title: Noddy, a mouse harboring a missense mutation in protocadherin-15, reveals the impact of disrupting a critical interaction site between tip-link cadherins in inner ear hair cells.
abstract: In hair cells of the inner ear, sound or head movement increases tension in fine filaments termed tip links, which in turn convey force to mechanosensitive ion channels to open them. Tip links are formed by a tetramer of two cadherin proteins: protocadherin 15 (PCDH15) and cadherin 23 (CDH23), which have 11 and 27 extracellular cadherin (EC) repeats, respectively. Mutations in either protein cause inner ear disorders in mice and humans. We showed recently that these two cadherins bind tip-to-tip in a "handshake" mode that involves the EC1 and EC2 repeats of both proteins. However, a paucity of appropriate animal models has slowed our understanding both of the interaction and of how mutations of residues within the predicted interface compromise tip link integrity. Here, we present noddy, a new mouse model for hereditary deafness. Identified in a forward genetic screen, noddy homozygotes lack inner ear function. Mapping and sequencing showed that noddy mutant mice harbor an isoleucine-to-asparagine (I108N) mutation in the EC1 repeat of PCDH15. Residue I108 interacts with CDH23 EC2 in the handshake and its mutation impairs the interaction in vitro. The noddy mutation allowed us to determine the consequences of blocking the handshake in vivo: tip link formation and bundle morphology are disrupted, and mechanotransduction channels fail to remain open at rest. These results offer new insights into the interaction between PCDH15 and CDH23 and help explain the etiology of human deafness linked to mutations in the tip-link interface.
authors: Otolaryngology Head & Neck Surgery, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors: Ruishuang
authors: R
authors: Geng
authors: Marcos
authors: M
authors: Sotomayor
authors: Kimberly J
authors: KJ
authors: Kinder
authors: Suhasini R
authors: SR
authors: Gopal
authors: John
authors: J
authors: Gerka-Stuyt
authors: Daniel H-C
authors: DH
authors: Chen
authors: Rachel E
authors: RE
authors: Hardisty-Hughes
authors: Greg
authors: G
authors: Ball
authors: Andy
authors: A
authors: Parker
authors: Rachelle
authors: R
authors: Gaudet
authors: David
authors: D
authors: Furness
authors: Steve D
authors: SD
authors: Brown
authors: David P
authors: DP
authors: Corey
authors: Kumar N
authors: KN
authors: Alagramam
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004569:Electroencephalography; D005038:Ethylnitrosourea / Q000494:pharmacology; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects / Q000235:genetics; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005838:Genotype; D006198:Hair Cells, Auditory / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D034381:Hearing Loss / Q000139:chemically induced / Q000235:genetics; D007759:Labyrinth Diseases / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D018625:Microscopy, Atomic Force; D009153:Mutagens / Q000494:pharmacology; D020125:Mutation, Missense / Q000187:drug effects / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics*; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds
chemical_list: C418976:CDHR15 protein, mouse; D000070585:Cadherin Related Proteins; D015820:Cadherins; C499091:Cdh23 protein, mouse; C073804:FM1 43; D009153:Mutagens; D011498:Protein Precursors; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; D005038:Ethylnitrosourea; D002118:Calcium