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

Hilde Van Esch*, Rita Colnaghi, Kathleen Freson, Petro Starokadomskyy, Andreas Zankl, Liesbeth Backx, Iga Abramowicz, Emily 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'Driscoll

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

14 Citations (Scopus)


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 α, δ, and ε. Collectively these multimeric polymerases ensure DNA replication proceeds at optimal rates approaching 2 × 10 3 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 δ and ε. The DNA polymerase α-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 α-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 α.

Original languageEnglish
Pages (from-to)957-967
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number5
Early online date18 Apr 2019
Publication statusPublished - 2 May 2019

Bibliographical note

Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.


  • growth retardation
  • intellectual disability
  • microcephaly
  • POLA1
  • polymerase alpha
  • X-linked


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