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 

机构地区：[1]Division of Nephrology,University of Leipzig Medical Center,Leipzig 04103,Germany [2]Clinical Physiology/Nutritional Medicine,Charitee Universitatsmedizin Berlin,Berlin 12203,Germany [3]Division of Dermatology,Venereology,and Allergology,University of Leipzig Medical Center,Leipzig 04103,Germany [4]Division of Prosthodontics and Materials Science,University of Leipzig Medical Center,Leipzig 04103,Germany [5]Center for Human Genetics,Bioscientia,Ingelheim 55218,Germany f Medizinische Genetik Mainz,Limbach Genetics,Mainz 55128,Germany

出　　处：《Genes & Diseases》2022年第5期1301-1314,共14页基因与疾病（英文）

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).

摘　　要：Formation of claudin-10 based tight junctions(TJs)is paramount to paracellular Na+transport in multiple epithelia.Sequence 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 glands.Here,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 claudin-10.In 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 proteins.Ultrastructures of reconstituted TJ strands show disturbed continuity and reduced abundance in the mutant case.Throughout,both major isoforms,claudin-10a and claudin-10b,are differentially affected with claudin-10b showing more severe molecular alterations.However,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 channels.Thus,mutant proteins prove pathogenic by compromising claudin-10 TJ strand assembly.Additional ex vivo investigations indicate their insertion into TJs to occur in a tissue-specific manner.

关 键 词：Claudin-10 HELIX syndrome Paracellular transport Salt-losing tubulopathy Tight junction 

分 类 号：O62[理学—有机化学]