POLD1 variants leading to reduced polymerase activity can cause hearing loss without syndromic features

Doo Yi Oh, Yoshihiro Matsumoto, Shin ichiro Kitajiri, Nayoung K.D. Kim, Min Young Kim, Ah Reum Kim, Mingyu Lee, Chung Lee, Alan E. Tomkinson, Tatsuya Katsuno, So Young Kim, Hyun Woo Shin, Jin Hee Han, Seungmin Lee, Woong Yang Park, Byung Yoon Choi

Research output: Contribution to journalArticlepeer-review


DNA polymerase δ, whose catalytic subunit is encoded by POLD1, is responsible for synthesizing the lagging strand of DNA. Single heterozygous POLD1 mutations in domains with polymerase and exonuclease activities have been reported to cause syndromic deafness as a part of multisystem metabolic disorder or predisposition to cancer. However, the phenotypes of diverse combinations of POLD1 genotypes have not been elucidated in humans. We found that five members of a multiplex family segregating autosomal recessive nonsyndromic sensorineural hearing loss (NS-SNHL) have revealed novel compound heterozygous POLD1 variants (p.Gly1100Arg and a presumptive null function variant, p.Ser197Hisfs*54). The recombinant p.Gly1100Arg polymerase δ showed a reduced polymerase activity by 30–40%, but exhibited normal exonuclease activity. The polymerase activity in cell extracts from the affected subject carrying the two POLD1 mutant alleles was about 33% of normal controls. We suggest that significantly decreased polymerase δ activity, but not a complete absence, with normal exonuclease activity could lead to NS-SNHL.

Original languageEnglish
Pages (from-to)913-920
Number of pages8
JournalHuman Mutation
Issue number5
StatePublished - 1 May 2020


  • POLD1
  • Pol δ
  • exonuclease
  • polymerase

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