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Hum Mol Genet. 2015 Jul 1;24(13):3742-51. doi: 10.1093/hmg/ddv118. Epub 2015 Apr 9.

Non-syndromic retinitis pigmentosa due to mutations in the mucopolysaccharidosis type IIIC gene, heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT).

Author information

1
Department of Human Genetics, Radboud Institute for Molecular Life Sciences.
2
Department of Ophthalmology, Tel-Aviv Medical Center, Tel-Aviv, Israel.
3
Alberto Moscona Department of Ophthalmology.
4
Department of Ophthalmology.
5
The Genetic Institute, Rambam Health Care Campus, Haifa, Israel, The Rappaport Faculty of Medicine.
6
The Rappaport Faculty of Medicine, Rappaport Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.
7
Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel and.
8
Radboud Institute for Molecular Life Sciences, Department of Neurology, Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen, The Netherlands.
9
Radboud Institute for Molecular Life Sciences.
10
Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.
11
Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Department of Ophthalmology.
12
The Rappaport Faculty of Medicine, Rappaport Research Institute, Technion-Israel Institute of Technology, Haifa, Israel, benyosef@tx.technion.ac.il.

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.

PMID:
25859010
PMCID:
PMC4459392
DOI:
10.1093/hmg/ddv118
[Indexed for MEDLINE]
Free PMC Article

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