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.

Missense mutations in the WD40 domain ofAHI1cause non-syndromic retinitis pigmentosa

“…A similar tissue-dependent activity-effect model was also suggested for other genes, for instance CLN3, CEP290, HGSNAT and MFSD8 that can be associated with syndromic and non-syndromic retinal diseases. [28][29][30][31] The hypothesis that the missense variants in the WD40 domain do not completely abolish Jouberin function is further supported by our observation that cultured fibroblasts of patient A-II:1 (c.2174G>A and c.2258A>T) had no disrupted cilium formation, while Tuz et al showed that mutations in individuals with JBTS cause impaired ciliogenesis in patient's fibroblasts. 27 Additionally, we did not observe mislocalisation of either IFT-B (IFT88) or IFT-A (WDR19), a phenotype that was previously detected in other severe ciliopathies.…”

Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies

“…Suzki et al have highlighted the extremely rare association between RP and MPSII, and a more recent study has shown that the disease gene for MPSIIIC (HGSNAT) can cause a nonsyndromic form of RP. 25,26 It appears likely that the homozygous truncating mutation we identified in GNS is causal for both MPS and RP within this extended family, although we cannot exclude the remote possibility that it is present in tight linkage disequilibrium with another mutation causing RP.…”

8p11 Microduplication Is Associated with Neonatal Stridor

“…The HGSNAT (heparan-alpha-glucosaminide Nacetyltransferase) gene encodes a lysosomal acetyltransferase, which is one of several enzymes involved in the lysosomal degradation of heparin sulfate. Mutations in this gene are associated with Sanfilippo syndrome type C (mucopolysaccharidosis) and retinitis pigmentosa [Canals et al, 2011;Haer-Wigman et al, 2015]. FNTA (farnesyltransferase) is a protein-encoding gene related to apoptotic cleavage of cellular protein.…”