USH1C explained

Harmonin is a protein that in humans is encoded by the USH1C gene.^{[1] [2] [3]} It is expressed in sensory cells of the inner ear and retina, where it plays a role in hearing, balance, and vision.^{[4] [5] [6]} Mutations at the USH1C locus cause Usher syndrome type 1c and nonsyndromic sensorineural deafness.^[7]

Gene and protein structure

The USH1C gene is located on chromosome 11 and contains 28 exons. Alternative splicing generates multiple mRNA transcript variants, some of which are associated with the rare disorder phenotypes of Usher syndrome and nonsyndromic sensorineural deafness. The encoded protein harmonin has multiple protein isoforms due to the alternative splicing, including a standard isoform with 552 amino acids. Harmonin contains a PDZ domain, which assists in attaching the protein to the cell membrane and to cytoskeletal components.

Inner ear function

Harmonin is found at the apex of inner hair cells (IHCs), which convert mechanical signals from sound waves into electrical signals interpreted by the brain as sound.^[8] IHCs have an apical bundle of actin-rich stereocilia that vary in height and are connected to each other by flexible tip links. Tip links are protein complexes of cadherin 23 (CDH23) and protocadherin 15 (PCDH15). Harmonin binds to proteins that are involved in connecting the tip link to the cytoskeleton.^{[9] [10] [11]} Sound waves physically displace the  bundle towards the tallest stereocilium, stretching the tip links and causing mechanically gated ion channels to open. Influx of calcium (Ca²⁺) and potassium (K⁺) depolarizes the hair cell, triggering the release of excitatory neurotransmitters onto the innervating nerve terminals. The process is called mechanoelectrical transduction and ultimately results in the perception of sound. Intact tip links and their associated proteins, including harmonin, are required for channel activation and normal hearing.

Mutations

USH1C mutations inherited in an autosomal recessive pattern have been identified as the genetic basis of both Usher syndrome type 1c and nonsyndromic sensorineural deafness type 18 (DFNB18). A diploid individual has two alleles, or copies, of the USH1C gene, one inherited from the maternal parent and one inherited from the paternal parent. A wild type USH1C allele encodes the functional harmonin protein, whereas a mutant USH1C allele cannot. Expression of the wild type USH1C allele is dominant over the mutant USH1C allele. An individual with two wild type alleles will be unaffected, an individual with one wild type allele and one mutant allele will be an asymptomatic carrier, and an individual with two mutant alleles will experience the disorder phenotype. The molecular personality of each USH1c mutation determines whether the resulting phenotype is nonsyndromic deafness or Usher syndrome.

A common mutation that causes Usher syndrome is a single nucleotide polymorphism (SNP) at nucleotide 216 that replaces the base guanine with the base adenine, creating a frameshift with a deletion of 35 base pairs.^{[12] [13]} The 216 G to A mutation introduces a cryptic splice site that is used instead of the wild-type splice site during post-transcriptional RNA processing. The consequent mis-splicing causes the 35-nucleotide deletion in the mature mRNA transcript. Since the change in the RNA sequence is not a multiple of three, the mRNA contains a frameshift and a premature stop codon after 189 nucleotides. If the mRNA were translated, a 135-amino-acid protein would be formed instead of wild type harmonin, but there is no evidence that protein is made from the misspliced mRNA. An individual will experience Usher syndrome type 1c if they are homozygous for the 216 G to A mutant allele, which is found at high frequencies in Acadian populations.

Usher syndrome

Usher syndrome is a rare autosomal recessive disorder caused by a mutation in one of several genes involved in hearing, balance, and vision. There are multiple types of Usher syndrome that vary in severity and symptomatology depending on the affected gene. Usher syndrome type 1c is caused by a mutation at the USH1C locus and is characterized by childhood onset of bilateral sensorineural hearing loss, vestibular dysfunction, and vision loss from retinitis pigmentosa. Usher syndrome type 1 is the most severe form of Usher syndrome.^[14] The prevalence of Usher syndrome is approximately 3-6 in 100,000 live births, rendering the disorder the most common cause of comorbid hearing and vision loss. Usher syndrome type 1c is prevalent in Acadian populations but is found worldwide.^[15] Although there is no cure, studies to evaluate potential gene therapies are ongoing.

