WS1 gene mutation analysis of Wolfram syndrome in a Chinese patient and a systematic review of literatures

Yu, Guang; Ming, Yu; Wang, Jiafeng; Cong-rong, Gao; Chen, Zhong-jin

doi:10.1007/s12020-010-9350-4

Cited by 18 publications

(11 citation statements)

References 29 publications

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“…Diabetes mellitus was believed to occur in the first decade of life, OA during the early second decade, DI and HL during the second decade, and urological and neurological abnormalities during 10–30 years ( 2 , 16 , 18 , 20 , 21 ). In our cohort, DM was almost developed in the early first decade, IGT developed in one’s 19 years.…”

Section: Discussionmentioning

confidence: 99%

Clinical Characteristics of Wolfram Syndrome in Chinese Population and a Novel Frameshift Mutation in WFS1

Duan

Tong

et al. 2018

Front. Endocrinol.

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ObjectiveWolfram syndrome (WS) is a rare, degenerative, and hereditary disorder characterized by ear diabetes mellitus (DM) and optic atrophy (OA). We aim to characterize clinical features in Chinese patients who had been poorly studied until now.MethodsWe performed a retrospective review of patients with WS seen in the Peking Union Medical College Hospital from 2002 to 2017. Data including demographic data, clinical presentations, examination results, family history, and genetic analysis were described.ResultsSix patients with WS were identified, meeting the diagnostic criteria of the coincidence of DM and OA before 15 years old or the existence of two WFS1 mutations. All were male, with the median age of 14.5 years (range 10–19 years). Blood glucose impairment, OA, and diabetes insipidus were present in all (100%), hearing impairment in four (66.7%), urological abnormalities in four (66.7%), neurological abnormalities in one (16.7%), and endocrine disorder in one (16.7%). Rare presentation includes cataract, glaucoma, and spina bifida occulta. Diabetes was insulin-dependent and not ketosis onset, with antibody to glutamic acid decarboxylase and islet cell negative. Genetic analysis revealed mutations in WFS1 in three patients. A novel frameshift mutation (p.Asp151Glufs*93) was identified in exon 4 of WFS1.ConclusionOur series of WS patients indicated that WS is a degenerative disease with a wide and variable spectrum, characterized by ear non-autoimmune DM and bilateral OA. Genetic analysis is recommended when suspected of WS.

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Section: Discussionmentioning

confidence: 99%

Clinical Characteristics of Wolfram Syndrome in Chinese Population and a Novel Frameshift Mutation in WFS1

Duan

Tong

et al. 2018

Front. Endocrinol.

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“…Currently, over 200 distinct mutations have been identified in WS patients, most of which are located in exon 8 [19], particularly, in the region that encodes for the transmembrane and C-terminal domain of the protein [3, 20, 21]. It has been established that WFS1 is important for maintaining ER homeostasis, but the mechanisms are still unclear [22].…”

Section: Etiology: Genetic Background Molecular Biology and Pathophymentioning

confidence: 99%

Wolfram syndrome, a rare neurodegenerative disease: from pathogenesis to future treatment perspectives

et al. 2019

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Background Wolfram syndrome (WS), a rare genetic disorder, is considered the best prototype of endoplasmic reticulum (ER) diseases. Classical WS features are childhood-onset diabetes mellitus, optic atrophy, deafness, diabetes insipidus, neurological signs, and other abnormalities. Two causative genes ( WFS1 and WFS2 ) have been identified. The transmission of the disease takes place in an autosomal recessive mode but autosomal dominant mutations responsible for WS-related disorders have been described. Prognosis is poor, death occurs at the median age of 39 years with a major cause represented by respiratory failure as a consequence of brain stem atrophy and neurodegeneration. The aim of this narrative review is to focus on etiology, pathogenesis and natural history of WS for an adequate patient management and for the discussion of future therapeutic interventions. Main body WS requires a multidisciplinary approach in order to be successfully treated. A prompt diagnosis decreases morbidity and mortality through prevention and treatment of complications. Being a monogenic pathology, WS represents a perfect model to study the mechanisms of ER stress and how this condition leads to cell death, in comparison with other prevalent diseases in which multiple factors interact to produce the disease manifestations. WS is also an important disease prototype to identify drugs and molecules associated with ER homeostasis. Evidence indicates that specific metabolic diseases (type 1 and type 2 diabetes), neurodegenerative diseases, atherosclerosis, inflammatory pathologies and also cancer are closely related to ER dysfunction. Conclusions Therapeutic strategies in WS are based on drug repurposing (i.e., investigation of approved drugs for novel therapeutic indications) with the aim to stop the progression of the disease by reducing the endoplasmic reticulum stress. An extensive understanding of WS from pathophysiology to therapy is fundamental and more studies are necessary to better manage this devastating disease and guarantee the patients a better quality of life and longer life expectancy.

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“…In 2010, 219 WS patients had been described with 172 different reported mutations in WFS1 , mostly (83%) in exon 8 [7], [8], [9]. Patient genotype do not present any mutation hotspot, highlighting the need to sequence first exon 8 for molecular diagnosis [10].…”

Section: Introductionmentioning

confidence: 99%

Impairment of Visual Function and Retinal ER Stress Activation in Wfs1-Deficient Mice

et al. 2014

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Wolfram syndrome is an early onset genetic disease (1/180,000) featuring diabetes mellitus and optic neuropathy, associated to mutations in the WFS1 gene. Wfs1−/− mouse model shows pancreatic beta cell atrophy, but its visual performance has not been investigated, prompting us to study its visual function and histopathology of the retina and optic nerve. Electroretinogram and visual evoked potentials (VEPs) were performed in Wfs1−/− and Wfs1+/+ mice at 3, 6, 9 and 12 months of age. Fundi were pictured with Micron III apparatus. Retinal ganglion cell (RGC) abundance was determined from Brn3a immunolabeling of retinal sections. RGC axonal loss was quantified by electron microscopy in transversal optic nerve sections. Endoplasmic reticulum stress was assessed using immunoglobulin binding protein (BiP), protein disulfide isomerase (PDI) and inositol-requiring enzyme 1 alpha (Ire1α) markers. Electroretinograms amplitudes were slightly reduced and latencies increased with time in Wfs1−/− mice. Similarly, VEPs showed decreased N+P amplitudes and increased N-wave latency. Analysis of unfolded protein response signaling revealed an activation of endoplasmic reticulum stress in Wfs1 −/− mutant mouse retinas. Altogether, progressive VEPs alterations with minimal neuronal cell loss suggest functional alteration of the action potential in the Wfs1 −/− optic pathways.

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WS1 gene mutation analysis of Wolfram syndrome in a Chinese patient and a systematic review of literatures

Cited by 18 publications

References 29 publications

Clinical Characteristics of Wolfram Syndrome in Chinese Population and a Novel Frameshift Mutation in WFS1

Clinical Characteristics of Wolfram Syndrome in Chinese Population and a Novel Frameshift Mutation in WFS1

Wolfram syndrome, a rare neurodegenerative disease: from pathogenesis to future treatment perspectives

Impairment of Visual Function and Retinal ER Stress Activation in Wfs1-Deficient Mice

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