Developmental hypomyelination in Wolfram syndrome: new insights from neuroimaging and gene expression analyses
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(2019) 14:279
REVIEW
Open Access
Developmental hypomyelination in Wolfram syndrome: new insights from neuroimaging and gene expression analyses Amjad Samara1, Rachel Rahn1,2,3, Olga Neyman1, Ki Yun Park1, Ahmad Samara4, Bess Marshall5, Joseph Dougherty1,3 and Tamara Hershey1,2,6*
Abstract Wolfram syndrome is a rare multisystem disorder caused by mutations in WFS1 or CISD2 genes leading to brain structural abnormalities and neurological symptoms. These abnormalities appear in early stages of the disease. The pathogenesis of Wolfram syndrome involves abnormalities in the endoplasmic reticulum (ER) and mitochondrial dynamics, which are common features in several other neurodegenerative disorders. Mutations in WFS1 are responsible for the majority of Wolfram syndrome cases. WFS1 encodes for an endoplasmic reticulum (ER) protein, wolframin. It is proposed that wolframin deficiency triggers the unfolded protein response (UPR) pathway resulting in an increased ER stress-mediated neuronal loss. Recent neuroimaging studies showed marked alteration in early brain development, primarily characterized by abnormal white matter myelination. Interestingly, ER stress and the UPR pathway are implicated in the pathogenesis of some inherited myelin disorders like Pelizaeus-Merzbacher disease, and Vanishing White Matter disease. In addition, exploratory gene-expression network-based analyses suggest that WFS1 expression occurs preferentially in oligodendrocytes during early brain development. Therefore, we propose that Wolfram syndrome could belong to a category of neurodevelopmental disorders characterized by ER stress-mediated myelination impairment. Further studies of myelination and oligodendrocyte function in Wolfram syndrome could provide new insights into the underlying mechanisms of the Wolfram syndromeassociated brain changes and identify potential connections between neurodevelopmental disorders and neurodegeneration. Keywords: WFS1, endoplasmic reticulum stress, Unfolded protein response, Neuroimaging, Hypomyelination, Neurodevelopment, Neurodegeneration
Background Wolfram syndrome (OMIM #222300; previously known as DIDMOAD) is a rare (1 in 500,000 to 1,000,000), autosomal recessive disease initially described as a combination of early-onset diabetes mellitus, progressive optic nerve atrophy, diabetes insipidus and sensorineural hearing loss [1]. About two-thirds of the patients * Correspondence: [email protected] 1 Department of Psychiatry, Washington University School of Medicine, 4525 Scott Avenue, St. Louis, MO 63110, USA 2 Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA Full list of author information is available at the end of the article
diagnosed with Wolfram syndrome will ultimately develop all four of the clinical conditions. Other features of Wolfram syndrome include bladder and bowel dysfunction, temperature dysregulation, gait abnormalities, and loss of the senses of smell and taste. Wolfram syndrome symptoms have a negative impact on individuals’ dail
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