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

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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 (US)
Pages (from-to)957-967
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number5
StatePublished - May 2 2019


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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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