Characterization of Novel WFS1 Variants in Three Diabetes Pedigrees
ChangQing Liu
Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. Endocrine and Metabolic Diseases Hospital of Shandong First Medical University. Shandong Institute of Endocrine & Metabolic Disease, Jinan, Shandong, China
Search for more papers by this authorHangYu Fang
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Search for more papers by this authorDong Wang
Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. Endocrine and Metabolic Diseases Hospital of Shandong First Medical University. Shandong Institute of Endocrine & Metabolic Disease, Jinan, Shandong, China
Search for more papers by this authorYiPing Cheng
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Search for more papers by this authorPing Shi
Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
Search for more papers by this authorChunXiao Yu
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
“Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, China
Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
Search for more papers by this authorXiaoHong Li
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
“Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, China
Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
Search for more papers by this authorHui Zhao
Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. Endocrine and Metabolic Diseases Hospital of Shandong First Medical University. Shandong Institute of Endocrine & Metabolic Disease, Jinan, Shandong, China
Search for more papers by this authorWei Hou
The Cancer Prevention and Control Hospital of Tai'an, Tai'an, Shangdong, China
Search for more papers by this authorCorresponding Author
ZhenKui Guo
Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. Endocrine and Metabolic Diseases Hospital of Shandong First Medical University. Shandong Institute of Endocrine & Metabolic Disease, Jinan, Shandong, China
Correspondence:
ZhenKui Guo ([email protected])
Chao Xu ([email protected])
QingBo Guan ([email protected])
Search for more papers by this authorCorresponding Author
Chao Xu
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
“Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, China
Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
Correspondence:
ZhenKui Guo ([email protected])
Chao Xu ([email protected])
QingBo Guan ([email protected])
Search for more papers by this authorCorresponding Author
QingBo Guan
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
“Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, China
Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
Correspondence:
ZhenKui Guo ([email protected])
Chao Xu ([email protected])
QingBo Guan ([email protected])
Search for more papers by this authorChangQing Liu
Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. Endocrine and Metabolic Diseases Hospital of Shandong First Medical University. Shandong Institute of Endocrine & Metabolic Disease, Jinan, Shandong, China
Search for more papers by this authorHangYu Fang
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Search for more papers by this authorDong Wang
Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. Endocrine and Metabolic Diseases Hospital of Shandong First Medical University. Shandong Institute of Endocrine & Metabolic Disease, Jinan, Shandong, China
Search for more papers by this authorYiPing Cheng
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Search for more papers by this authorPing Shi
Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
Search for more papers by this authorChunXiao Yu
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
“Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, China
Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
Search for more papers by this authorXiaoHong Li
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
“Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, China
Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
Search for more papers by this authorHui Zhao
Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. Endocrine and Metabolic Diseases Hospital of Shandong First Medical University. Shandong Institute of Endocrine & Metabolic Disease, Jinan, Shandong, China
Search for more papers by this authorWei Hou
The Cancer Prevention and Control Hospital of Tai'an, Tai'an, Shangdong, China
Search for more papers by this authorCorresponding Author
ZhenKui Guo
Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. Endocrine and Metabolic Diseases Hospital of Shandong First Medical University. Shandong Institute of Endocrine & Metabolic Disease, Jinan, Shandong, China
Correspondence:
ZhenKui Guo ([email protected])
Chao Xu ([email protected])
QingBo Guan ([email protected])
Search for more papers by this authorCorresponding Author
Chao Xu
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
“Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, China
Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
Correspondence:
ZhenKui Guo ([email protected])
Chao Xu ([email protected])
QingBo Guan ([email protected])
Search for more papers by this authorCorresponding Author
QingBo Guan
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
“Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, China
Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
Correspondence:
ZhenKui Guo ([email protected])
Chao Xu ([email protected])
QingBo Guan ([email protected])
Search for more papers by this authorFunding: This work was supported by the National Key Research and Development Program of China (2023YFC2506006 and 2023YFC2506000) and the Shandong Provincial Natural Science Foundation (ZR2023QH104) of China, the China Postdoctoral Science Foundation (2023TQ0202 and 2023M742158) and the Shandong Postdoctoral Science Foundation (SDBX2023035), and National Natural Science Foundation of China (82270839).
ChangQing Liu and HangYu Fang contributed equally to this work.
