Clinical Characteristics and Audiological Profiles of Patients with Pathogenic Variants of WFS1
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patient Enrollment
2.2. Evaluation of Hearing Function
2.3. Genetic Analysis
2.4. Statistical Analysis
3. Results
3.1. Clinical Characteristics of Patients with WFS1 Variants
3.2. Vestibular Symptoms and Functions in DFNA6/14/38
3.3. Progression of Hearing Loss in DFNA6/14/38
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Petit, C.; Levilliers, J.; Hardelin, J.-P. Molecular Genetics of Hearing Loss. Annu. Rev. Genet. 2001, 35, 589–645. [Google Scholar] [CrossRef] [PubMed]
- Roman-Naranjo, P.; Gallego-Martinez, A.; Lopez Escamez, J.A. Genetics of vestibular syndromes. Curr. Opin. Neurol. 2018, 31, 105–110. [Google Scholar] [CrossRef] [PubMed]
- Deafness Variation Database. Available online: http://deafnessvariationdatabase.org/ (accessed on 13 October 2023).
- Azaiez, H.; Booth, K.T.; Ephraim, S.S.; Crone, B.; Black-Ziegelbein, E.A.; Marini, R.J.; Shearer, A.E.; Sloan-Heggen, C.M.; Kolbe, D.; Casavant, T.; et al. Genomic Landscape and Mutational Signatures of Deafness-Associated Genes. Am. J. Hum. Genet. 2018, 103, 484–497. [Google Scholar] [CrossRef] [PubMed]
- Bespalova, I.N.; Van Camp, G.; Bom, S.J.; Brown, D.J.; Cryns, K.; DeWan, A.T.; Erson, A.E.; Flothmann, K.; Kunst, H.P.; Kurnool, P.; et al. Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss. Hum. Mol. Genet. 2001, 10, 2501–2508. [Google Scholar] [CrossRef] [PubMed]
- Van Camp, G.; Kunst, H.; Flothmann, K.; McGuirt, W.; Wauters, J.; Marres, H.; Verstreken, M.; Bespalova, I.N.; Burmeister, M.; Van de Heyning, P.H.; et al. A gene for autosomal dominant hearing impairment (DFNA14) maps to a region on chromosome 4p16.3 that does not overlap the DFNA6 locus. J. Med. Genet. 1999, 36, 532–536. [Google Scholar] [CrossRef] [PubMed]
- Hofmann, S.; Philbrook, C.; Gerbitz, K.-D.; Bauer, M.F. Wolfram syndrome: Structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product. Hum. Mol. Genet. 2003, 12, 2003–2012. [Google Scholar] [CrossRef] [PubMed]
- Takeda, K.; Inoue, H.; Tanizawa, Y.; Matsuzaki, Y.; Oba, J.; Watanabe, Y.; Shinoda, K.; Oka, Y. WFS1 (Wolfram syndrome 1) gene product: Predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain. Hum. Mol. Genet. 2001, 10, 477–484. [Google Scholar] [CrossRef] [PubMed]
- Fonseca, S.G.; Ishigaki, S.; Oslowski, C.M.; Lu, S.; Lipson, K.L.; Ghosh, R.; Hayashi, E.; Ishihara, H.; Oka, Y.; Permutt, M.A.; et al. Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. J. Clin. Investig. 2010, 120, 744–755. [Google Scholar] [CrossRef]
- Yurimoto, S.; Hatano, N.; Tsuchiya, M.; Kato, K.; Fujimoto, T.; Masaki, T.; Kobayashi, R.; Tokumitsu, H. Identification and characterization of wolframin, the product of the wolfram syndrome gene (WFS1), as a novel calmodulin-binding protein. Biochemistry 2009, 48, 3946–3955. [Google Scholar] [CrossRef]
