Human Adenylate Kinase 2 Deficiency Causes a Profound Haematopoietic Defect Associated with Sensorineural Deafness
Human Adenylate Kinase 2 Deficiency Causes a Profound Haematopoietic Defect Associated with Sensorineural Deafness
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人腺苷酸激酶 2 缺乏会导致与感音神经性耳聋相关的严重造血缺陷
DOI：
10.1182/blood.v112.11.lba-2.lba-2
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发表时间：
2008
期刊：
影响因子：
20.3
通讯作者：
A. Fischer
中科院分区：
文献类型：
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作者：
M. Cavazzana‐Calvo;C. Lagresle;E. Six;C. Picard;F. Rieux;Vincent Michel;Andrea Ditadi;Corinne Demerens;E. Morillon;F. Valensi;K. Simon;J. Mullikin;L. Noroski;C. Besse;N. Wulffraat;A. Ferster;M. Abecasis;F. Calvo;C. Petit;F. Candotti;L. Abel;A. Fischer
人腺苷酸激酶2缺乏引起与感音神经性耳聋相关的最深刻的人类造血缺陷。网状发育不良（RD）是一种常染色体隐性的人类严重联合免疫缺陷（SCID），其特征是骨髓谱系的早期分化阻滞和与双侧感音神经性耳聋相关的淋巴细胞成熟的严重损害。受影响的新生儿缺乏多形核中性粒细胞是导致严重感染比通常在其他形式的SCID中观察到的更早发生的原因。此外，RD相关的中性粒细胞减少症的特征是对G-CSF缺乏反应性。我们在7例RD患者中发现了腺苷酸激酶2 （AK2）基因的双等位基因突变。这些突变导致蛋白表达缺失或强烈下降。RD患者骨髓细胞中AK2表达的恢复克服了中性粒细胞分化停滞，这是其在一组有限的造血谱系发展中的特殊需求。最后，我们确定AK2在内耳血管纹区特异性表达。该基因在特定细胞系分化中的功能正在迅速发展，表明原发性免疫缺陷的研究继续为人类淋巴-造血发育提供关键信息。此外，AK2酶似乎是不同生物系统的关键分子，如淋巴造血和大脑发育。
Human adenylate kinase 2 deficiency causes the most profound human haematopoietic defect associated with sensorineural deafness. Reticular dysgenesis (RD) is an autosomal recessive form of human severe combined immunodeficiency (SCID) characterized by an early differentiation block in the myeloid lineage and a profound impairment in lymphoid maturation associated with bilateral sensorineural deafness. The lack of polymorphonuclear neutrophils in affected newborns is responsible for the occurrence of severe infections earlier than usually observed in the other forms of SCID. Furthermore, RD associated neutropenia is characterized by the lack of responsiveness to G-CSF. We have identified bi-allelic mutations in the adenylate kinase 2 (AK2) gene is seven patients affected with RD. These mutations resulted in the absence or a strong decrease in protein expression. Restoration of AK2 expression in the bone marrow cells of RD patients overcomes the neutrophil differentiation arrest, underlying its specific requirement in the development of a restricted set of haematopoietic lineages. Lastly, we established that AK2 is specifically expressed in the stria vascularis region of the inner ear. The function of this gene in the differentiation of a given set of cell lineages is rapidly in progress, showing that studies of primary immunodeficiencies continue to provide key information on human lympho-haematopoietic development. Moreover the AK2 enzyme seems a key molecule in different biological systems such as the lympho-haematopoiesis and the brain development.