Defective claudin-10 causes a novel variation of HELIX syndrome through compromised tight junction strand assembly

作     者：Sebastian Sewerin Jorg Piontek Ria Schonauer Sonja Grunewald Angelika Rauch Steffen Neuber Carsten Bergmann Dorothee Gunzel Jan Halbritte 

作者机构：Division of NephrologyUniversity of Leipzig Medical CenterLeipzig 04103Germany Clinical Physiology/Nutritional MedicineCharitee Universitatsmedizin BerlinBerlin 12203Germany Division of DermatologyVenereologyand AllergologyUniversity of Leipzig Medical CenterLeipzig 04103Germany Division of Prosthodontics and Materials ScienceUniversity of Leipzig Medical CenterLeipzig 04103Germany Center for Human GeneticsBioscientiaIngelheim 55218Germany f Medizinische Genetik MainzLimbach GeneticsMainz 55128Germany 

出 版 物：《Genes & Diseases》 (基因与疾病（英文）)

年 卷 期：2022年第9卷第5期

页      面：1301-1314页

核心收录：

学科分类：081704[工学-应用化学] 07[理学] 08[工学] 0817[工学-化学工程与技术] 070303[理学-有机化学] 0703[理学-化学] 

基　　金：supported by Deutsche Forschungsgemeinschaft(DFG)grants(No.GU 447/14-1,14-2 to DG,PI 837/4-1,4-2 to JP,and(No.HA 6908/2-1 to JH,respectively) by Else Kroner-Fresenius-Stiftung grant(No.2016_A52 to JH) JH receives additional funding from the DFG(No.6908/3-1) CB is an employee of Limbach and holds a part-time faculty appointment at the University of Freiburg His research laboratory receives support from the DFG(No.BE 3910/8-1 and BE 3910/9-1) from the Federal Ministry of Education and Research(BMBF,No.01GM1903I and 01GM1903G) 

主　　题：Claudin-10 HELIX syndrome Paracellular transport Salt-losing tubulopathy Tight junction 

摘      要：Formation of claudin-10 based tight junctions(TJs)is paramount to paracellular Na+transport in multiple *** variants in CLDN10 have been linked to HELIX syndrome,a salt-losing tubulopathy with altered handling of divalent cations accompanied by dysfunctional salivary,sweat,and lacrimal ***,we investigate molecular basis and phenotypic consequences of a newly identified homozygous CLDN10 variant that translates into a single amino acid substitution within the fourth transmembrane helix of *** addition to hypohidrosis(H),electrolyte(E)imbalance with impaired urine concentrating ability,and hypolacrimia(L),phenotypic findings include altered salivary electrolyte composition and amelogenesis imperfecta but neither ichthyosis(I)nor xerostomia(X).Employing cellular TJ reconstitution assays,we demonstrate perturbation of cis-and trans-interactions between mutant claudin-10 *** of reconstituted TJ strands show disturbed continuity and reduced abundance in the mutant ***,both major isoforms,claudin-10a and claudin-10b,are differentially affected with claudin-10b showing more severe molecular ***,expression of the mutant in renal epithelial cells with endogenous TJs results in wild-type-like ion selectivity and conductivity,indicating that aberrant claudin-10 is generally capable of forming functional paracellular ***,mutant proteins prove pathogenic by compromising claudin-10 TJ strand *** ex vivo investigations indicate their insertion into TJs to occur in a tissue-specific manner.