ABSTRACT
Background
Mutations in the WFS1 gene are implicated in Wolfram syndrome (WS), Wolfram-like syndrome (WFLS), and maturity-onset diabetes of the young (MODY). Wolfram syndrome 1 (WFS1) is a diabetes-related gene encoding wolframin, a glycoprotein with nine transmembrane domains localized in the endoplasmic reticulum. However, the relationship between WFS1 mutations and their associated phenotypes remains incompletely understood, requiring additional patient data collection for further investigation. Here we collected and analyzed clinical data from three diabetes pedigrees, and to assess the genotype-phenotype correlation.
Methods
High-throughput sequencing was employed to detect WFS1 gene mutations, followed by pathogenicity and conservation analysis using bioinformatics software. A three-dimensional wolframin protein structure was constructed to investigate the potential effects of the mutations. Moreover, the distribution of WFS1 mutations and their associated clinical phenotypes were analyzed by summarizing genetic variations of the WFS1 gene recorded in the Human Gene Mutation Database.
Results
Four heterozygous WFS1 mutations were identified in three diabetes families. Among these, c.1523_1524del/p.Y508Cfs*34 was identified as a frameshift mutation, while the others were missense mutations. Bioinformatics predictions revealed that c.766A>G/p.K256E is a benign and novel mutation, whereas the remaining mutations were classified as pathogenic. Furthermore, c.985T>A/p.F329I was validated as a MODY-associated mutation within a specific family. A comprehensive summary of all reported WFS1 mutations indicated that mutations associated with WS phenotypes are approximately 18.7 times more frequent than those associated with MODY phenotypes. Missense mutations accounted for the highest proportion of WFS1 mutations associated with different clinical phenotypes, with the majority located in exon 8.
Conclusions
This study identified a novel WFS1 mutation, c.766A>G/p.K256E, expanding the known mutation spectrum of the WFS1 gene. The findings suggest that inactivating mutations and benign missense mutations are associated with more severe WS phenotypes compared to purely pathogenic missense mutations. Moreover, c.985T>A/p.F329I was validated as a MODY associated mutation. Finally, by summarizing the genotype–phenotype relationships of WFS1, it is concluded that the WFS1 gene shows a different association with WS, WFSL and MODY.
Conflicts of Interest
The authors declare no conflicts of interest.
References
- 1C. de Muijnck, J. B. Brink, A. A. Bergen, C. J. F. Boon, and M. M. van Genderen, “Delineating Wolfram-Like Syndrome: A Systematic Review and Discussion of the WFS1-Associated Disease Spectrum,” Survey of Ophthalmology 68, no. 4 (2023): 641–654.
- 2K. Hu, M. Zatyka, D. Astuti, et al., “WFS1 Protein Expression Correlates With Clinical Progression of Optic Atrophy in Patients With Wolfram Syndrome,” Journal of Medical Genetics 59, no. 1 (2022): 65–74.
- 3H. Inoue, Y. Tanizawa, J. Wasson, et al., “A Gene Encoding a Transmembrane Protein Is Mutated in Patients With Diabetes Mellitus and Optic Atrophy (Wolfram Syndrome),” Nature Genetics 20, no. 2 (1998): 143–148.
- 4T. M. Strom, K. Hörtnagel, S. Hofmann, et al., “Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness (DIDMOAD) Caused by Mutations in a Novel Gene (Wolframin) Coding for a Predicted Transmembrane Protein,” Human Molecular Genetics 7, no. 13 (1998): 2021–2028.
- 5C. Hardy, F. Khanim, R. Torres, et al., “Clinical and Molecular Genetic Analysis of 19 Wolfram Syndrome Kindreds Demonstrating a Wide Spectrum of Mutations in WFS1,” American Journal of Human Genetics 65, no. 5 (1999): 1279–1290.
- 6C. Philbrook, E. Fritz, and H. Weiher, “Expressional and Functional Studies of Wolframin, the Gene Function Deficient in Wolfram Syndrome, in Mice and Patient Cells,” Experimental Gerontology 40, no. 8–9 (2005): 671–678.
- 7A. A. Osman, M. Saito, C. Makepeace, M. A. Permutt, P. Schlesinger, and M. Mueckler, “Wolframin Expression Induces Novel Ion Channel Activity in Endoplasmic Reticulum Membranes and Increases Intracellular Calcium,” Journal of Biological Chemistry 278, no. 52 (2003): 52755–52762.