- Yamada, T.; Ishihara, H.; Tamura, A.; Takahashi, R.; Yamaguchi, S.; Takei, D.; Tokita, A.; Satake, C.; Tashiro, F.; Katagiri, H.; et al. WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells. Hum. Mol. Genet. 2006, 15, 1600–1609. [Google Scholar] [CrossRef]
- Fonseca, S.G.; Fukuma, M.; Lipson, K.L.; Nguyen, L.X.; Allen, J.R.; Oka, Y.; Urano, F. WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells. J. Biol. Chem. 2005, 280, 39609–39615. [Google Scholar] [CrossRef] [PubMed]
- Yamaguchi, S.; Ishihara, H.; Tamura, A.; Yamada, T.; Takahashi, R.; Takei, D.; Katagiri, H.; Oka, Y. Endoplasmic reticulum stress and N-glycosylation modulate expression of WFS1 protein. Biochem. Biophys. Res. Commun. 2004, 325, 250–256. [Google Scholar] [CrossRef]
- Zatyka, M.; Ricketts, C.; da Silva Xavier, G.; Minton, J.; Fenton, S.; Hofmann-Thiel, S.; Rutter, G.A.; Barrett, T.G. Sodium-potassium ATPase 1 subunit is a molecular partner of Wolframin, an endoplasmic reticulum protein involved in ER stress. Hum. Mol. Genet. 2008, 17, 190–200. [Google Scholar] [CrossRef] [PubMed]
- Yoshida, H.; Haze, K.; Yanagi, H.; Yura, T.; Mori, K. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J. Biol. Chem. 1998, 273, 33741–33749. [Google Scholar] [CrossRef] [PubMed]
- Hildebrand, M.S.; Sorensen, J.L.; Jensen, M.; Kimberling, W.J.; Smith, R.J. Autoimmune disease in a DFNA6/14/38 family carrying a novel missense mutation in WFS1. Am. J. Med. Genet. Part A 2008, 146A, 2258–2265. [Google Scholar] [CrossRef]
- Rigoli, L.; Lombardo, F.; Di Bella, C. Wolfram syndrome and WFS1 gene. Clin. Genet. 2011, 79, 103–117. [Google Scholar] [CrossRef] [PubMed]
- Cryns, K.; Thys, S.; Van Laer, L.; Oka, Y.; Pfister, M.; Van Nassauw, L.; Smith, R.J.; Timmermans, J.-P.; Van Camp, G. The WFS1 gene, responsible for low frequency sensorineural hearing loss and Wolfram syndrome, is expressed in a variety of inner ear cells. Histochem. Cell Biol. 2003, 119, 247–256. [Google Scholar] [CrossRef] [PubMed]
- Khanim, F.; Kirk, J.; Latif, F.; Barrett, T.G. WFS1/wolframin mutations, Wolfram syndrome, and associated diseases. Hum. Mutat. 2001, 17, 357–367. [Google Scholar] [CrossRef]
- Colosimo, A.; Guida, V.; Rigoli, L.; Di Bella, C.; De Luca, A.; Briuglia, S.; Stuppia, L.; Carmelo Salpietro, D.; Dallapiccola, B. Molecular detection of novel WFS1 mutations in patients with Wolfram syndrome by a DHPLC-based assay. Hum. Mutat. 2003, 21, 622–629. [Google Scholar] [CrossRef]
- Gasparin, M.R.R.; Crispim, F.; Paula, S.L.; Freire, M.B.S.; Dalbosco, I.S.; Manna, T.D.; Salles, J.E.N.; Gasparin, F.; Guedes, A.; Marcantonio, J.M.; et al. Identification of novel mutations of the WFS1 gene in Brazilian patients with Wolfram syndrome. Eur. J. Endocrinol. 2009, 160, 309–316. [Google Scholar] [CrossRef]
