Neurodevelopmental abnormalities associated with severe congenital neutropenia due to the R86X mutation in the HAX1 gene
Neurodevelopmental abnormalities associated with severe congenital neutropenia due to the R86X mutation in the HAX1 gene
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DOI：
10.1136/jmg.2008.058297
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发表时间：
2008-12-01
影响因子：
4
通讯作者：
Kobayashi, M.
中科院分区：
文献类型：
--
作者：
Ishikawa, N.;Okada, S.;Kobayashi, M.
目的：重度先天性中性粒细胞减少症（SCN），也称为Kostmann综合征（SCN 3，OMIM 610738），包括由不同遗传异常引起的各种血液学疾病。ELA 2的突变是常染色体显性或散发形式的最常见原因。最近，HAX 1突变已被确定为某些常染色体隐性形式SCN的原因，包括Kostmann首次报道的原始家系中存在的突变。我们试图确定HAX 1基因突变和日本SCN病例的临床特征之间的关系。方法：在18例日本SCN患者中分析了涉及SCN（ELA 2，HAX 1，Gfi-1，WAS和P14）的基因。这些患者的临床特征从病历中获得。HAX 1的免疫印迹进行外周血白细胞从患者和/或他们的parents.Results的细胞提取物：我们发现5例HAX 1缺乏症和11例ELA 2基因突变。在HAX 1缺陷中，在三个受影响的个体中鉴定出纯合的单碱基对取代（256 C> T），其导致无义改变R86 X。两名同胞患者显示了由单个碱基对取代（256 C> T）和核苷酸376-434处的59 bp缺失组成的复合杂合突变。在任何杂合子携带者中都没有检测到表型。所有HAX 1缺乏症患者都经历了发育迟缓。三名携带R86 X的患者也患有癫痫发作。相比之下，没有SCN患者ELA 2基因杂合突变遭受任何神经发育异常。结论：这些研究结果表明，在HAX 1基因的R86 X突变是一个异常，在日本SCN患者HAX 1缺乏症，并可能导致神经发育异常和严重的骨髓造血缺陷。
Objective: Severe congenital neutropenia (SCN), also known as Kostmann syndrome (SCN3, OMIM 610738), includes a variety of haematological disorders caused by different genetic abnormalities. Mutations in ELA2 are most often the cause in autosomal dominant or sporadic forms. Recently, mutations in HAX1 have been identified as the cause of some autosomal recessive forms of SCN, including those present in the original pedigree first reported by Kostmann. We sought to determine the relationship between HAX1 gene mutations and the clinical characteristics of Japanese cases of SCN.Methods: The genes implicated in SCN ( ELA2, HAX1, Gfi-1, WAS, and P14) were analysed in 18 Japanese patients with SCN. The clinical features of these patients were obtained from medical records. Immunoblotting of HAX1 was performed on cell extracts from peripheral blood leucocytes from patients and/or their parents.Results: We found five patients with HAX1 deficiency and 11 patients with mutations in the ELA2 gene. In HAX1 deficiency, a homozygous single base pair substitution (256C > T), which causes the nonsense change R86X, was identified in three affected individuals. Two sibling patients showed a compound heterozygous mutation consisting of a single base pair substitution (256C > T) and a 59 bp deletion at nucleotides 376-434. There was no detectable phenotype in any heterozygous carrier. All patients with HAX1 deficiency had experienced developmental delay. Three patients carrying R86X also suffered from epileptic seizures. In contrast, no SCN patient with heterozygous mutations in the ELA2 gene suffered from any neurodevelopmental abnormality.Conclusions: These findings suggest that the R86X mutation in the HAX1 gene is an abnormality in Japanese SCN patients with HAX1 deficiency and may lead to neurodevelopmental abnormalities and severe myelopoietic defects.