Gene therapy

Human hearing develops by 19 weeks gestation.^[16] At birth, individuals with Usher syndrome type 1c already have sensorineural hearing loss from mutant harmonin, and mammalian hearing loss is presently irreversible. It is hypothesized that gene therapy to correct the USH1C mutation and restore the wild type harmonin protein is most effective during the critical developmental window that is hypothesized to close one week before hearing onset.^[17] Studies of mouse models of Usher syndrome type 1c note that hearing develops in mice at postnatal day 12.^[18] Gene therapy to deliver an antisense oligonucleotide to the mouse inner ear rescued wild type harmonin mRNA splicing as well as hearing and vestibular function when delivered at embryonic day 12.5 or postnatal days 1-5 but was significantly less effective thereafter. The antisense oligonucleotide sequence is complementary to a segment of the 216 G to A mutant mRNA and mechanically blocks the cryptic splice site so that the wild type splice site is used. Likewise, gene therapy to deliver an adeno-associated viral (AAV) vector encoding wild type harmonin to the mouse inner ear rescued hearing and vestibular function when delivered on postnatal days 0-1 but was ineffective at postnatal days 10-12.^[19]

Gene therapy is controversial due to ethical and social considerations.^{[20] [21] [22]} For example, some members of the deaf community embrace hearing loss as a positive aspect of their identity and culture that they do not wish to change, whereas other members seek therapeutic interventions. However, there is widespread interest in developing gene therapies to provide treatment options for patients, especially when the symptoms of a genetic disorder are debilitating and difficult to manage with conventional strategies.

