Takada Sanami, Okano Tsubasa, Tanita Kay, Tsukada Kaima, Watanabe Masato, Hijikata Atsushi, Naruto Takuya, Yeh Tzu-Wen, Kasuga Saki, Tokimasa Sadao, Taniguchi-Ikeda Mariko, Ogata Reina, Ikeda Azusa, Goto Tomohide, Osaka Hitoshi, Takagi Masatoshi, Imai Kohsuke, Morio Tomohiro, van der Burg Mirjam, Shimada Mikio, Kanegane Hirokazu
Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan.
Laboratory for Zero-Carbon Energy, Institute of Integrated Research, Institute of Science Tokyo, Tokyo, Japan.
J Allergy Clin Immunol Glob. 2025 Jun 11;4(3):100514. doi: 10.1016/j.jacig.2025.100514. eCollection 2025 Aug.
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.
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.
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.
Whole-exome sequencing revealed compound heterozygous 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.
Our case indicated that variant-induced DNA repair abnormalities may be associated with immunodeficiency.
DNA修复对于维持基因组完整性至关重要，并且在免疫系统中发挥重要作用。DNA修复途径的缺陷通常与免疫缺陷相关，包括B细胞缺陷，这与B细胞成熟过程中V(D)J重组、类别转换和体细胞高频突变期间对DNA修复的需求一致。多核苷酸激酶3'-磷酸酶（PNKP）在DNA修复中起重要作用。PNKP缺乏症的特征是神经发育异常；然而，免疫缺陷尚未见报道。
我们关注一对患有小头畸形、眼部异常和低丙种球蛋白血症的PNKP缺乏症同胞。我们旨在分析PNKP缺乏对B细胞发育的影响。
进行全外显子组测序以确定低丙种球蛋白血症的遗传原因。使用患者来源的成纤维细胞分析DNA修复效率。使用患者的外周血以及其他无严重免疫缺陷的PNKP缺乏症患者分析免疫表型和B细胞受体库。
全外显子组测序揭示了复合杂合变异。成纤维细胞显示在辐射诱导的双链/单链DNA断裂后DNA修复存在缺陷。流式细胞术显示总B细胞和类别转换记忆B细胞计数减少。B细胞受体库分析表明这些患者体细胞高频突变的频率降低，而其他PNKP缺乏症患者表现出正常的B细胞受体库模式。
我们的病例表明变异诱导的DNA修复异常可能与免疫缺陷有关。
