Clinical Spectrum Associated with Wolfram Syndrome Type 1 and Type 2: A Review on Genotype-Phenotype Correlations

Overview

Journal Int J Environ Res Public Health

Publisher MDPI

Specialties Environmental Health
Public Health

Date 2021 May 5

PMID 33946243

Citations 19

Authors

Maurizio Delvecchio

Matteo Iacoviello

Antonino Pantaleo

Nicoletta Resta

Affiliations

Soon will be listed here.

Abstract

Wolfram syndrome is a rare neurodegenerative disorder that is typically characterized by diabetes mellitus and optic atrophy. Other common features are diabetes insipidus and hearing loss, but additional less-frequent findings may also be present. The phenotype spectrum is quite wide, and penetrance may be incomplete. The syndrome is progressive, and thus, the clinical picture may change during follow-up. Currently, two different subtypes of this syndrome have been described, and they are associated with two different disease-genes, () and . These genes encode a transmembrane protein and an endoplasmic reticulum intermembrane protein, respectively. These genes are detected in different organs and account for the pleiotropic features of this syndrome. In this review, we describe the phenotypes of both syndromes and discuss the most pertinent literature about the genotype-phenotype correlation. The clinical presentation of Wolfram syndrome type 1 suggests that the pathogenic variant does not predict the phenotype. There are few papers on Wolfram syndrome type 2 and, thus, predicting the phenotype on the basis of genotype is not yet supported. We also discuss the most pertinent approach to gene analysis.

Citing Articles

Patients with a Wide Range of Disorders Related to Gene Variants: Novel Mutations and Genotype-Phenotype Correlations.

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A WFS1 variant disrupting acceptor splice site uncovers the impact of alternative splicing on beta cell apoptosis in a patient with Wolfram syndrome.

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Wolfram Syndrome Type I Case Report and Review-Focus on Early Diagnosis and Genetic Variants.

Jurca A, Galea-Holhos L, Jurca A, Atasie D, Petchesi C, Severin E Medicina (Kaunas). 2024; 60(7).

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ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome.

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References

Chang N, Nguyen M, Germain M, Shore G . Antagonism of Beclin 1-dependent autophagy by BCL-2 at the endoplasmic reticulum requires NAF-1. EMBO J. 2009; 29(3):606-18. PMC: 2830692. DOI: 10.1038/emboj.2009.369. View

Fonseca S, Fukuma M, Lipson K, Nguyen L, Allen J, Oka Y . 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(47):39609-15. DOI: 10.1074/jbc.M507426200. View

Chen Y, Wu C, Kirby R, Kao C, Tsai T . A role for the CISD2 gene in lifespan control and human disease. Ann N Y Acad Sci. 2010; 1201:58-64. DOI: 10.1111/j.1749-6632.2010.05619.x. View

Elli F, Ghirardello S, Giavoli C, Gangi S, Dioni L, Crippa M . A new structural rearrangement associated to Wolfram syndrome in a child with a partial phenotype. Gene. 2012; 509(1):168-72. DOI: 10.1016/j.gene.2012.06.077. View

Delvecchio M, Mozzillo E, Salzano G, Iafusco D, Frontino G, Patera P . Monogenic Diabetes Accounts for 6.3% of Cases Referred to 15 Italian Pediatric Diabetes Centers During 2007 to 2012. J Clin Endocrinol Metab. 2017; 102(6):1826-1834. DOI: 10.1210/jc.2016-2490. View

Matsunaga K, Tanabe K, Inoue H, Okuya S, Ohta Y, Akiyama M . Wolfram syndrome in the Japanese population; molecular analysis of WFS1 gene and characterization of clinical features. PLoS One. 2014; 9(9):e106906. PMC: 4161373. DOI: 10.1371/journal.pone.0106906. View

Riachi M, Yilmaz S, Kurnaz E, Aycan Z, Cetinkaya S, Tranebjaerg L . Functional assessment of variants associated with Wolfram syndrome. Hum Mol Genet. 2019; 28(22):3815-3824. DOI: 10.1093/hmg/ddz212. View