- 8D. Takei, H. Ishihara, S. Yamaguchi, et al., “WFS1 Protein Modulates the Free ca(2+) Concentration in the Endoplasmic Reticulum,” FEBS Letters 580, no. 24 (2006): 5635–5640.
- 9S. G. Fonseca, M. Fukuma, K. L. Lipson, et al., “WFS1 Is a Novel Component of the Unfolded Protein Response and Maintains Homeostasis of the Endoplasmic Reticulum in Pancreatic Beta-Cells,” Journal of Biological Chemistry 280, no. 47 (2005): 39609–39615.
- 10L. Wang, H. Liu, X. Zhang, et al., “WFS1 Functions in ER Export of Vesicular Cargo Proteins in Pancreatic Beta-Cells,” Nature Communications 12, no. 1 (2021): 6996.
- 11C. M. Oslowski and F. Urano, “The Binary Switch That Controls the Life and Death Decisions of ER Stressed Beta Cells,” Current Opinion in Cell Biology 23, no. 2 (2011): 207–215.
- 12M. Zhu, Y. Li, G. Dong, et al., “Prevalence and Phenotypic Features of Diabetes due to Recessive, Non-Syndromic WFS1 Mutations,” European Journal of Endocrinology 186, no. 2 (2021): 163–170.
- 13F. Urano, “Wolfram Syndrome: Diagnosis, Management, and Treatment,” Current Diabetes Reports 16, no. 1 (2016): 6.
- 14T. G. Barrett, S. E. Bundey, and A. F. Macleod, “Neurodegeneration and Diabetes: UK Nationwide Study of Wolfram (DIDMOAD) Syndrome,” Lancet 346, no. 8988 (1995): 1458–1463.
- 15L. Hansen, H. Eiberg, T. Barrett, et al., “Mutation Analysis of the WFS1 Gene in Seven Danish Wolfram Syndrome Families; Four New Mutations Identified,” European Journal of Human Genetics 13, no. 12 (2005): 1275–1284.
- 16S. Kumar, “Wolfram Syndrome: Important Implications for Pediatricians and Pediatric Endocrinologists,” Pediatric Diabetes 11, no. 1 (2010): 28–37.
- 17F. Reschke, J. Rohayem, P. Maffei, et al., “Collaboration for Rare Diabetes: Understanding New Treatment Options for Wolfram Syndrome,” Endocrine 71, no. 3 (2021): 626–633.
- 18T. G. Barrett and S. E. Bundey, “Wolfram (DIDMOAD) Syndrome,” Journal of Medical Genetics 34, no. 10 (1997): 838–841.
- 19L. Rigoli, V. Caruso, G. Salzano, and F. Lombardo, “Wolfram Syndrome 1: From Genetics to Therapy,” International Journal of Environmental Research and Public Health 19, no. 6 (2022): 3225.
- 20M. Tosur and L. H. Philipson, “Precision Diabetes: Lessons Learned From Maturity-Onset Diabetes of the Young (MODY),” Journal of Diabetes Investigation 13, no. 9 (2022): 1465–1471.
- 21A. Bonnefond, R. Unnikrishnan, A. Doria, et al., “Monogenic Diabetes Nature Reviews,” Disease Primers 9, no. 1 (2023): 12.
- 22H. Liang, Y. Zhang, M. Li, et al., “Recognition of Maturity-Onset Diabetes of the Young in China,” Journal of Diabetes Investigation 12, no. 4 (2021): 501–509.
- 23 American Diabetes Association Professional Practice Committee, “2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes-2024,” Diabetes Care 47, no. Suppl 1 (2024): S20–S42.
- 24D. T. Broome, K. M. Pantalone, S. R. Kashyap, and L. H. Philipson, “Approach to the Patient With MODY-Monogenic Diabetes,” Journal of Clinical Endocrinology and Metabolism 106, no. 1 (2021): 237–250.
- 25L. L. Bonnycastle, P. S. Chines, T. Hara, et al., “Autosomal Dominant Diabetes Arising From a Wolfram Syndrome 1 Mutation,” Diabetes 62, no. 11 (2013): 3943–3950.
