Original Research Article | Published:

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

Genetics in Medicine | Download Citation

The last four authors contributed equally to this work.




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.

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This study was financially supported by the Foundation Fighting Blindness USA (BR-GE-0214-0639 to D.S., E.B., and T.B.-Y.), Israel Science Foundation (2154/15 to S.K.), Chief Scientist Office of the Israeli Ministry of Health and the Lirot association (300009177 to S.K. and 300011893 to D.S. and T.B.-Y.), the Yedidut Research Grant (to E.B.), the Deutsche Forschungsgemeinschaft (DI 575/10-1 to T.D.), and the Swiss National Science Foundation (156260 to C.R.). The authors thank all patients and family members for their participation in this study, and Torben Lübke for critically reading the manuscript. Geto Mengisto, Kerstin Fentker and Mai-Britt Ilse, Inbar Erdinest, and Devora Marks-Ohana are acknowledged for expert technical assistance.

Author information


  1. Department of Ophthalmology, Hadassah–Hebrew University Medical Center, Jerusalem, Israel

    • Samer Khateb
    • , Netta Pollack
    • , Alexey Obolensky
    • , Eyal Banin
    •  & Dror Sharon
  2. Department of Chemistry, Biochemistry I, Bielefeld University, Bielefeld, Germany

    • Björn Kowalewski
    •  & Thomas Dierks
  3. Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, Lausanne, Switzerland

    • Nicola Bedoni
    •  & Carlo Rivolta
  4. Department of Biochemistry, University of Kiel, Kiel, Germany

    • Markus Damme
  5. Monique and Jacques Roboh Department of Genetic Research and the Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    • Ann Saada
  6. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

    • Tamar Ben-Yosef
  7. Department of Otolaryngology—Head and Neck Surgery, Hadassah–Hebrew University Medical Center, Jerusalem, Israel

    • Menachem Gross
  8. Department of Genetics and Genome Biology, University of Leicester, Leicester, UK

    • Carlo Rivolta


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Competing interests

The authors declare no conflict of interest

Corresponding authors

Correspondence to Thomas Dierks or Eyal Banin or Carlo Rivolta or Dror Sharon.

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Supplementary material is linked to the online version of the paper at http://www.nature.com/gim