- Jung, J.; Lee, J.S.; Cho, K.J.; Yu, S.; Yoon, J.H.; Yung Gee, H.; Choi, J.Y. Genetic Predisposition to Sporadic Congenital Hearing Loss in a Pediatric Population. Sci. Rep. 2017, 7, 45973. [Google Scholar] [CrossRef]
- Song, M.H.; Jung, J.; Rim, J.H.; Choi, H.J.; Lee, H.J.; Noh, B.; Lee, J.S.; Gee, H.Y.; Choi, J.Y. Genetic Inheritance of Late-Onset, Down-Sloping Hearing Loss and Its Implications for Auditory Rehabilitation. Ear Hear. 2020, 41, 114–124. [Google Scholar] [CrossRef]
- Jung, J.; Kim, H.S.; Lee, M.G.; Yang, E.J.; Choi, J.Y. Novel COCH p.V123E Mutation, Causative of DFNA9 Sensorineural Hearing Loss and Vestibular Disorder, Shows Impaired Cochlin Post-Translational Cleavage and Secretion. Hum. Mutat. 2015, 36, 1168–1175. [Google Scholar] [CrossRef]
- Rim, J.H.; Noh, B.; Koh, Y.I.; Joo, S.Y.; Oh, K.S.; Kim, K.; Kim, J.A.; Kim, D.H.; Kim, H.Y.; Yoo, J.E.; et al. Differential genetic diagnoses of adult post-lingual hearing loss according to the audiogram pattern and novel candidate gene evaluation. Hum. Genet. 2022, 141, 915–927. [Google Scholar] [CrossRef]
- Sun, Y.; Xiang, J.; Liu, Y.; Chen, S.; Yu, J.; Peng, J.; Liu, Z.; Chen, L.; Sun, J.; Yang, Y.; et al. Increased diagnostic yield by reanalysis of data from a hearing loss gene panel. BMC Med. Genom. 2019, 12, 76. [Google Scholar] [CrossRef]
- Xiang, J.; Jin, Y.; Song, N.; Chen, S.; Shen, J.; Xie, W.; Sun, X.; Peng, Z.; Sun, Y. Comprehensive genetic testing improves the clinical diagnosis and medical management of pediatric patients with isolated hearing loss. BMC Med. Genom. 2022, 15, 142. [Google Scholar] [CrossRef]
- Oza, A.M.; DiStefano, M.T.; Hemphill, S.E.; Cushman, B.J.; Grant, A.R.; Siegert, R.K.; Shen, J.; Chapin, A.; Boczek, N.J.; Schimmenti, L.A.; et al. Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss. Hum. Mutat. 2018, 39, 1593–1613. [Google Scholar] [CrossRef]
- Cryns, K.; Sivakumaran, T.A.; Van den Ouweland, J.M.; Pennings, R.J.; Cremers, C.W.; Flothmann, K.; Young, T.L.; Smith, R.J.; Lesperance, M.M.; Camp, G.V. Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease. Hum. Mutat. 2003, 22, 275–287. [Google Scholar]
- Kasakura-Kimura, N.; Masuda, M.; Mutai, H.; Masuda, S.; Morimoto, N.; Ogahara, N.; Misawa, H.; Sakamoto, H.; Saito, K.; Matsunaga, T. WFS1 and GJB2 mutations in patients with bilateral low-frequency sensorineural hearing loss. Laryngoscope 2017, 127, E324–E329. [Google Scholar] [CrossRef]
- Kobayashi, M.; Miyagawa, M.; Nishio, S.-y.; Moteki, H.; Fujikawa, T.; Ohyama, K.; Sakaguchi, H.; Miyanohara, I.; Sugaya, A.; Naito, Y. WFS1 mutation screening in a large series of Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis. PLoS ONE 2018, 13, e0193359. [Google Scholar] [CrossRef]
