Abstract：
BACKGROUND: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has an essential role in the non-homologous end-joining pathway that repairs DNA double-strand breaks in V(D)J recombination involved in the expression of T- and B-cell receptors. Whereas homozygous mutations in PRKDC define the scid mouse, a model that has been widely used in biology, human mutations in PRKDC are extremely rare and the disease spectrum has not been described so far.
OBJECTIVE: To provide an update on the genetics, clinical spectrum, immunological profile, and therapy of DNA-PKcs deficiency in human.
METHODS: The clinical, biological, and treatment data from the 6 cases published to date and from 1 new patient were obtained and analyzed. Rubella PCR was performed on available granuloma material.
RESULTS: We report on 7 patients; Six patients displayed the autosomal recessive p.L3062R mutation in PRKDC gene encoding DNA-PKcs. Atypical severe combined immunodeficiency with inflammatory lesions, granulomas, and autoimmunity was the predominant clinical manifestation (n=5/7). Rubella viral strain was detected in the granuloma of 1 patient over the 2 tested. T-cell counts, including naïve CD4+CD45RA+ T cells and T-cell function were low at diagnosis for 6 patients. For most patients with available values naïve CD4+CD45RA+ T cells decreased over time (n=5/6). Hematopoietic stem cell transplantation (HSCT) was performed in 5 patients, of whom 4 are still alive without transplant-related morbidity. Sustained T- and B-cell reconstitution was respectively observed for 4 and 3 patients, after a median follow-up of 8 years (range 3-16 y).
CONCLUSIONS: DNA-PKcs deficiency mainly manifests as an inflammatory disease with granuloma and autoimmune features, along with severe infections.
OBJECTIVE: To provide an update on the genetics, clinical spectrum, immunological profile, and therapy of DNA-PKcs deficiency in human.
METHODS: The clinical, biological, and treatment data from the 6 cases published to date and from 1 new patient were obtained and analyzed. Rubella PCR was performed on available granuloma material.
RESULTS: We report on 7 patients; Six patients displayed the autosomal recessive p.L3062R mutation in PRKDC gene encoding DNA-PKcs. Atypical severe combined immunodeficiency with inflammatory lesions, granulomas, and autoimmunity was the predominant clinical manifestation (n=5/7). Rubella viral strain was detected in the granuloma of 1 patient over the 2 tested. T-cell counts, including naïve CD4+CD45RA+ T cells and T-cell function were low at diagnosis for 6 patients. For most patients with available values naïve CD4+CD45RA+ T cells decreased over time (n=5/6). Hematopoietic stem cell transplantation (HSCT) was performed in 5 patients, of whom 4 are still alive without transplant-related morbidity. Sustained T- and B-cell reconstitution was respectively observed for 4 and 3 patients, after a median follow-up of 8 years (range 3-16 y).
CONCLUSIONS: DNA-PKcs deficiency mainly manifests as an inflammatory disease with granuloma and autoimmune features, along with severe infections.
摘要：
背景：DNA依赖性蛋白激酶催化亚基（DNA-PKcs）在非同源末端连接途径中具有重要作用，该途径修复涉及T细胞和B细胞受体表达的V（D）J重组中的DNA双链断裂。而PRKDC中的纯合突变定义了scid小鼠，在生物学中广泛使用的模型，PRKDC中的人类突变极为罕见，迄今为止尚未描述疾病谱。
目的：为了提供有关遗传学的最新信息，临床谱，免疫学特征，以及人类DNA-PKcs缺乏症的治疗。
方法：临床，生物，收集并分析了迄今为止发表的6例病例和1例新患者的治疗数据。对可用的肉芽肿材料进行风疹PCR。
结果：我们报告了7例患者；6例患者在编码DNA-PKcs的PRKDC基因中显示出常染色体隐性p.L3062R突变。非典型重度联合免疫缺陷伴炎性病变，肉芽肿,自身免疫是主要的临床表现（n=5/7）。在2例测试中，在1例患者的肉芽肿中检测到风疹病毒株。T细胞计数,包括初始CD4+CD45RA+T细胞和T细胞功能在6例患者诊断时很低。对于具有可用值的大多数患者,初始CD4+CD45RA+T细胞随时间减少(n=5/6)。5例患者进行造血干细胞移植(HSCT),其中4人仍然活着，没有移植相关的发病率。4例和3例患者分别观察到持续的T细胞和B细胞重建，中位随访8年（范围3-16年）。
结论：DNA-PKcs缺乏主要表现为具有肉芽肿和自身免疫特征的炎性疾病，伴随着严重的感染。
目的：为了提供有关遗传学的最新信息，临床谱，免疫学特征，以及人类DNA-PKcs缺乏症的治疗。
方法：临床，生物，收集并分析了迄今为止发表的6例病例和1例新患者的治疗数据。对可用的肉芽肿材料进行风疹PCR。
结果：我们报告了7例患者；6例患者在编码DNA-PKcs的PRKDC基因中显示出常染色体隐性p.L3062R突变。非典型重度联合免疫缺陷伴炎性病变，肉芽肿,自身免疫是主要的临床表现（n=5/7）。在2例测试中，在1例患者的肉芽肿中检测到风疹病毒株。T细胞计数,包括初始CD4+CD45RA+T细胞和T细胞功能在6例患者诊断时很低。对于具有可用值的大多数患者,初始CD4+CD45RA+T细胞随时间减少(n=5/6)。5例患者进行造血干细胞移植(HSCT),其中4人仍然活着，没有移植相关的发病率。4例和3例患者分别观察到持续的T细胞和B细胞重建，中位随访8年（范围3-16年）。
结论：DNA-PKcs缺乏主要表现为具有肉芽肿和自身免疫特征的炎性疾病，伴随着严重的感染。
