2. Academic Validation
  3. A homozygous founder missense variant in arylsulfatase G abolishes its enzymatic activity causing atypical Usher syndrome in humans

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

  • Genet Med. 2018 Sep;20(9):1004-1012. doi: 10.1038/gim.2017.227.
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
Affiliations

Affiliations

  • 1 Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
  • 2 Department of Chemistry, Biochemistry I, Bielefeld University, Bielefeld, Germany.
  • 3 Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
  • 4 Department of Biochemistry, University of Kiel, Kiel, Germany.
  • 5 Monique and Jacques Roboh Department of Genetic Research and the Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
  • 6 Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
  • 7 Department of Otolaryngology-Head and Neck Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
  • 8 Department of Chemistry, Biochemistry I, Bielefeld University, Bielefeld, Germany. thomas.dierks@uni-bielefeld.de.
  • 9 Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. banine@cc.huji.ac.il.
  • 10 Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, Lausanne, Switzerland. carlo.rivolta@unil.ch.
  • 11 Department of Genetics and Genome Biology, University of Leicester, Leicester, UK. carlo.rivolta@unil.ch.
  • 12 Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. dror.sharon1@gmail.com.
PMID: 29300381 DOI: 10.1038/gim.2017.227
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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