Genomics of Wolfram Syndrome 1 (WFS1)

Kõks, Sulev

doi:10.3390/biom13091346

Cited by 12 publications

(8 citation statements)

References 79 publications

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“…However, this syndrome is more severe than CLSD, because it presents spastic quadriplegia with multiple contractures, seizures, and pseudobulbar palsy. Generally, other conditions, which have defective ER-Golgi network as their physiopathological basis, like Wolfram syndrome, also exhibit neurological and psychiatric alterations [28]. From these observations, it can be deducible that genetic defects leading to ER stress can generally cause neurological and psychiatric abnormalities, as reported in the literature [6].…”

Section: Discussionmentioning

confidence: 90%

First Case of a Dominant De Novo SEC23A Mutation with Neurological and Psychiatric Features: New Insights into Cranio-Lenticulo-Sutural Dysplasia with Literature Review

Minale,

De Falco,

Agolini

et al. 2024

Genes

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Cranio-lenticulo-sutural dysplasia (CLSD, OMIM #607812) is a rare genetic condition characterized by late-closing fontanels, skeletal defects, dysmorphisms, and congenital cataracts that are caused by bi-allelic or monoallelic variants in the SEC23A gene. Autosomal recessive inheritance (AR-CLSD) has been extensively documented in several cases with homozygous or compound heterozygous variants in SEC23A, whereas autosomal dominant inheritance (AD-CLSD) involving heterozygous inherited variants has been reported just in three patients. The SEC23A gene encodes for one of the main components of a protein coat complex known as coat-protein-complex II (COPII), responsible for the generation of the envelope of the vesicles exported from the endoplasmic reticulum (ER) toward the Golgi complex (GC). AR-CLSD and AD-CLSD exhibit common features, although each form also presents distinctive and peculiar characteristics. Herein, we describe a rare case of a 10-year-old boy with a history of an anterior fontanel that closed only at the age of 9. The patient presents with short proportionate stature, low weight, and neurological impairment, including intellectual disability, global developmental delay, abnormal coordination, dystonia, and motor tics, along with dysmorphisms such as a wide anterior fontanel, hypertelorism, frontal bossing, broad nose, high-arched palate, and micrognathia. Trio clinical exome was performed, and a de novo heterozygous missense variant in SEC23A (p.Arg716Cys) was identified. This is the first reported case of CLSD caused by a de novo heterozygous missense variant in SEC23A presenting specific neurological manifestations never described before. For the first time, we have conducted a comprehensive phenotype–genotype correlation using data from our patient and the eight most well-documented cases in the literature. Our work has allowed us to identify the main specific and characteristic signs of both forms of CLSD (AR-CLSD, AD CLSD), offering valuable insights that can guide physicians in the diagnostic process. Notably, detailed descriptions of neurological features such as intellectual disability, global developmental delay, and motor impairment have not been documented before. Furthermore, our literature overview is crucial in the current landscape of CLSD due to the absence of guidelines for the clinical diagnosis and proper follow-up of these patients, especially during childhood.

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Section: Discussionmentioning

confidence: 90%

First Case of a Dominant De Novo SEC23A Mutation with Neurological and Psychiatric Features: New Insights into Cranio-Lenticulo-Sutural Dysplasia with Literature Review

Minale,

De Falco,

Agolini

et al. 2024

Genes

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“…Wolfram syndrome 1 (WFS1) is a rare autosomal recessive genetic disorder characterized by diabetes insipidus, diabetes mellites, optic atrophy, and deafness [ 105 , 106 , 107 ]. The WFS1 gene encodes the protein wolframin, an ER localized glycoprotein that has been linked to β-cell ER stress, Ca 2+ ER handling, and proteostasis.…”

Section: Mutations That Affect Ca 2+ Er ...mentioning

confidence: 99%

“…The WFS1 gene encodes the protein wolframin, an ER localized glycoprotein that has been linked to β-cell ER stress, Ca 2+ ER handling, and proteostasis. To date, there are over 200 mutations in WSF1 that result in a loss of function (LOF) and cause WFS1 [ 105 , 108 ]. Patients with two LOF WSF1 mutations show diabetic phenotypes, and carriers with one WSF1 LOF allele show an increased risk for developing T2D [ 109 ].…”

