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

Research output: Contribution to journalArticle

  • 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
Original languageEnglish
Pages (from-to)957-967
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number5
Early online date18 Apr 2019
DateAccepted/In press - 4 Mar 2019
DateE-pub ahead of print - 18 Apr 2019
DatePublished (current) - 2 May 2019


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.

Additional information

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

    Research areas

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


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