RESUMEN

L.P. Li, L. Venkataraman, S. Chen, and H.J. Fu. Function of WFS1 and WFS2 in the Central Nervous System: Implications for Wolfram Syndrome and Alzheimer's Disease. NEUROSCI BIOBEHAV REVXXX-XXX,2020.-Wolfram syndrome (WS) is a rare monogenetic spectrum disorder characterized by insulin-dependent juvenile-onset diabetes mellitus, diabetes insipidus, optic nerve atrophy, hearing loss, progressive neurodegeneration, and a wide spectrum of psychiatric manifestations. Most WS patients belong to Wolfram Syndrome type 1 (WS1) caused by mutations in the Wolfram Syndrome 1 (WFS1/Wolframin) gene, while a small fraction of patients belongs to Wolfram Syndrome type 2 (WS2) caused by pathogenic variants in the CDGSH Iron Sulfur Domain 2 (CISD2/WFS2) gene. Although currently there is no treatment for this life-threatening disease, the molecular mechanisms underlying the pathogenesis of WS have been proposed. Interestingly, Alzheimer's disease (AD), an age-dependent neurodegenerative disease, shares some common mechanisms with WS. In this review, we focus on the function of WFS1 and WFS2 in the central nervous system as well as their implications in WS and AD. We also propose three future directions for elucidating the role of WFS1 and WFS2 in WS and AD.

Asunto(s)

Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Síndrome de Wolfram , Enfermedad de Alzheimer/genética , Sistema Nervioso Central , Humanos , Proteínas de la Membrana/genética , Mutación , Síndrome de Wolfram/genética

RESUMEN

AIMS: Wolfram syndrome (WS) is a rare recessive neurodegenerative disorder characterized by diabetes mellitus and optic atrophy. Mortality and morbidity rate of the disease is high in adulthood due to neurological and respiratory defects. So far, two WS genes, WFS1 (more than 90% of cases) and CISD2, have been identified. In the present study, we aimed to determine the role of WFS2 in a group of Iranian WS families. METHODS: We recruited 27 families with the clinical diagnosis of WS. Homozygosity mapping was implemented using short tandem repeat polymorphic markers and bi-directional sequencing of the CISD2 gene in families negative for WFS1 mutations. The candidate variant was checked among family members. In silico analysis and protein modeling were applied to assess the pathogenic effect of the variant. Tetra-primers ARMS PCR was set up for checking the variant in 50 ethnic-matched controls. RESULTS: One family showed homozygosity by descent at WFS2. A novel missense variant, c.310T > C (p.S104P), was found in exon 2 of the CISD2 gene. Computational predictions revealed its pathogenic effect on protein structure, function, and stability. Parents and his healthy brother were heterozygous for the variant. The variant was not observed in the control group. CONCLUSIONS: This is the first study that elucidates the role of the CISD2 gene among Iranian WS families with a novel disease-causing missense variant. Next-generation sequencing could unravel disease-causing genes in remained families to expand genetic heterogeneity of WS.

Asunto(s)

Proteínas de la Membrana/genética , Mutación Puntual , Síndrome de Wolfram/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Niño , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Homocigoto , Humanos , Irán , Masculino , Proteínas de la Membrana/metabolismo , Mutación , Mutación Missense , Polimorfismo Genético , Síndrome de Wolfram/diagnóstico

RESUMEN

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.

Asunto(s)

Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/terapia , Síndrome de Wolfram/diagnóstico , Síndrome de Wolfram/terapia , Adolescente , Adulto , Niño , Preescolar , Ensayos Clínicos como Asunto , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/etiología , Diabetes Mellitus Tipo 1/terapia , Progresión de la Enfermedad , Desarrollo de Medicamentos , Reposicionamiento de Medicamentos , Retículo Endoplásmico/metabolismo , Femenino , Genes Recesivos , Humanos , Lactante , Comunicación Interdisciplinaria , Masculino , Proteínas de la Membrana/genética , Enfermedades Neurodegenerativas/complicaciones , Enfermedades Neurodegenerativas/etiología , Pronóstico , Calidad de Vida , Síndrome de Wolfram/complicaciones , Síndrome de Wolfram/etiología , Adulto Joven

RESUMEN

NAF-1 is an important [2Fe-2S] NEET protein associated with human health and disease. A mis-splicing mutation in NAF-1 results in Wolfram Syndrome type 2, a lethal childhood disease. Upregulation of NAF-1 is found in epithelial breast cancer cells, and suppression of NAF-1 expression by knockdown significantly suppresses tumor growth. Key to NAF-1 function is the NEET fold with its [2Fe-2S] cluster. In this work, the high-resolution structure of native NAF-1 was determined to 1.65 Šresolution (R factor = 13.5%) together with that of a mutant in which the single His ligand of its [2Fe-2S] cluster, His114, was replaced by Cys. The NAF-1 H114C mutant structure was determined to 1.58 Šresolution (R factor = 16.0%). All structural differences were localized to the cluster binding site. Compared with native NAF-1, the [2Fe-2S] clusters of the H114C mutant were found to (i) be 25-fold more stable, (ii) have a redox potential that is 300 mV more negative and (iii) have their cluster donation/transfer function abolished. Because no global structural differences were found between the mutant and the native (wild-type) NAF-1 proteins, yet significant functional differences exist between them, the NAF-1 H114C mutant is an excellent tool to decipher the underlying biological importance of the [2Fe-2S] cluster of NAF-1 in vivo.

Asunto(s)

Proteínas Hierro-Azufre/genética , Mutación Puntual , Cristalografía por Rayos X , Proteínas Hierro-Azufre/química , Proteínas Hierro-Azufre/metabolismo , Ligandos , Electroforesis en Gel de Poliacrilamida Nativa , Espectrofotometría Ultravioleta