Samer Khateb1, Björn Kowalewski2, Nicola Bedoni3, Markus Damme4, Netta Pollack1, Ann Saada5, Alexey Obolensky1, Tamar Ben-Yosef6, Menachem Gross7, Thomas Dierks8, Eyal Banin9, Carlo Rivolta10,11, Dror Sharon12. 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.
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.
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.
Authors: Rosalie M Nolen; Robert B Hufnagel; Thomas B Friedman; Amy E Turriff; Carmen C Brewer; Christopher K Zalewski; Kelly A King; Talah T Wafa; Andrew J Griffith; Brian P Brooks; Wadih M Zein Journal: Ophthalmic Genet Date: 2020-05-06 Impact factor: 1.803
Authors: Eric Nisenbaum; Torin P Thielhelm; Aida Nourbakhsh; Denise Yan; Susan H Blanton; Yilai Shu; Karl R Koehler; Aziz El-Amraoui; Zhengyi Chen; Byron L Lam; Xuezhong Liu Journal: Ear Hear Date: 2022 Jan/Feb Impact factor: 3.562
Authors: Nicholas H Fowler; May I El-Rashedy; Emad A Chishti; Craig W Vander Kooi; Ramiro S Maldonado Journal: Ophthalmic Genet Date: 2021-02-25 Impact factor: 1.274
Authors: Neil J Ingham; Victoria Rook; Francesca Di Domenico; Elysia James; Morag A Lewis; Giorgia Girotto; Annalisa Buniello; Karen P Steel Journal: Hear Res Date: 2020-01-02 Impact factor: 3.208
Authors: Alon M Douek; Mitra Amiri Khabooshan; Jason Henry; Sebastian-Alexander Stamatis; Florian Kreuder; Georg Ramm; Minna-Liisa Änkö; Donald Wlodkowic; Jan Kaslin Journal: Int J Mol Sci Date: 2021-05-31 Impact factor: 5.923
Authors: Austin D Igelman; Cristy Ku; Mariana Matioli da Palma; Michalis Georgiou; Elena R Schiff; Byron L Lam; Eeva-Marja Sankila; Jeeyun Ahn; Lindsey Pyers; Ajoy Vincent; Juliana Maria Ferraz Sallum; Wadih M Zein; Jin Kyun Oh; Ramiro S Maldonado; Joseph Ryu; Stephen H Tsang; Michael B Gorin; Andrew R Webster; Michel Michaelides; Paul Yang; Mark E Pennesi Journal: Ophthalmic Genet Date: 2021-07-05 Impact factor: 1.274