Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Hospital for Sick Children, 24 Boulevard du Montparnasse, INSERM U1163, Paris, France.
Paris Cité University, Imagine Institute, Paris, France.
J Clin Immunol. 2022 Aug;42(6):1244-1253. doi: 10.1007/s10875-022-01268-8. Epub 2022 May 18.
Autosomal recessive (AR) PKCδ deficiency is a rare inborn error of immunity (IEI) characterized by autoimmunity and susceptibility to bacterial, fungal, and viral infections. PKCδ is involved in the intracellular production of reactive oxidative species (ROS).
We studied a 5-year old girl presenting with a history of Burkholderia cepacia infection. She had no history of autoimmunity, lymphocyte counts were normal, and no auto-antibodies were detected in her plasma. We performed a targeted panel analysis of 407 immunity-related genes and immunological investigations of the underlying genetic condition in this patient.
Consistent with a history suggestive of chronic granulomatous disease (CGD), oxidative burst impairment was observed in the patient's circulating phagocytes in a dihydrorhodamine 123 (DHR) assay. However, targeted genetic panel analysis identified no candidate variants of known CGD-causing genes. Two heterozygous candidate variants were detected in PRKCD: c.285C > A (p.C95*) and c.376G > T (p.D126Y). The missense variant was also predicted to cause abnormal splicing, as it is located at the splice donor site of exon 5. TOPO-TA cloning confirmed that exon 5 was completely skipped, resulting in a truncated protein. No PKCδ protein was detected in the patient's neutrophils and monocyte-derived macrophages. The monocyte-derived macrophages of the patient produced abnormally low levels of ROS, as shown in an Amplex Red assay.
PKCδ deficiency should be considered in young patients with CGD-like clinical manifestations and abnormal DHR assay results, even in the absence of clinical and biological manifestations of autoimmunity.
常染色体隐性（AR）蛋白激酶 C δ（PKCδ）缺陷是一种罕见的先天性免疫缺陷病（IEI），其特征为自身免疫和易发生细菌、真菌和病毒感染。PKCδ参与活性氧（ROS）的细胞内产生。
我们研究了一名 5 岁女孩，其病史为伯克霍尔德氏菌感染。她无自身免疫病史，淋巴细胞计数正常，血浆中未检测到自身抗体。我们对该患者进行了 407 个免疫相关基因的靶向panel 分析和潜在遗传状况的免疫学研究。
与慢性肉芽肿病（CGD）的病史一致，患者循环吞噬细胞在二氢罗丹明 123（DHR）测定中存在氧化爆发障碍。然而，靶向基因panel 分析未发现已知 CGD 致病基因的候选变异。在 PRKCD 中检测到两个杂合候选变异：c.285C > A（p.C95*）和 c.376G > T（p.D126Y）。该错义变异也被预测会导致异常剪接，因为它位于外显子 5 的剪接受体位点。TOPO-TA 克隆证实外显子 5 完全缺失，导致截短蛋白。患者的中性粒细胞和单核细胞衍生的巨噬细胞中未检测到 PKCδ 蛋白。患者的单核细胞衍生巨噬细胞产生的 ROS 水平异常低，如 Amplex Red 测定所示。
即使没有自身免疫的临床和生物学表现，对于具有 CGD 样临床表现和异常 DHR 测定结果的年轻患者，应考虑 PKCδ 缺陷。
