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A homozygous founder missense variant in arylsulfatase G abolishes its enzymatic activity causing atypical Usher syndrome in humans

Khateb, Samer and Kowalewski, Björn and Bedoni, Nicola and Damme, Markus and Pollack, Netta and Saada, Ann and Obolensky, Alexey and Ben-Yosef, Tamar and Gross, Menachem and Dierks, Thomas and Banin, Eyal and Rivolta, Carlo and Sharon, Dror. (2018) A homozygous founder missense variant in arylsulfatase G abolishes its enzymatic activity causing atypical Usher syndrome in humans. Genetics in medicine, 20 (9). pp. 1004-1012.

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Abstract

We aimed to identify the cause of disease in patients suffering from a distinctive, atypical form of Usher syndrome.; Whole-exome and genome sequencing were performed in five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and sensorineural hearing loss. Functional analysis of the wild-type and mutant proteins was performed in human fibrosarcoma cells.; We identified a homozygous founder missense variant, c.133G>T (p.D45Y) in arylsulfatase G (ARSG). All patients shared a distinctive retinal phenotype with ring-shaped atrophy along the arcades engirdling the fovea, resulting in ring scotoma. In addition, patients developed moderate to severe sensorineural hearing loss. Both vision and hearing loss appeared around the age of 40 years. The identified variant affected a fully conserved amino acid that is part of the catalytic site of the enzyme. Functional analysis of the wild-type and mutant proteins showed no basal activity of p.D45Y.; Homozygosity for ARSG-p.D45Y in humans leads to protein dysfunction, causing an atypical combination of late-onset Usher syndrome. Although there is no evidence for generalized clinical manifestations of lysosomal storage diseases in this set of patients, we cannot rule out the possibility that mild and late-onset symptoms may appear.
Faculties and Departments:03 Faculty of Medicine
09 Associated Institutions > Institute of Molecular and Clinical Ophthalmology Basel (IOB)
UniBasel Contributors:Rivolta, Carlo
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Springer Nature
ISSN:1098-3600
e-ISSN:1530-0366
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:12 May 2021 13:39
Deposited On:02 Mar 2021 13:09

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