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

Am J Hum Genet. 2019 May 2;104(5):957-967. doi: 10.1016/j.ajhg.2019.03.006.

Hilde Van Esch ¹, Rita Colnaghi ², Kathleen Freson ³, Petro Starokadomskyy ⁴, Andreas Zankl ⁵, Liesbeth Backx ⁶, Iga Abramowicz ², Emily Outwin ², Luis Rohena ⁷, Claire Faulkner ⁸, Gary M Leong ⁹, Ruth A Newbury-Ecob ¹⁰, Rachel C Challis ¹¹, Katrin Õunap ¹², Jacques Jaeken ¹³, Eve Seuntjens ¹⁴, Koen Devriendt ¹⁵, Ezra Burstein ¹⁶, Karen J Low ¹⁰, Mark O'Driscoll ¹⁷

Affiliations

1 Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium; Laboratory for the Genetics of Cognition, Department of Human Genetics, Katholieke Universiteit Leuven, 3000 Leuven, Belgium. Electronic address: [email protected].
2 Genome Damage and Stability Centre, University of Sussex, BN1 9RQ Sussex, UK.
3 Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
4 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
5 Department of Clinical Genetics, the Children's Hospital at Westmead, Westmead, NSW 2145, Australia; Children's Hospital Westmead Clinical School, Sydney Medical School, the University of Sydney, Westmead, NSW 2145, Australia; Bone Biology Division and Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
6 Laboratory for the Genetics of Cognition, Department of Human Genetics, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
7 Division of Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, TX 78234, USA.
8 Bristol Genetics Laboratory, Southmead Hospital, BS10 5NB Bristol, UK.
9 Department of Paediatrics, Nepean Hospital, Nepean Clinical School, the University of Sydney, Kingswood, NSW 2747, Australia.
10 Clinical Genetics, St. Michael's Hospital, University Hospitals NHS Trust, BS2 8HW Bristol, UK.
11 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XU Edinburgh, UK.
12 Department of Clinical Genetics, United Laboratories, Tartu University Hospital and Institute of Clinical Medicine, University of Tartu, Tartu 50406, Estonia.
13 Center for Metabolic Diseases, University Hospitals Leuven, 3000 Leuven, Belgium.
14 Developmental Neurobiology, Department of Biology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
15 Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium.
16 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390 Texas, USA.
17 Genome Damage and Stability Centre, University of Sussex, BN1 9RQ Sussex, UK. Electronic address: [email protected].

PMID: 31006512 DOI: 10.1016/j.ajhg.2019.03.006

Abstract

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 × 10³ 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.

Keywords

POLA1; X-linked; growth retardation; intellectual disability; microcephaly; polymerase alpha.

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