- 26I. Hasballa and D. Maggi, “MODY Only Monogenic? A Narrative Review of the Novel Rare and Low-Penetrant Variants,” International Journal of Molecular Sciences 25, no. 16 (2024): 8790.
- 27D. Du, A. Tuhuti, Y. Ma, et al., “Wolfram Syndrome Type 1: A Case Series,” Orphanet Journal of Rare Diseases 18, no. 1 (2023): 359.
- 28R. Chimienti, S. Torchio, G. Siracusano, et al., “A WFS1 Variant Disrupting Acceptor Splice Site Uncovers the Impact of Alternative Splicing on Beta Cell Apoptosis in a Patient With Wolfram Syndrome,” Diabetologia 68, no. 1 (2025): 128–151.
- 29K. G. Maxwell, P. Augsornworawat, L. Velazco-Cruz, et al., “Gene-Edited Human Stem Cell-Derived Beta Cells From a Patient With Monogenic Diabetes Reverse Preexisting Diabetes in Mice,” Science Translational Medicine 12, no. 540 (2020): eaax9106.
- 30L. Crouzier, A. Danese, Y. Yasui, et al., “Activation of the Sigma-1 Receptor Chaperone Alleviates Symptoms of Wolfram Syndrome in Preclinical Models,” Science Translational Medicine 14, no. 631 (2022): eabh3763.
- 31T. A. Sivakumaran and M. M. Lesperance, “A PCR-RFLP Assay for the A716T Mutation in the WFS1 Gene, a Common Cause of Low-Frequency Sensorineural Hearing Loss,” Genetic Testing 6, no. 3 (2002): 229–231.
- 32I. N. Bespalova, G. van Camp, S. J. Bom, et al., “Mutations in the Wolfram Syndrome 1 Gene (WFS1) are a Common Cause of Low Frequency Sensorineural Hearing Loss,” Human Molecular Genetics 10, no. 22 (2001): 2501–2508.
- 33H. Fukuoka, Y. Kanda, S. Ohta, and S. I. Usami, “Mutations in the WFS1 Gene Are a Frequent Cause of Autosomal Dominant Nonsyndromic Low-Frequency Hearing Loss in Japanese,” Journal of Human Genetics 52, no. 6 (2007): 510–515.
- 34S. Patergnani, M. S. Bataillard, A. Danese, et al., “The Wolfram-Like Variant WFS1(E864K) Destabilizes MAM and Compromises Autophagy and Mitophagy in Human and Mice,” Autophagy 20, no. 9 (2024): 2055–2066.
- 35T. Urakami, “Maturity-Onset Diabetes of the Young (MODY): Current Perspectives on Diagnosis and Treatment,” Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 12 (2019): 1047–1056.
- 36K. Cryns, T. A. Sivakumaran, J. M. W. van den Ouweland, et al., “Mutational Spectrum of the WFS1 Gene in Wolfram Syndrome, Nonsyndromic Hearing Impairment, Diabetes Mellitus, and Psychiatric Disease,” Human Mutation 22, no. 4 (2003): 275–287.
- 37Y. Ji, S. Wang, Y. Cheng, et al., “Identification and Characterization of Novel Compound Variants in SLC25A26 Associated With Combined Oxidative Phosphorylation Deficiency 28,” Gene 804 (2021): 145891.
- 38M. E. Blanco-Aguirre, D. R. D. la Parra, H. Tapia-Garcia, et al., “Identification of Unsuspected Wolfram Syndrome Cases Through Clinical Assessment and WFS1 Gene Screening in Type 1 Diabetes Mellitus Patients,” Gene 566, no. 1 (2015): 63–67.
- 39A. Zmyslowska, M. Borowiec, P. Fichna, et al., “Delayed Recognition of Wolfram Syndrome Frequently Misdiagnosed as Type 1 Diabetes With Early Chronic Complications,” Experimental and Clinical Endocrinology & Diabetes 122, no. 1 (2014): 35–38.
- 40M. Li, S. Wang, K. Xu, et al., “High Prevalence of a Monogenic Cause in Han Chinese Diagnosed With Type 1 Diabetes, Partly Driven by Nonsyndromic Recessive WFS1 Mutations,” Diabetes 69, no. 1 (2020): 121–126.
