title: Non-syndromic retinitis pigmentosa due to mutations in the mucopolysaccharidosis type IIIC gene, heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT).
abstract: Retinitis pigmentosa (RP), the most common form of inherited retinal degeneration, is clinically and genetically heterogeneous and can appear as syndromic or non-syndromic. Mucopolysaccharidosis type IIIC (MPS IIIC) is a lethal disorder, caused by mutations in the heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT) gene and characterized by progressive neurological deterioration, with retinal degeneration as a prominent feature. We identified HGSNAT mutations in six patients with non-syndromic RP. Whole exome sequencing (WES) in an Ashkenazi Jewish Israeli RP patient revealed a novel homozygous HGSNAT variant, c.370A>T, which leads to partial skipping of exon 3. Screening of 66 Ashkenazi RP index cases revealed an additional family with two siblings homozygous for c.370A>T. WES in three Dutch siblings with RP revealed a complex HGSNAT variant, c.[398G>C; 1843G>A] on one allele, and c.1843G>A on the other allele. HGSNAT activity levels in blood leukocytes of patients were reduced compared with healthy controls, but usually higher than those in MPS IIIC patients. All patients were diagnosed with non-syndromic RP and did not exhibit neurological deterioration, or any phenotypic features consistent with MPS IIIC. Furthermore, four of the patients were over 60 years old, exceeding by far the life expectancy of MPS IIIC patients. HGSNAT is highly expressed in the mouse retina, and we hypothesize that the retina requires higher HGSNAT activity to maintain proper function, compared with other tissues associated with MPS IIIC, such as the brain. This report broadens the spectrum of phenotypes associated with HGSNAT mutations and highlights the critical function of HGSNAT in the human retina.
authors: Department of Human Genetics, Radboud Institute for Molecular Life Sciences.
authors: Lonneke
authors: L
authors: Haer-Wigman
authors: Department of Ophthalmology, Tel-Aviv Medical Center, Tel-Aviv, Israel.
authors: Hadas
authors: H
authors: Newman
authors: Alberto Moscona Department of Ophthalmology.
authors: Rina
authors: R
authors: Leibu
authors: Department of Ophthalmology.
authors: Nathalie M
authors: NM
authors: Bax
authors: The Genetic Institute, Rambam Health Care Campus, Haifa, Israel, The Rappaport Faculty of Medicine.
authors: Hagit N
authors: HN
authors: Baris
authors: The Rappaport Faculty of Medicine, Rappaport Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.
authors: Leah
authors: L
authors: Rizel
authors: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel and.
authors: Eyal
authors: E
authors: Banin
authors: The Rappaport Faculty of Medicine, Rappaport Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.
authors: Amir
authors: A
authors: Massarweh
authors: Department of Human Genetics, Radboud Institute for Molecular Life Sciences.
authors: Susanne
authors: S
authors: Roosing
authors: Radboud Institute for Molecular Life Sciences, Department of Neurology, Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Dirk J
authors: DJ
authors: Lefeber
authors: Radboud Institute for Molecular Life Sciences.
authors: Marijke N
authors: MN
authors: Zonneveld-Vrieling
authors: Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors: Ofer
authors: O
authors: Isakov
authors: Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors: Noam
authors: N
authors: Shomron
authors: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel and.
authors: Dror
authors: D
authors: Sharon
authors: Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Department of Ophthalmology.
authors: Anneke I
authors: AI
authors: Den Hollander
authors: Department of Ophthalmology.
authors: Carel B
authors: CB
authors: Hoyng
authors: Department of Human Genetics, Radboud Institute for Molecular Life Sciences.
authors: Frans P M
authors: FP
authors: Cremers
authors: The Rappaport Faculty of Medicine, Rappaport Research Institute, Technion-Israel Institute of Technology, Haifa, Israel, benyosef@tx.technion.ac.il.
authors: Tamar
authors: T
authors: Ben-Yosef
mesh_terms: D000123:Acetyltransferases / Q000235:genetics*; D000328:Adult; D000368:Aged; D000818:Animals; D058070:Asymptomatic Diseases; D001483:Base Sequence; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008969:Molecular Sequence Data; D009084:Mucopolysaccharidosis III / Q000201:enzymology* / Q000235:genetics; D010375:Pedigree; D017354:Point Mutation; D012160:Retina / Q000201:enzymology; D012174:Retinitis Pigmentosa / Q000201:enzymology* / Q000235:genetics
chemical_list: D000123:Acetyltransferases; C514442:HGSNAT protein, human