Mild Phenotype of Wolfram Syndrome Associated With a Common Pathogenic Variant Is Predicted by a Structural Model of Wolframin.
Journal
Neurology. Genetics
ISSN: 2376-7839
Titre abrégé: Neurol Genet
Pays: United States
ID NLM: 101671068
Informations de publication
Date de publication:
Apr 2021
Apr 2021
Historique:
received:
22
12
2020
accepted:
27
01
2021
entrez:
25
3
2021
pubmed:
26
3
2021
medline:
26
3
2021
Statut:
epublish
Résumé
To describe the The clinical, laboratory, and genetic features of 8 homozygotes were collected. A model of the wolframin protein was constructed, and NMA was used to simulate the effect of the variant on protein thermodynamics. Mean age at Wolfram syndrome (WS) diagnosis among homozygotes was 30 years; diabetes (7/8) was diagnosed at mean age 19 years (15-21 years), and bilateral optic atrophy (with MRI evidence of optic/chiasm atrophy) (6/8) at mean age 29 years (15-48 years). The oldest patient (62 years) also had gait difficulties, memory problems, parietal and cerebellar atrophy, and white matter hyperintense lesions. All retained functional vision with independent ambulation and self-care; none had diabetes insipidus or hearing loss. The p.R558C variant caused less impairment of protein entropy than WFS1 variants associated with a more severe phenotype. The p.R558C variant causes a milder, late-onset phenotype of WS. We report a structural model of wolframin protein based on empirical functional studies and use NMA modeling to show a genotype-phenotype correlation across all homozygotes. Clinicians should be alert to this condition in patients with juvenile diabetes and patients of any age with a combination of diabetes and optic atrophy. Computational NMA has potential benefit for prediction of the genotype-phenotype relationship.
Identifiants
pubmed: 33763535
doi: 10.1212/NXG.0000000000000578
pii: NG2020016915
pmc: PMC7983365
doi:
Types de publication
Journal Article
Langues
eng
Pagination
e578Informations de copyright
Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
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