Pol, caused facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome") in a large, consanguineous family. The mutation resulted in alternative splicing in the conserved region of intron 34, which strongly decreased protein expression of Pol1 and also to a lesser extent the Pol2 subunit. We observed impairment in proliferation and G1- to S-phase progression in patients’ T lymphocytes. Pol1 depletion also impaired G1- to S-phase progression in B lymphocytes, chondrocytes, and osteoblasts. Our results evidence the developmental impact of a Pol catalytic subunit deficiency in humans and its causal relationship with a newly recognized, inherited disorder.
Print ISSN:
0022-1007
Digitale ISSN:
1540-9538
Thema:
Medizin
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