Molecular analysis of digenic inheritance in Bartter syndrome with sensorineural deafness
Molecular analysis of digenic inheritance in Bartter syndrome with sensorineural deafness
复制标题
DOI：
10.1136/jmg.2007.052944
复制
发表时间：
2008-03-01
影响因子：
4
通讯作者：
Matsuo, M.
中科院分区：
文献类型：
--
作者：
Nozu, K.;Inagaki, T.;Matsuo, M.
背景：巴特综合征是一种伴有低血钾性代谢性碱中毒的遗传性疾病。感音神经性耳聋(SND，OMIM602522)是由编码Barttin的BSND基因突变引起的一种新的表型，Barttin是氯离子通道ClC-KA和ClC-KB的一个β亚基，被归类为IV型BS。IV型BS具有最严重的表型，导致危及生命的新生儿容量衰竭和婴儿期发生的慢性肾功能衰竭。最近的一份报告描述了一例BS合并SND，来自一个血缘关系的家庭，其CLCNKA和CLCNKB基因显示出纯合子突变。该病例提示了CLCNKA和CLCNKB基因双突变导致的BS伴SND的双基因遗传的可能性。主题和结果：本报告报道了一名来自非血缘家庭的2岁女孩，患有BS并伴有SND。在我们的病例中，鉴定出四个功能丧失突变，包括CLCNKA和CLCNKB中双亲等位基因的突变。父亲的等位基因在CLCNKA中存在无义突变(Q260X)，在CLCNKB中存在剪接点突变(IVS17+1g>；a)。母系等位基因有一个大的缺失突变(约12kbp)，从CLCNKA延伸到CLCNKB。我们的案例提供了明确的证据，CLCNKA和CLCNKB两个等位基因中的功能缺失等位基因导致的表型与BSND(IV型BS)突变的表型无法区分。结论：遗传学的最新进展使人们对许多人类遗传性疾病有了更好的了解，但大多数是单基因疾病，更复杂的遗传模式仍未解决。我们的病例提供了孟德尔遗传病范围之外的双基因遗传的明确证据。
Background: Bartter syndrome (BS) is a genetic disorder accompanied by hypokalaemic metabolic alkalosis. BS with sensorineural deafness (SND, OMIM602522) is a newly identified phenotype caused by mutations in the BSND gene that encodes barttin, a beta-subunit for chloride channel ClC-Ka and ClC-Kb and classified as type IV BS. Type IV BS features the most severe phenotype entailing life-threatening neonatal volume depletion and chronic renal failure developing during infancy. A recent report described a case of BS with SND from a consanguineous family who showed homozygous mutations in the CLCNKA and CLCNKB genes. This case indicated the possibility of the occurrence of digenic inheritance in BS with SND resulting from double mutations in the CLCNKA and CLCNKB genes. Subject and results: The current report concerns a 2year-old girl from a non-consanguineous family with BS accompanied by SND. In our case, four loss-of-function mutations, consisting of mutations in both parental alleles in both CLCNKA and CLCNKB, were identified. The paternal allele had a nonsense mutation (Q260X) in CLCNKA and a splicing site mutation (IVS17+1 g > a) in CLCNKB. The maternal allele had a large deletion mutation (about 12 kbp) extending from CLCNKA to CLCNKB. Our case provides clear evidence that loss-of-function alleles in both alleles of both CLCNKA and CLCNKB results in a phenotype indistinguishable from that of mutations in BSND (type IV BS). Conclusions: Recent advances in genetics have resulted in a better understanding of many human inherited diseases, but most of them are monogenic disorders and more complex inheritance patterns remain unresolved. Our case provides clear evidence of digenic inheritance outside the scope of Mendelian inheritance disorders.