Van Esch, Hilde, Colnaghi, Rita, Freson, Kathleen, Starokadomskyy, Petro, Zankl, Andreas, Backx, Liesbeth, Abramowicz, Iga, Outwin, Emily, Rohena, Luis, Faulkner, Claire, Leong, Gary M, Newbury-Ecob, Ruth A, Challis, Rachel C, Õunap, Katrin, Jaeken, Jacques, Seuntjens, Eve, Devriendt, Koen, Burstein, Ezra, Low, Karen J and O'Driscoll, Mark (2019) Defective DNA polymerase α-primase leads to X-linked intellectual disability associated with severe growth retardation, microcephaly, and hypogonadism. American Journal of Human Genetics, 104 (5). pp. 957-967. ISSN 1537-6605

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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 × 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 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.

Item Type:	Article
Schools and Departments:	School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups:	Genome Damage and Stability Centre
Subjects:	Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics > QH0447 Genes. Alleles. Genome Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics > QH0460 Mutations R Medicine > RB Pathology > RB024 Pathological anatomy and histology R Medicine > RB Pathology > RB127 Manifestations of disease R Medicine > RJ Pediatrics > RJ0047.3 Genetic aspects R Medicine > RJ Pediatrics > RJ0101 Child health. Child health services
Related URLs:	Publisher
Depositing User:	Mark O'Driscoll
Date Deposited:	26 Apr 2019 12:21
Last Modified:	01 Jul 2019 13:01
URI:	http://sro.sussex.ac.uk/id/eprint/83390

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