Section: Mutations That Affect Ca 2+ Er ...mentioning

confidence: 99%

Disrupted Endoplasmic Reticulum Ca2+ Handling: A Harβinger of β-Cell Failure

Dobson,

Jacobson

2024

Biology

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The β-cell workload increases in the setting of insulin resistance and reduced β-cell mass, which occurs in type 2 and type 1 diabetes, respectively. The prolonged elevation of insulin production and secretion during the pathogenesis of diabetes results in β-cell ER stress. The depletion of β-cell Ca2+ER during ER stress activates the unfolded protein response, leading to β-cell dysfunction. Ca2+ER is involved in many pathways that are critical to β-cell function, such as protein processing, tuning organelle and cytosolic Ca2+ handling, and modulating lipid homeostasis. Mutations that promote β-cell ER stress and deplete Ca2+ER stores are associated with or cause diabetes (e.g., mutations in ryanodine receptors and insulin). Thus, improving β-cell Ca2+ER handling and reducing ER stress under diabetogenic conditions could preserve β-cell function and delay or prevent the onset of diabetes. This review focuses on how mechanisms that control β-cell Ca2+ER are perturbed during the pathogenesis of diabetes and contribute to β-cell failure.

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“…Given the monogenic cause of the disease, research efforts have focused on elucidating the role of the WFS1 protein in WS pathogenesis. In Wolfram patients, loss-of-function and missense mutations lead to a complete absence or a decreased stability of the WFS1 protein, suggesting that WS is caused by a loss of WFS1 function [19, 23]. WFS1 encodes for an endoplasmic reticulum (ER) membrane protein that resides at the mitochondria-associated ER membranes (MAMs) [12, 35].…”

Section: Introductionmentioning

confidence: 99%

“…Wolfram syndrome (WS) type 1 is a rare hereditary disease affecting 1 in 770.000 newborns that, in most cases, is caused by recessive mutations in the Wolfram syndrome 1 ( WFS1) gene [23, 69]. The disease symptoms are often referred to as ‘DIDMOAD’, an acronym of diabetes insipidus, diabetes mellitus, optic atrophy and deafness.…”

Section: Introductionmentioning

confidence: 99%

A deep phenotyping study in mouse and iPSC models to understand the role of oligodendroglia in optic neuropathy in Wolfram syndrome

Ahuja,

Vandenabeele,

Nami

et al. 2024

Preprint

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Wolfram syndrome (WS) is a rare childhood disease characterized by diabetes mellitus, diabetes insipidus, blindness, deafness, neurodegeneration and eventually early death, due to autosomal recessive mutations in theWFS1(andWFS2) gene. While it is categorized as a neurodegenerative disease, it is increasingly becoming clear that other cell types besides neurons may be affected and contribute to the pathogenesis. MRI studies in patients and phenotyping studies in WS rodent models indicate white matter/myelin loss, implicating a role for oligodendroglia in WS-associated neurodegeneration. In this study, we sought to determine if oligodendroglia are affected in WS and whether their dysfunction may be the primary cause of the observed optic neuropathy and brain neurodegeneration. We demonstrate that 7.5-month-oldWfs1Δexon8mice display signs of abnormal myelination and a reduced number of oligodendrocyte precursor cells (OPCs) as well as abnormal axonal conduction in the optic nerve. An MRI study of the brain furthermore revealed grey and white matter loss in the cerebellum, brainstem, and superior colliculus, as is seen in WS patients. To further dissect the role of oligodendroglia in WS, we performed a transcriptomics study of WS patient iPSC-derived OPCs and pre-myelinating oligodendrocytes. Transcriptional changes compared to isogenic control cells were found for genes with a role in ER function. However, a deep phenotyping study of these WS patient iPSC-derived oligodendroglia unveiled normal differentiation, mitochondria-associated endoplasmic reticulum (ER) membrane interactions and mitochondrial function, and no overt signs of ER stress. Overall, the current study indicates that oligodendroglia functions are largely preserved in the WS mouse and patient iPSC-derived models used in this study. These findings do not support a major defect in oligodendroglia function as the primary cause of WS, and warrant further investigation of neurons and neuron-oligodendroglia interactions as a target for future neuroprotective or -restorative treatments for WS.

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Genomics of Wolfram Syndrome 1 (WFS1)

Cited by 12 publications

References 79 publications

First Case of a Dominant De Novo SEC23A Mutation with Neurological and Psychiatric Features: New Insights into Cranio-Lenticulo-Sutural Dysplasia with Literature Review

First Case of a Dominant De Novo SEC23A Mutation with Neurological and Psychiatric Features: New Insights into Cranio-Lenticulo-Sutural Dysplasia with Literature Review

Disrupted Endoplasmic Reticulum Ca2+ Handling: A Harβinger of β-Cell Failure

A deep phenotyping study in mouse and iPSC models to understand the role of oligodendroglia in optic neuropathy in Wolfram syndrome

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