低钾失盐性肾小管病患者WNK基因突变研究

Mutations of WNK gene in patients with hypokalemic salt-losing tubulopathies

目的通过对低钾失盐性肾小管病(SLTs)家系WNK基因外显子扩增测序,初步探讨SLTs的分子遗传学机制。方法以经CLCNKB和SLC12A3基因测序不符合典型Bartter综合征或Gitelman综合征基因型的8个SLTs家系为研究对象,抽提患者及患病/非患病亲属的外周血DNA,设计引物扩增WNK4和WNK1的外显子序列,送测序并进行序列比对。结果对8个SLTs家系的WNK基因扫描发现2个WNK1杂合错义突变,分别为Ile1172→Met(I1172M)和Ser2047→Asn(S2047N),且仅存在于家系患病者中,非患病家族成员及正常对照中均未检出。结论在8个SLTs家系患病者中发现2个伴氨基酸改变的WNK1杂合突变(I1172M和S2047N),提示WNK激酶可能是非婴儿期SLTs的第三个致病基因。

Objective To explore the molecular mechanisms involved in hypokalemic salt-losing tubulopathies （SLTs） through genetic screening of WNK gene in patients with SLTs. Methods Forty-four kindreds of SLTs were diagnosed Batter＇s syndrome or Gitelman＇s syndrome after CLCNKB and SLC12A3 sequencing and analysis,8 of whose phenotype can not be simply attributed to CLCNKB or SLC12A3 mutations. Primers for PCR-amplified exons of WNK4 and WNK1 gene in genomic DNA were designed,and direct sequencing was performed to analyse the PCR products. Results Two missense mutations of WNK1,Ile 1172→Met （I1172M） and Ser 2047→Asn （S2047N）,were identified. Both of these 2 mutations segregated with the disease in SLTs kindred. Conclusion Two heterozygote missense mutations of WNK1 gene （I1172M and S2047N） were found in 8 SLTs kindreds,indicating that WNK1 might be another gene responsible for hypokalemic salt-losing tubulopathies.