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. Epub 2019 Apr 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • DNA Polymerase I / genetics*
  • DNA Primase / genetics*
  • Exome Sequencing
  • Female
  • Genetic Diseases, X-Linked / etiology*
  • Genetic Diseases, X-Linked / pathology
  • Genotype
  • Growth Disorders / etiology*
  • Growth Disorders / pathology
  • Humans
  • Hypogonadism / etiology*
  • Hypogonadism / pathology
  • Infant
  • Intellectual Disability / etiology*
  • Intellectual Disability / pathology
  • Male
  • Microcephaly / etiology*
  • Microcephaly / pathology
  • Middle Aged
  • Mutation*
  • Pedigree

Substances

  • DNA Primase
  • DNA polymerase alpha-primase
  • DNA Polymerase I