Further reading

• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–174 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–156 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Scanlan MJ, Chen YT, Williamson B, Gure AO, Stockert E, Gordan JD, Türeci O, Sahin U, Pfreundschuh M, Old LJ . 6 . Characterization of human colon cancer antigens recognized by autologous antibodies . International Journal of Cancer . 76 . 5 . 652–658 . May 1998 . 9610721 . 10.1002/(SICI)1097-0215(19980529)76:5<652::AID-IJC7>3.0.CO;2-P . free .
• Jain PK, Lalwani AK, Li XC, Singleton TL, Smith TN, Chen A, Deshmukh D, Verma IC, Smith RJ, Wilcox ER . 6 . A gene for recessive nonsyndromic sensorineural deafness (DFNB18) maps to the chromosomal region 11p14-p15.1 containing the Usher syndrome type 1C gene . Genomics . 50 . 2 . 290–292 . June 1998 . 9653658 . 10.1006/geno.1998.5320 .
• Saouda M, Mansour A, Bou Moglabey Y, El Zir E, Mustapha M, Chaib H, Nehmé A, Mégarbané A, Loiselet J, Petit C, Slim R . 6 . The Usher syndrome in the Lebanese population and further refinement of the USH2A candidate region . Human Genetics . 103 . 2 . 193–198 . August 1998 . 9760205 . 10.1007/s004390050806 . 6040572 .
• Scanlan MJ, Williamson B, Jungbluth A, Stockert E, Arden KC, Viars CS, Gure AO, Gordan JD, Chen YT, Old LJ . 6 . Isoforms of the human PDZ-73 protein exhibit differential tissue expression . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1445 . 1 . 39–52 . April 1999 . 10209257 . 10.1016/s0167-4781(99)00033-0 .
• Kobayashi I, Imamura K, Kubota M, Ishikawa S, Yamada M, Tonoki H, Okano M, Storch WB, Moriuchi T, Sakiyama Y, Kobayashi K . 6 . Identification of an autoimmune enteropathy-related 75-kilodalton antigen . Gastroenterology . 117 . 4 . 823–830 . October 1999 . 10500064 . 10.1016/S0016-5085(99)70340-9 . free .
• Scanlan MJ, Gordan JD, Williamson B, Stockert E, Bander NH, Jongeneel V, Gure AO, Jäger D, Jäger E, Knuth A, Chen YT, Old LJ . 6 . Antigens recognized by autologous antibody in patients with renal-cell carcinoma . International Journal of Cancer . 83 . 4 . 456–464 . November 1999 . 10508479 . 10.1002/(SICI)1097-0215(19991112)83:4<456::AID-IJC4>3.0.CO;2-5 . free .
• Bitner-Glindzicz M, Lindley KJ, Rutland P, Blaydon D, Smith VV, Milla PJ, Hussain K, Furth-Lavi J, Cosgrove KE, Shepherd RM, Barnes PD, O'Brien RE, Farndon PA, Sowden J, Liu XZ, Scanlan MJ, Malcolm S, Dunne MJ, Aynsley-Green A, Glaser B . 6 . A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene . Nature Genetics . 26 . 1 . 56–60 . September 2000 . 10973248 . 10.1038/79178 . 2237489 .
• Zwaenepoel I, Verpy E, Blanchard S, Meins M, Apfelstedt-Sylla E, Gal A, Petit C . Identification of three novel mutations in the USH1C gene and detection of thirty-one polymorphisms used for haplotype analysis . Human Mutation . 17 . 1 . 34–41 . 2001 . 11139240 . 10.1002/1098-1004(2001)17:1<34::AID-HUMU4>3.0.CO;2-O . 10069513 .
• Ishikawa S, Kobayashi I, Hamada J, Tada M, Hirai A, Furuuchi K, Takahashi Y, Ba Y, Moriuchi T . 6 . Interaction of MCC2, a novel homologue of MCC tumor suppressor, with PDZ-domain Protein AIE-75 . Gene . 267 . 1 . 101–110 . April 2001 . 11311560 . 10.1016/S0378-1119(01)00378-X .
• Ahmed ZM, Riazuddin S, Bernstein SL, Ahmed Z, Khan S, Griffith AJ, Morell RJ, Friedman TB, Riazuddin S, Wilcox ER . 6 . Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F . American Journal of Human Genetics . 69 . 1 . 25–34 . July 2001 . 11398101 . 1226045 . 10.1086/321277 .
• Savas S, Frischhertz B, Pelias MZ, Batzer MA, Deininger PL, Keats BB . The USH1C 216G-->A mutation and the 9-repeat VNTR(t,t) allele are in complete linkage disequilibrium in the Acadian population . Human Genetics . 110 . 1 . 95–97 . January 2002 . 11810303 . 10.1007/s00439-001-0653-7 . 39688683 .
• Ouyang XM, Xia XJ, Verpy E, Du LL, Pandya A, Petit C, Balkany T, Nance WE, Liu XZ . 6 . Mutations in the alternatively spliced exons of USH1C cause non-syndromic recessive deafness . Human Genetics . 111 . 1 . 26–30 . July 2002 . 12136232 . 10.1007/s00439-002-0736-0 . 8137208 .
• Siemens J, Kazmierczak P, Reynolds A, Sticker M, Littlewood-Evans A, Müller U . The Usher syndrome proteins cadherin 23 and harmonin form a complex by means of PDZ-domain interactions . Proceedings of the National Academy of Sciences of the United States of America . 99 . 23 . 14946–14951 . November 2002 . 12407180 . 137525 . 10.1073/pnas.232579599 . free . 2002PNAS...9914946S .
• Boëda B, El-Amraoui A, Bahloul A, Goodyear R, Daviet L, Blanchard S, Perfettini I, Fath KR, Shorte S, Reiners J, Houdusse A, Legrain P, Wolfrum U, Richardson G, Petit C . 6 . Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle . The EMBO Journal . 21 . 24 . 6689–6699 . December 2002 . 12485990 . 139109 . 10.1093/emboj/cdf689 .
• Weil D, El-Amraoui A, Masmoudi S, Mustapha M, Kikkawa Y, Lainé S, Delmaghani S, Adato A, Nadifi S, Zina ZB, Hamel C, Gal A, Ayadi H, Yonekawa H, Petit C . 6 . Usher syndrome type I G (USH1G) is caused by mutations in the gene encoding SANS, a protein that associates with the USH1C protein, harmonin . Human Molecular Genetics . 12 . 5 . 463–471 . March 2003 . 12588794 . 10.1093/hmg/ddg051 . free .

