Center for Vision and Eye Banking Research, Eversight, Cleveland, OH, 44103, USA.
Center for Vision and Eye Banking Research, Eversight, Cleveland, OH, 44103, USA.
Exp Eye Res. 2023 Apr;229:109433. doi: 10.1016/j.exer.2023.109433. Epub 2023 Feb 27.
Heparan-α-glucosaminide N-acetyltransferase (HGSNAT) participates in lysosomal degradation of heparan sulfate. Mutations in the gene encoding this enzyme cause mucopolysaccharidosis IIIC (MPS IIIC) or Sanfilippo syndrome type C. MPS IIIC patients exhibit progressive neurodegeneration, leading to dementia and death in early adulthood. Currently there is no approved treatment for MPS IIIC. Incidences of non-syndromic retinitis pigmentosa and early signs of night blindness are reported in some MPS IIIC patients, however the majority of ocular phenotypes are not well characterized. The goal of this study was to investigate retinal degeneration phenotype in the Hgsnat knockout mouse model of MPS IIIC and a cadaveric human MPS IIIC eye. Cone and rod photoreceptors in the eyes of homozygous 6-month-old Hgsnat knockout mice and their wild-type counterparts were analyzed using cone arrestin, S-opsin, M-opsin and rhodopsin antibodies. Histological observation was performed on the eye from a 35-year-old MPS IIIC donor. We observed a nearly 50% reduction in the rod photoreceptors density in the Hgsnat knockout mice compared to the littermate wild-type controls. Cone photoreceptor density was unaltered at this age. Severe retinal degeneration was also observed in the MPS IIIC donor eye. To our knowledge, this is the first report characterizing ocular phenotypes arising from deleterious variants in the Hgsnat gene associated with MPS IIIC clinical phenotype. Our findings indicate retinal manifestations may be present even before behavioral manifestations. Thus, we speculate that ophthalmological evaluations could be used as diagnostic indicators of early disease, progression, and end-point evaluation for future MPS IIIC therapies.
乙酰氨基葡萄糖苷酶 N-乙酰转移酶（HGSNAT）参与硫酸乙酰肝素的溶酶体降解。编码该酶的基因突变会导致黏多糖贮积症 IIIC（MPS IIIC）或 Sanfilippo 综合征 C 型。MPS IIIC 患者表现出进行性神经退行性变，导致早发性痴呆和死亡。目前，MPS IIIC 没有批准的治疗方法。一些 MPS IIIC 患者报告有非综合征性视网膜色素变性和夜盲的早期迹象，但大多数眼部表型尚未得到很好的描述。本研究的目的是研究 MPS IIIC 的 Hgsnat 基因敲除小鼠模型和尸检人 MPS IIIC 眼中的视网膜变性表型。使用 cone arrestin、S-opsin、M-opsin 和视紫红质抗体分析 6 个月大的 Hgsnat 基因敲除小鼠及其野生型同窝对照的视锥和视杆光感受器。对来自 35 岁 MPS IIIC 供体的眼睛进行组织学观察。与同窝对照野生型相比，Hgsnat 基因敲除小鼠的视杆光感受器密度减少了近 50%。在这个年龄，视锥光感受器密度没有改变。在 MPS IIIC 供体眼中也观察到严重的视网膜变性。据我们所知，这是首次描述与 MPS IIIC 临床表型相关的 Hgsnat 基因有害变异引起的眼部表型。我们的发现表明，即使在行为表现之前，也可能出现视网膜表现。因此，我们推测眼科评估可作为早期疾病、进展和未来 MPS IIIC 治疗终点评估的诊断指标。
