Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea.
نویسندگان
چکیده
Congenital sodium diarrhea (CSD) refers to an intractable diarrhea of intrauterine onset with high fecal sodium loss. CSD is clinically and genetically heterogeneous. Syndromic CSD is caused by SPINT2 mutations. While we recently described four cases of the non-syndromic form of CSD that were caused by dominant activating mutations in intestinal receptor guanylate cyclase C (GC-C), the genetic cause for the majority of CSD is still unknown. Therefore, we aimed to determine the genetic cause for non-GC-C non-syndromic CSD in 18 patients from 16 unrelated families applying whole-exome sequencing and/or chromosomal microarray analyses and/or direct Sanger sequencing. SLC9A3 missense, splicing and truncation mutations, including an instance of uniparental disomy, and whole-gene deletion were identified in nine patients from eight families with CSD. Two of these nine patients developed inflammatory bowel disease (IBD) at 4 and 16 years of age. SLC9A3 encodes Na(+)/H(+) antiporter 3 (NHE3), which is the major intestinal brush-border Na(+)/H(+) exchanger. All mutations were in the NHE3 N-terminal transport domain, and all missense mutations were in the putative membrane-spanning domains. Identified SLC9A3 missense mutations were functionally characterized in plasma membrane NHE null fibroblasts. SLC9A3 missense mutations compromised NHE3 activity by reducing basal surface expression and/or loss of basal transport function of NHE3 molecules, whereas acute regulation was normal. This study identifies recessive mutations in NHE3, a downstream target of GC-C, as a cause of CSD and implies primary basal NHE3 malfunction as a predisposition for IBD in a subset of patients.
منابع مشابه
Reduced NHE3 activity results in congenital diarrhea and can predispose to inflammatory bowel disease.
TO THE EDITORS: With great interest we read the review just published in the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology on “Novel developments in differentiating the role of renal and intestinal sodium hydrogen exchanger 3” by Dominguez Rieg and colleagues (2). The authors review recent studies that address the impact of NHE3 loss of function on renal and ...
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عنوان ژورنال:
- Human molecular genetics
دوره 24 23 شماره
صفحات -
تاریخ انتشار 2015