External links

• GeneReviews/NCBI/NIH/UW entry on Usher Syndrome Type I

Notes and References

1. Verpy E, Leibovici M, Zwaenepoel I, Liu XZ, Gal A, Salem N, Mansour A, Blanchard S, Kobayashi I, Keats BJ, Slim R, Petit C . 6 . A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C . Nature Genetics . 26 . 1 . 51–55 . September 2000 . 10973247 . 10.1038/79171 . 9383331 .
2. Ahmed ZM, Smith TN, Riazuddin S, Makishima T, Ghosh M, Bokhari S, Menon PS, Deshmukh D, Griffith AJ, Riazuddin S, Friedman TB, Wilcox ER . 6 . Nonsyndromic recessive deafness DFNB18 and Usher syndrome type IC are allelic mutations of USHIC . Human Genetics . 110 . 6 . 527–531 . June 2002 . 12107438 . 10.1007/s00439-002-0732-4 . 24276167 .
3. Web site: Entrez Gene: USH1C Usher syndrome 1C (autosomal recessive, severe).
4. Bitner-Glindzicz M, Lindley KJ, Rutland P, Blaydon D, Smith VV, Milla PJ, Hussain K, Furth-Lavi J, Cosgrove KE, Shepherd RM, Barnes PD, O'Brien RE, Farndon PA, Sowden J, Liu XZ, Scanlan MJ, Malcolm S, Dunne MJ, Aynsley-Green A, Glaser B . 6 . A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene . Nature Genetics . 26 . 1 . 56–60 . September 2000 . 10973248 . 10.1038/79178 . 2237489 .
5. Gregory FD, Bryan KE, Pangršič T, Calin-Jageman IE, Moser T, Lee A . Harmonin inhibits presynaptic Cav1.3 Ca²⁺ channels in mouse inner hair cells . Nature Neuroscience . 14 . 9 . 1109–1111 . August 2011 . 21822269 . 3164920 . 10.1038/nn.2895 .
6. Gregory FD, Pangrsic T, Calin-Jageman IE, Moser T, Lee A . Harmonin enhances voltage-dependent facilitation of Cav1.3 channels and synchronous exocytosis in mouse inner hair cells . The Journal of Physiology . 591 . 13 . 3253–3269 . July 2013 . 23613530 . 3717226 . 10.1113/jphysiol.2013.254367 .
7. Millán JM, Aller E, Jaijo T, Blanco-Kelly F, Gimenez-Pardo A, Ayuso C . An update on the genetics of usher syndrome . Journal of Ophthalmology . 2011 . 417217 . 2010-12-23 . 21234346 . 3017948 . 10.1155/2011/417217 . free .
8. Grillet N, Xiong W, Reynolds A, Kazmierczak P, Sato T, Lillo C, Dumont RA, Hintermann E, Sczaniecka A, Schwander M, Williams D, Kachar B, Gillespie PG, Müller U . 6 . Harmonin mutations cause mechanotransduction defects in cochlear hair cells . English . Neuron . 62 . 3 . 375–387 . May 2009 . 19447093 . 2691393 . 10.1016/j.neuron.2009.04.006 .
9. Boëda B, El-Amraoui A, Bahloul A, Goodyear R, Daviet L, Blanchard S, Perfettini I, Fath KR, Shorte S, Reiners J, Houdusse A, Legrain P, Wolfrum U, Richardson G, Petit C . 6 . Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle . The EMBO Journal . 21 . 24 . 6689–6699 . December 2002 . 12485990 . 139109 . 10.1093/emboj/cdf689 .
10. Siemens J, Kazmierczak P, Reynolds A, Sticker M, Littlewood-Evans A, Müller U . The Usher syndrome proteins cadherin 23 and harmonin form a complex by means of PDZ-domain interactions . Proceedings of the National Academy of Sciences of the United States of America . 99 . 23 . 14946–14951 . November 2002 . 12407180 . 137525 . 10.1073/pnas.232579599 . 2002PNAS...9914946S . free .
