AP1S1 missense mutations cause a congenital enteropathy via an epithelial barrier defect
- PDF / 2,495,681 Bytes
- 13 Pages / 595.276 x 790.866 pts Page_size
- 92 Downloads / 156 Views
ORIGINAL INVESTIGATION
AP1S1 missense mutations cause a congenital enteropathy via an epithelial barrier defect Katharina M. C. Klee1 · Andreas R. Janecke2,3 · Hasret A. Civan4 · Štefan Rosipal5 · Peter Heinz‑Erian2 · Lukas A. Huber1 · Thomas Müller2 · Georg F. Vogel1,2 Received: 10 February 2020 / Accepted: 10 April 2020 © The Author(s) 2020
Abstract Congenital diarrheal disorders (CDD) comprise > 50 monogenic entities featuring chronic diarrhea of early-onset, including defects in nutrient and electrolyte absorption, enterocyte polarization, enteroendocrine cell differentiation, and epithelial integrity. Diarrhea is also a predominant symptom in many immunodeficiencies, congenital disorders of glycosylation, and in some defects of the vesicular sorting and transporting machinery. We set out to identify the etiology of an intractable diarrhea in 2 consanguineous families by whole-exome sequencing, and identified two novel AP1S1 mutations, c.269T>C (p.Leu90Pro) and c.346G>A (p.Glu116Lys). AP1S1 encodes the small subunit of the adaptor protein 1 complex (AP-1), which plays roles in clathrin coat-assembly and trafficking between trans-Golgi network, endosomes and the plasma membrane. An AP1S1 knock-out (KO) of a CaCo2 intestinal cell line was generated to characterize intestinal AP1S1 deficiency as well as identified mutations by stable expression in KO background. Morphology and prototype transporter protein distribution were comparable between parental and KO cells. We observed altered localization of tight-junction proteins ZO-1 and claudin 3, decreased transepithelial electrical resistance and an increased dextran permeability of the CaCo2-AP1S1-KO monolayer. In addition, lumen formation in 3D cultures of these cells was abnormal. Re-expression of wild-type AP1S1 in CaCo2-AP1S1-KO cells reverted these abnormalities, while expression of AP1S1 containing either missense mutation did not. Our data indicate that loss of AP1S1 function causes an intestinal epithelial barrier defect, and that AP1S1 mutations can cause a non-syndromic form of congenital diarrhea, whereas 2 reported truncating AP1S1 mutations caused MEDNIK syndrome, characterized by mental retardation, enteropathy, deafness, neuropathy, ichthyosis, and keratodermia.
Introduction Katharina M. C. Klee and Andreas R. Janecke contributed equally. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00439-020-02168-w) contains supplementary material, which is available to authorized users. * Georg F. Vogel georg.vogel@i‑med.ac.at 1
Institute of Cell Biology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria
2
Department of Pediatrics I, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
3
Division of Human Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria
4
Pediatric Gastroenterology, Bakirkor Training and Research Hospital, 34140 Istanbul, Turkey
5
Pediatric Clinic of Preventive Medicine in Poprad, Jarmocna 27, 058 01 Poprad‑Veľká, Slo
Data Loading...
