Missense mutations in the ABCB6 transporter cause dominant familialpseudohyperkalemia
Missense mutations in the ABCB6 transporter cause dominant familialpseudohyperkalemia
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DOI：
10.1002/ajh.23357
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发表时间：
2013-01-01
影响因子：
12.8
通讯作者：
Iolascon, Achille
中科院分区：
文献类型：
--
作者：
Andolfo, Immacolata;Alper, Seth L.;Iolascon, Achille
家族性假性高钾血症(FP)是一种显性的红细胞特征，其特征是在室温或低于室温下储存的全血中血清[K+]升高，而没有额外的血液学异常。3个多代FP家系中20例受累个体2q35q36关键区间内候选基因的功能基因定位和序列分析两个新的ABCB6基因杂合性错义突变与疾病表型共分离。这两个基因组替换改变了ABCB6密码子375内的两个相邻核苷酸，ABCB6是一种卟啉转运体，在红细胞膜上承载着朗格里斯血型抗原系统。ABCB6R375Q突变不会改变成熟红细胞或红系前体细胞的mRNA或蛋白质水平，也不会改变蛋白质的定位，但预计会适度改变蛋白质结构。CD34+红系前体细胞和红白血病细胞系HEL和K562在体外红系分化过程中ABCB6mRNA和蛋白水平升高。这些数据表明，在2号染色体连锁FP家系患者中发现的ABCB6多肽残基375位的两个错义突变可能与该病的红细胞K+泄漏特征有关。上午好。J.血醇。2013年。(C)2012年威利期刊公司。
Familial Pseudohyperkalemia (FP) is a dominant red cell trait characterized by increased serum [K+] in whole blood stored at or below room temperature, without additional hematological abnormalities. Functional gene mapping and sequencing analysis of the candidate genes within the 2q35q36 critical interval identifiedin 20 affected individuals among three multigenerational FP familiestwo novel heterozygous missense mutations in the ABCB6 gene that cosegregated with disease phenotype. The two genomic substitutions altered two adjacent nucleotides within codon 375 of ABCB6, a porphyrin transporter that, in erythrocyte membranes, bears the Langereis blood group antigen system. The ABCB6 R375Q mutation did not alter the levels of mRNA or protein, or protein localization in mature erythrocytes or erythroid precursor cells, but it is predicted to modestly alter protein structure. ABCB6 mRNA and protein levels increase during in vitro erythroid differentiation of CD34+ erythroid precursors and the erythroleukemia cell lines HEL and K562. These data suggest that the two missense mutations in residue 375 of the ABCB6 polypeptide found in affected individuals of families with chromosome 2-linked FP could contribute to the red cell K+ leak characteristic of this condition. Am. J. Hematol. 2013. (c) 2012 Wiley Periodicals, Inc.