11. Yu IM, Planelles-Herrero VJ, Sourigues Y, Moussaoui D, Sirkia H, Kikuti C, Stroebel D, Titus MA, Houdusse A . 6 . Myosin 7 and its adaptors link cadherins to actin . Nature Communications . 8 . 1 . 15864 . June 2017 . 28660889 . 5493754 . 10.1038/ncomms15864 . 2017NatCo...815864Y .
12. Lentz J, Savas S, Ng SS, Athas G, Deininger P, Keats B . The USH1C 216G-->A splice-site mutation results in a 35-base-pair deletion . Human Genetics . 116 . 3 . 225–227 . February 2005 . 15578223 . 10.1007/s00439-004-1217-4 . 31987210 .
13. Wang L, Kempton JB, Jiang H, Jodelka FM, Brigande AM, Dumont RA, Rigo F, Lentz JJ, Hastings ML, Brigande JV . 6 . Fetal antisense oligonucleotide therapy for congenital deafness and vestibular dysfunction . Nucleic Acids Research . 48 . 9 . 5065–5080 . May 2020 . 32249312 . 7229850 . 10.1093/nar/gkaa194 .
14. Reiners J, Nagel-Wolfrum K, Jürgens K, Märker T, Wolfrum U . Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease . Experimental Eye Research . 83 . 1 . 97–119 . July 2006 . 16545802 . 10.1016/j.exer.2005.11.010 .
15. de Joya EM, Colbert BM, Tang PC, Lam BL, Yang J, Blanton SH, Dykxhoorn DM, Liu X . 6 . Usher Syndrome in the Inner Ear: Etiologies and Advances in Gene Therapy . International Journal of Molecular Sciences . 22 . 8 . 3910 . April 2021 . 33920085 . 8068832 . 10.3390/ijms22083910 . free .
16. Locher H, Frijns JH, van Iperen L, de Groot JC, Huisman MA, Chuva de Sousa Lopes SM . Neurosensory development and cell fate determination in the human cochlea . Neural Development . 8 . 1 . 20 . October 2013 . 24131517 . 3854452 . 10.1186/1749-8104-8-20 . free .
17. Ponnath A, Depreux FF, Jodelka FM, Rigo F, Farris HE, Hastings ML, Lentz JJ . Rescue of Outer Hair Cells with Antisense Oligonucleotides in Usher Mice Is Dependent on Age of Treatment . Journal of the Association for Research in Otolaryngology . 19 . 1 . 1–16 . February 2018 . 29027038 . 5783922 . 10.1007/s10162-017-0640-x .
18. Shnerson A, Willott JF . Ontogeny of the acoustic startle response in C57BL/6J mouse pups . Journal of Comparative and Physiological Psychology . 94 . 1 . 36–40 . February 1980 . 7372853 . 10.1037/h0077648 .
19. Pan B, Askew C, Galvin A, Heman-Ackah S, Asai Y, Indzhykulian AA, Jodelka FM, Hastings ML, Lentz JJ, Vandenberghe LH, Holt JR, Géléoc GS . 6 . Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c . Nature Biotechnology . 35 . 3 . 264–272 . March 2017 . 28165476 . 5340578 . 10.1038/nbt.3801 .
20. Web site: Katz S . 2020 . Why deaf people oppose using gene editing to "cure" deafness . 2022-05-08 . Discover Magazine . en.
21. Web site: Mullin E . 2021-01-26 . Gene therapy could end deafness. Should it? . 2022-05-08 . Future Human . en.
22. Gonçalves GA, Paiva RM . Gene therapy: advances, challenges and perspectives . Einstein . 15 . 3 . 369–375 . 2017 . 29091160 . 5823056 . 10.1590/S1679-45082017RB4024 .