- 41T. Kokumai, S. Suzuki, N. Nishikawa, et al., “Early Diagnosis of Wolfram Syndrome by Ophthalmologic Screening in a Patient With Type 1B Diabetes Mellitus: A Case Report,” Journal of Clinical Research in Pediatric Endocrinology 16, no. 1 (2024): 102–105.
- 42J. Rohayem, C. Ehlers, B. Wiedemann, et al., “Diabetes and Neurodegeneration in Wolfram Syndrome: A Multicenter Study of Phenotype and Genotype,” Diabetes Care 34, no. 7 (2011): 1503–1510.
- 43A. K. Annamalai, S. Ellard, M. Shanmugam, T. P. Jai Juganya, and E. de Franco, “Juvenile Diabetes and Visual Impairment: Wolfram Syndrome,” QJM 112, no. 10 (2019): 803–804.
- 44A. Zmyslowska, W. Fendler, A. Szadkowska, et al., “Glycemic Variability in Patients With Wolfram Syndrome Is Lower Than in Type 1 Diabetes,” Acta Diabetologica 52, no. 6 (2015): 1057–1062.
- 45K. Amo-Shiinoki, K. Tanabe, W. Nishimura, et al., “Beta Cell Dedifferentiation, the Underlying Mechanism of Diabetes in Wolfram Syndrome,” Science Translational Medicine 17, no. 786 (2025): eadp2332.
- 46A. J. Vora and J. S. Lilleyman, “Wolfram Syndrome: Mitochondrial Disorder,” Lancet 342, no. 8878 (1993): 1059.
- 47C. Angebault, J. Fauconnier, S. Patergnani, et al., “ER-Mitochondria Cross-Talk Is Regulated by the ca(2+) Sensor NCS1 and Is Impaired in Wolfram Syndrome,” Science Signaling 11, no. 553 (2018): eaaq1380.
- 48M. Liiv, A. Vaarmann, D. Safiulina, et al., “ER Calcium Depletion as a Key Driver for Impaired ER-To-Mitochondria Calcium Transfer and Mitochondrial Dysfunction in Wolfram Syndrome,” Nature Communications 15, no. 1 (2024): 6143.
- 49H. J. Lee, Y. H. Jung, G. E. Choi, et al., “Urolithin A Suppresses High Glucose-Induced Neuronal Amyloidogenesis by Modulating TGM2-Dependent ER-Mitochondria Contacts and Calcium Homeostasis,” Cell Death and Differentiation 28, no. 1 (2021): 184–202.
- 50S. Lu, K. Kanekura, T. Hara, et al., “A Calcium-Dependent Protease as a Potential Therapeutic Target for Wolfram Syndrome,” Proceedings of the National Academy of Sciences of the United States of America 111, no. 49 (2014): E5292–E5301.
- 51T. Hara, J. Mahadevan, K. Kanekura, M. Hara, S. Lu, and F. Urano, “Calcium Efflux From the Endoplasmic Reticulum Leads to Beta-Cell Death,” Endocrinology 155, no. 3 (2014): 758–768.
- 52B. Yusta, L. L. Baggio, J. L. Estall, et al., “GLP-1 Receptor Activation Improves Beta Cell Function and Survival Following Induction of Endoplasmic Reticulum Stress,” Cell Metabolism 4, no. 5 (2006): 391–406.
- 53Y. Sakakibara, M. Sekiya, N. Fujisaki, X. Quan, and K. M. Iijima, “Knockdown of wfs1, a Fly Homolog of Wolfram Syndrome 1, in the Nervous System Increases Susceptibility to Age- and Stress-Induced Neuronal Dysfunction and Degeneration in Drosophila,” PLoS Genetics 14, no. 1 (2018): e1007196.
- 54G. Rossi, G. Ordazzo, N. N. Vanni, et al., “MCT1-Dependent Energetic Failure and Neuroinflammation Underlie Optic Nerve Degeneration in Wolfram Syndrome Mice,” eLife 12 (2023): 12.
- 55K. Ahuja, M. Vandenabeele, F. Nami, et al., “A Deep Phenotyping Study in Mouse and iPSC Models to Understand the Role of Oligodendroglia in Optic Neuropathy in Wolfram Syndrome,” Acta Neuropathologica Communications 12, no. 1 (2024): 140.
