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Defective DNA polymerase a-primase leads to X-linked intellectual disability associated with severe growth retardation, microcephaly, and hypogonadism.

journal contribution
posted on 2023-06-21, 06:01 authored by Hilde Van Esch, Rita Colnaghi, Kathleen Freson, Petro Starokadomskyy, Andreas Zankl, Liesbeth Backx, Iga Abramowicz, Emily OutwinEmily Outwin, Luis Rohena, Claire Faulkner, Gary M Leong, Ruth A Newbury-Ecob, Rachel C Challis, Katrin Õunap, Jacques Jaeken, Eve Seuntjens, Koen Devriendt, Ezra Burstein, Karen J Low, Mark O'DriscollMark O'Driscoll
Replicating the human genome efficiently and accurately is a daunting challenge involving the duplication of upward of three billion base pairs. At the core of the complex machinery that achieves this task are three members of the B family of DNA polymerases: DNA polymerases a, d, and e. Collectively these multimeric polymerases ensure DNA replication proceeds at optimal rates approaching 2 × 10 nucleotides/min with an error rate of less than one per million nucleotides polymerized. The majority of DNA replication of undamaged DNA is conducted by DNA polymerases d and e. The DNA polymerase a-primase complex performs limited synthesis to initiate the replication process, along with Okazaki-fragment synthesis on the discontinuous lagging strand. An increasing number of human disorders caused by defects in different components of the DNA-replication apparatus have been described to date. These are clinically diverse and involve a wide range of features, including variable combinations of growth delay, immunodeficiency, endocrine insufficiencies, lipodystrophy, and cancer predisposition. Here, by using various complementary approaches, including classical linkage analysis, targeted next-generation sequencing, and whole-exome sequencing, we describe distinct missense and splice-impacting mutations in POLA1 in five unrelated families presenting with an X-linked syndrome involving intellectual disability, proportionate short stature, microcephaly, and hypogonadism. POLA1 encodes the p180 catalytic subunit of DNA polymerase a-primase. A range of replicative impairments could be demonstrated in lymphoblastoid cell lines derived from affected individuals. Our findings describe the presentation of pathogenic mutations in a catalytic component of a B family DNA polymerase member, DNA polymerase a.

History

Publication status

  • Published

File Version

  • Accepted version

Journal

American Journal of Human Genetics

ISSN

1537-6605

Publisher

Elsevier

Issue

5

Volume

104

Page range

957-967

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Research groups affiliated with

  • Genome Damage and Stability Centre Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2019-04-26

First Open Access (FOA) Date

2019-10-18

First Compliant Deposit (FCD) Date

2019-04-24

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