- Wei, Q.; Zhu, H.; Qian, X.; Chen, Z.; Yao, J.; Lu, Y.; Cao, X.; Xing, G. Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss. J. Transl. Med. 2014, 12, 311. [Google Scholar] [CrossRef] [PubMed]
- Cryns, K.; Pfister, M.; Pennings, R.J.; Bom, S.J.; Flothmann, K.; Caethoven, G.; Kremer, H.; Schatteman, I.; Köln, K.A.; Tóth, T. Mutations in the WFS1 gene that cause low-frequency sensorineural hearing loss are small non-inactivating mutations. Hum. Genet. 2002, 110, 389–394. [Google Scholar] [CrossRef] [PubMed]
- Lim, H.D.; Lee, S.M.; Yun, Y.J.; Lee, D.H.; Lee, J.H.; Oh, S.-H.; Lee, S.-Y. WFS1 autosomal dominant variants linked with hearing loss: Update on structural analysis and cochlear implant outcome. BMC Med. Genom. 2023, 16, 79. [Google Scholar] [CrossRef] [PubMed]
- Velde, H.M.; Huizenga, X.J.; Yntema, H.G.; Haer-Wigman, L.; Beynon, A.J.; Oostrik, J.; Pegge, S.A.; Kremer, H.; Lanting, C.P.; Pennings, R.J. Genotype and Phenotype Analyses of a Novel WFS1 Variant (c. 2512C> T p.(Pro838Ser)) Associated with DFNA6/14/38. Genes 2023, 14, 457. [Google Scholar] [CrossRef] [PubMed]
- Sun, Y.; Cheng, J.; Lu, Y.; Li, J.; Lu, Y.; Jin, Z.; Dai, P.; Wang, R.; Yuan, H. Identification of two novel missense WFS1 mutations, H696Y and R703H, in patients with non-syndromic low-frequency sensorineural hearing loss. J. Genet. Genom. 2011, 38, 71–76. [Google Scholar] [CrossRef] [PubMed]
- Qian, X.; Qin, L.; Xing, G.; Cao, X. Phenotype Prediction of Pathogenic Nonsynonymous Single Nucleotide Polymorphisms in WFS1. Sci. Rep. 2015, 5, 14731. [Google Scholar] [CrossRef] [PubMed]
- Inoue, H.; Tanizawa, Y.; Wasson, J.; Behn, P.; Kalidas, K.; Bernal-Mizrachi, E.; Mueckler, M.; Marshall, H.; Donis-Keller, H.; Crock, P.; et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat. Genet. 1998, 20, 143–148. [Google Scholar] [CrossRef]
- Fukuoka, H.; Kanda, Y.; Ohta, S.; Usami, S. Mutations in the WFS1 gene are a frequent cause of autosomal dominant nonsyndromic low-frequency hearing loss in Japanese. J. Hum. Genet. 2007, 52, 510–515. [Google Scholar] [CrossRef] [PubMed]
- Rendtorff, N.D.; Lodahl, M.; Boulahbel, H.; Johansen, I.R.; Pandya, A.; Welch, K.O.; Norris, V.W.; Arnos, K.S.; Bitner-Glindzicz, M.; Emery, S.B. Identification of p. A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment. Am. J. Med. Genet. Part A 2011, 155, 1298–1313. [Google Scholar] [CrossRef]
- Rigoli, L.; Bramanti, P.; Di Bella, C.; De Luca, F. Genetic and clinical aspects of Wolfram syndrome 1, a severe neurodegenerative disease. Pediatr. Res. 2018, 83, 921–929. [Google Scholar] [CrossRef]
- Mehrparvar, A.H.; Mirmohammadi, S.J.; Ghoreyshi, A.; Mollasadeghi, A.; Loukzadeh, Z. High-frequency audiometry: A means for early diagnosis of noise-induced hearing loss. Noise Health 2011, 13, 402–406. [Google Scholar] [CrossRef]
Characteristics | Value (n = 10) |
---|---|
Age (yr) | 32.4 ± 19.9 |