Urano F . Wolfram Syndrome: Diagnosis, Management, and Treatment. Curr Diab Rep. 2016; 16(1):6. PMC: 4705145. DOI: 10.1007/s11892-015-0702-6. View

Ramadan J, Steiner S, ONeill C, Nunemaker C . The central role of calcium in the effects of cytokines on beta-cell function: implications for type 1 and type 2 diabetes. Cell Calcium. 2011; 50(6):481-90. PMC: 3223281. DOI: 10.1016/j.ceca.2011.08.005. View

10.

Papadimitriou D, Manolakos E, Bothou C, Zoupanos G, Papoulidis I, Orru S . Maternal uniparental disomy of chromosome 4 and homozygous novel mutation in the WFS1 gene in a paediatric patient with Wolfram syndrome. Diabetes Metab. 2015; 41(5):433-5. DOI: 10.1016/j.diabet.2015.06.003. View

11.

Pallotta M, Tascini G, Crispoldi R, Orabona C, Mondanelli G, Grohmann U . Wolfram syndrome, a rare neurodegenerative disease: from pathogenesis to future treatment perspectives. J Transl Med. 2019; 17(1):238. PMC: 6651977. DOI: 10.1186/s12967-019-1993-1. View

12.

Fonseca S, Ishigaki S, Oslowski C, Lu S, Lipson K, Ghosh R . Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. J Clin Invest. 2010; 120(3):744-55. PMC: 2827948. DOI: 10.1172/JCI39678. View

13.

Ajlouni K, Jarrah N, El-Khateeb M, El-Zaheri M, El Shanti H, Lidral A . Wolfram syndrome: identification of a phenotypic and genotypic variant from Jordan. Am J Med Genet. 2002; 115(1):61-5. DOI: 10.1002/ajmg.10345. View

14.

Rouzier C, Moore D, Delorme C, Lacas-Gervais S, Ait-El-Mkadem S, Fragaki K . A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions. Hum Mol Genet. 2017; 26(9):1599-1611. PMC: 5411739. DOI: 10.1093/hmg/ddx060. View

15.

Hofmann S, Philbrook C, Gerbitz K, Bauer M . Wolfram syndrome: structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product. Hum Mol Genet. 2003; 12(16):2003-12. DOI: 10.1093/hmg/ddg214. View

16.

Pourreza M, Sobhani M, Rahimi A, Aramideh M, Kajbafzadeh A, Noori-Daloii M . Homozygosity mapping and direct sequencing identify a novel pathogenic variant in the CISD2 gene in an Iranian Wolfram syndrome family. Acta Diabetol. 2019; 57(1):81-87. DOI: 10.1007/s00592-019-01381-y. View

17.

De Franco E, Flanagan S, Yagi T, Abreu D, Mahadevan J, Johnson M . Dominant ER Stress-Inducing Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts. Diabetes. 2017; 66(7):2044-2053. PMC: 5482085. DOI: 10.2337/db16-1296. View

18.

Wiley S, Andreyev A, Divakaruni A, Karisch R, Perkins G, Wall E . Wolfram Syndrome protein, Miner1, regulates sulphydryl redox status, the unfolded protein response, and Ca2+ homeostasis. EMBO Mol Med. 2013; 5(6):904-18. PMC: 3779451. DOI: 10.1002/emmm.201201429. View

19.

Pakdemirli E, Karabulut N, Bir L, Sermez Y . Cranial magnetic resonance imaging of Wolfram (DIDMOAD) syndrome. Australas Radiol. 2005; 49(2):189-91. DOI: 10.1111/j.1440-1673.2005.01420.x. View

20.

Rigoli L, Bramanti P, Di Bella C, De Luca F . Correction: Genetic and clinical aspects of Wolfram syndrome 1, a severe neurodegenerative disease. Pediatr Res. 2018; 84(5):787. DOI: 10.1038/s41390-018-0146-1. View