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. 2018 Sep;20(9):1004-1012.
doi: 10.1038/gim.2017.227. Epub 2018 Jan 4.

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

Samer Khateb  1 , Björn Kowalewski  2 , Nicola Bedoni  3 , Markus Damme  4 , Netta Pollack  1 , Ann Saada  5 , Alexey Obolensky  1 , Tamar Ben-Yosef  6 , Menachem Gross  7 , Thomas Dierks  8 , Eyal Banin  9 , Carlo Rivolta  10   11 , Dror Sharon  12
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Free article

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

Samer Khateb et al. Genet Med. 2018 Sep.
Free article

Abstract

Purpose: We aimed to identify the cause of disease in patients suffering from a distinctive, atypical form of Usher syndrome.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Usher syndrome; arylsulfatase G; lysosomal storage disease; retinitis pigmentosa; whole-exome sequencing.

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