Sex | |
Male | 5 (50) |
Female | 5 (50) |
Age of onset | |
1st decade | 4 (40.0) |
2nd decade | 3 (30.0) |
3rd decade | 1 (10.0) |
4th decade | 1 (10.0) |
5th decade | 1 (10.0) |
Side | |
Both | 10 (100.0) |
Pure tone average (dB HL) | |
Right | 52.8 ± 25.3 |
Left | 49.5 ± 25.1 |
Hearing loss severity | |
Normal (0–25 dB HL) | 1 (10.0) |
Mild (25–39 dB HL) | 0 (0.0) |
Moderate (40–69 dB HL) | 7 (70.0) |
Severe (70–89 dB HL) | 1 (10.0) |
Profound (>90 dB HL) | 1 (10.0) |
Pure tone audiometry pattern | |
Low/Mid | 6 (60.0) |
Flat/ski | 4 (40.0) |
Vestibular Symptoms | |
Yes | 4 (40.0) |
No | 6 (60.0) |
Gene Symbol | Individual | Age | Sex | Nucleotide Change | Amino Acid Change | Zygosity | gnomAD (EAS) | SIFT | Mutation Taster | PhyloP | GERP++ | REVEL | CADD Phred | ACMG/AMP Guideline |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
WFS1 | YUHL 30-21 | 14 | F | c.2419A>C | p.Ser807Arg | Het | Absent | Damaging | Disease Causing | Conserved | Conserved | 0.521 | 25.6 | [29] |
WFS1 | YUHL 173-21 | 24 | M | c.2515G>C | p.Val839Leu | Het | Absent | Deleterious | Disease Causing | Conserved | Conserved | 0.622 | 24.2 | Likely pathogenic (PS2, PM2, PP3, PP4) |
WFS1 | YUHL 277-21 YUHL 292-21 YUHL 1115-21 | 2 62 51 | M M F | c.1514G>C | p.Cys505Ser | Het | 0.000381 | Tolerated | Disease Causing | Conserved | Conserved | 0.731 | 16.89 | Likely pathogenic (PM2, PM5, PM6) |
WFS1 | YUHL 613-21 | 53 | M | c.2053C>T | p.Arg685Cys | Het | 0.000555 | Damaging | Disease Causing | Non-conserved | Conserved | 0.797 | 32 | Likely pathogenic (PM2, PM5, PP3, PP4) |
WFS1 | YUHL 914-21 | 24 | F | c.1480G>A | p.Gly494Ser | Het | 0.000401 | Tolerated | Disease Causing | Conserved | Conserved | 0.862 | 23.6 | [30] |
WFS1 | YUHL 1048-21 | 35 | M | c.1846G>T | p.Ala616Ser | Het | 0.000163 | Tolerated | Polymorphism | Conserved | Conserved | 0.570 | 13.98 | [31] |
WFS1 | YUHL 1143-21 | 14 | F | c.1957C>T | p.Arg653Cys | Het | 0.000551 | Damaging | Disease Causing | Non-conserved | Conserved | 0.817 | 32 | [32] |
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Jung, J.; Jang, S.H.; Won, D.; Gee, H.Y.; Choi, J.Y.; Jung, J. Clinical Characteristics and Audiological Profiles of Patients with Pathogenic Variants of WFS1. J. Clin. Med. 2024, 13, 4851. https://doi.org/10.3390/jcm13164851
Jung J, Jang SH, Won D, Gee HY, Choi JY, Jung J. Clinical Characteristics and Audiological Profiles of Patients with Pathogenic Variants of WFS1. Journal of Clinical Medicine. 2024; 13(16):4851. https://doi.org/10.3390/jcm13164851
Chicago/Turabian StyleJung, Joonho, Seung Hyun Jang, Dongju Won, Heon Yung Gee, Jae Young Choi, and Jinsei Jung. 2024. "Clinical Characteristics and Audiological Profiles of Patients with Pathogenic Variants of WFS1" Journal of Clinical Medicine 13, no. 16: 4851. https://doi.org/10.3390/jcm13164851