B-cell immunodeficiency associated with polynucleotide kinase 3′-phosphatase (PNKP) deficiency

Sanami Takada, MD, PhD; Tsubasa Okano, MD, PhD; Kay Tanita, MD, PhD; Kaima Tsukada, PhD; Masato Watanabe, MD; Atsushi Hijikata, PhD; Takuya Naruto, PhD; Tzu-Wen Yeh, PhD; Saki Kasuga, MD, PhD; Sadao Tokimasa, MD, PhD; Mariko Taniguchi-Ikeda, MD, PhD; Reina Ogata, MD; Azusa Ikeda, MD, PhD; Tomohide Goto, MD, PhD; Hitoshi Osaka, MD, PhD; Masatoshi Takagi, MD, PhD; Kohsuke Imai, MD, PhD; Tomohiro Morio, MD, PhD; Mirjam van der Burg, PhD; Mikio Shimada, PhD; Hirokazu Kanegane, MD, PhD

doi:10.1016/j.jacig.2025.100514

Journal of Allergy and Clinical Immunology: Global (Aug 2025)

B-cell immunodeficiency associated with polynucleotide kinase 3′-phosphatase (PNKP) deficiency

Sanami Takada, MD, PhD,
Tsubasa Okano, MD, PhD,
Kay Tanita, MD, PhD,
Kaima Tsukada, PhD,
Masato Watanabe, MD,
Atsushi Hijikata, PhD,
Takuya Naruto, PhD,
Tzu-Wen Yeh, PhD,
Saki Kasuga, MD, PhD,
Sadao Tokimasa, MD, PhD,
Mariko Taniguchi-Ikeda, MD, PhD,
Reina Ogata, MD,
Azusa Ikeda, MD, PhD,
Tomohide Goto, MD, PhD,
Hitoshi Osaka, MD, PhD,
Masatoshi Takagi, MD, PhD,
Kohsuke Imai, MD, PhD,
Tomohiro Morio, MD, PhD,
Mirjam van der Burg, PhD,
Mikio Shimada, PhD,
Hirokazu Kanegane, MD, PhD

Affiliations

Sanami Takada, MD, PhD: Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
Tsubasa Okano, MD, PhD: Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
Kay Tanita, MD, PhD: Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
Kaima Tsukada, PhD: Laboratory for Zero-Carbon Energy, Institute of Integrated Research, Institute of Science Tokyo, Tokyo, Japan
Masato Watanabe, MD: Faculty of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
Atsushi Hijikata, PhD: School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
Takuya Naruto, PhD: Department of Lifetime Clinical Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
Tzu-Wen Yeh, PhD: Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
Saki Kasuga, MD, PhD: Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan
Sadao Tokimasa, MD, PhD: Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan
Mariko Taniguchi-Ikeda, MD, PhD: Department of Clinical Genetics, Fujita Health University Hospital, Toyoake, Japan
Reina Ogata, MD: Department of Pediatrics, National Hospital Organization Kokura Medical Center, Fukuoka, Japan
Azusa Ikeda, MD, PhD: Department of Neurology, Kanagawa Children’s Medical Center, Kanagawa, Japan
Tomohide Goto, MD, PhD: Department of Neurology, Kanagawa Children’s Medical Center, Kanagawa, Japan
Hitoshi Osaka, MD, PhD: Department of Pediatrics, Jichi Medical University, Tochigi, Japan
Masatoshi Takagi, MD, PhD: Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
Kohsuke Imai, MD, PhD: Department of Pediatrics, National Defense Medical College, Tokorozawa, Japan
Tomohiro Morio, MD, PhD: Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
Mirjam van der Burg, PhD: Department of Pediatrics, Laboratory for Pediatric Immunology, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, The Netherlands
Mikio Shimada, PhD: Laboratory for Zero-Carbon Energy, Institute of Integrated Research, Institute of Science Tokyo, Tokyo, Japan; Corresponding authors: Mikio Shimada, PhD, Laboratory for Zero-Carbon Energy, Institute of Integrated Research, Institute of Science Tokyo, 2-12-1-N1-30 Ookayama, Meguro-ku, Tokyo, 152-8550, Japan.
Hirokazu Kanegane, MD, PhD: Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan; Hirokazu Kanegane, MD, PhD, Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

DOI: https://doi.org/10.1016/j.jacig.2025.100514
Journal volume & issue: Vol. 4, no. 3
p. 100514

Abstract

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Background: DNA repair is crucial for maintaining genomic integrity and plays a significant role in the immune system. Defects in DNA repair pathways are often associated with immunodeficiency, including B-cell defects, which are consistent with the need for DNA repair during V(D)J recombination, class switching, and somatic hypermutation during B-cell maturation. Polynucleotide kinase 3′-phosphatase (PNKP) plays a significant role in DNA repair. PNKP deficiency is characterized by neurologic developmental abnormalities; however, immunodeficiency has not yet been reported. Objective: We focused on a pair of PNKP-deficient siblings who presented with microcephaly, eye abnormalities, and hypogammaglobulinemia. We aimed to analyze the effect of PNKP deficiency on B-cell development. Methods: Whole-exome sequencing was performed to identify the genetic cause of hypogammaglobulinemia. DNA repair efficiency was analyzed using patient-derived fibroblasts. The immune phenotype and B-cell receptor repertoire were analyzed using the patient’s peripheral blood, alongside other patients with PNKP deficiency without severe immunodeficiency. Results: Whole-exome sequencing revealed compound heterozygous PNKP variants. Fibroblasts revealed defects in DNA repair in response to radiation-induced double/single-stranded DNA breaks. Flow cytometry revealed reduced total B-cell and class-switched memory B-cell counts. The B-cell receptor repertoire analysis demonstrated reduced frequencies of somatic hypermutations in these patients, whereas other patients with PNKP deficiency exhibited normal B-cell receptor repertoire patterns. Conclusion: Our case indicated that PNKP variant–induced DNA repair abnormalities may be associated with immunodeficiency.

Published in Journal of Allergy and Clinical Immunology: Global

ISSN: 2772-8293 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Immunologic diseases. Allergy
Website: https://www.sciencedirect.com/journal/journal-of-allergy-and-clinical-immunology-global

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