Abstract：
MECOM deficiency is a recently identified inborn error of immunity and inherited bone marrow failure syndrome caused by haploinsufficiency of the hematopoietic transcription factor MECOM. It is unique among inherited bone marrow failure syndromes, many of which present during later childhood or adolescence, because of the early age of onset and severity of the pancytopenia, emphasizing the importance and gene dose dependency of MECOM during hematopoiesis. B-cell lymphopenia and hypogammaglobulinemia have been described in a subset of patients with MECOM deficiency. While the mechanisms underlying the B-cell deficiency are currently unknown, recent work has provided mechanistic insights into the function of MECOM in hematopoietic stem cell (HSC) maintenance. MECOM binds to regulatory enhancers that control the expression of a network of genes essential for HSC maintenance and self-renewal. Heterozygous mutations, as seen in MECOM-deficient bone marrow failure, lead to dysregulated MECOM network expression. Extra-hematopoietic manifestations of MECOM deficiency, including renal and cardiac anomalies, radioulnar synostosis, clinodactyly, and hearing loss, have been reported. Individuals with specific genotypes have some of the systemic manifestations with isolated mild thrombocytopenia or without hematologic abnormalities, highlighting the tissue specificity of mutations in some MECOM domains. Those infants with MECOM-associated bone marrow failure require HSC transplantation for survival. Here, we review the expanding cohort of patient phenotypes and accompanying genotypes resulting in MECOM deficiency, and the proposed mechanisms underlying MECOM regulation of human HSC maintenance and B-cell development.
摘要：
MECOM缺乏症是最近发现的由造血转录因子MECOM单倍体不足引起的先天性免疫错误和遗传性骨髓衰竭综合征。它在遗传性骨髓衰竭综合征中是独一无二的，其中许多存在于童年或青春期后期，由于全血细胞减少症的发病年龄和严重程度，强调MECOM在造血过程中的重要性和基因剂量依赖性。已经在MECOM缺乏症患者的一部分中描述了B细胞淋巴细胞减少和低丙种球蛋白血症。虽然目前尚不清楚B细胞缺乏的潜在机制，最近的工作为MECOM在造血干细胞（HSC）维持中的功能提供了机械见解。MECOM与调控增强子结合,所述调控增强子控制HSC维持和自我更新所必需的基因网络的表达。杂合突变,如MECOM缺乏的骨髓衰竭所示，导致MECOM网络表达失调。MECOM缺乏的造血外表现，包括肾脏和心脏异常，径向骨滑膜，clindactyly,听力损失,已被报道。具有特定基因型的个体有一些全身性表现，有孤立的轻度血小板减少症或无血液学异常。突出了一些MECOM结构域突变的组织特异性。那些患有MECOM相关骨髓衰竭的婴儿需要HSC移植才能存活。这里,我们回顾了导致MECOM缺陷的患者表型和伴随基因型的扩展队列，以及MECOM调控人类HSC维持和B细胞发育的潜在机制。
