HGSNAT – Retinitis Pigmentosa

Autosomal recessive variants in HGSNAT, the gene encoding lysosomal heparan-α-glucosaminide N-acetyltransferase, have been implicated in nonsyndromic retinitis pigmentosa (RP), expanding its phenotypic spectrum beyond mucopolysaccharidosis IIIC. Patients present with progressive rod-cone degeneration but lack the neurological and somatic features typical of MPS IIIC.

Genetic studies in an Ashkenazi Jewish cohort identified six RP patients with homozygous or compound heterozygous HGSNAT variants, including c.370A>T (p.Arg124Trp) in two unrelated families ([PMID:25859010]). A subsequent CNV screen in 57 RP cases uncovered a heterozygous deletion of exons 7–8 (c.634-408_820+338delinsAGAATATG, p.Glu212GlyfsTer2) in one patient, who also carried c.1843G>A (p.Ala615Thr) on the other allele ([PMID:27608171]).

The largest cohort to date comprised 17 nonsyndromic RP individuals from 15 families, all harboring biallelic HGSNAT variants such as c.370A>T (p.Arg124Trp) and c.1843G>A (p.Ala615Thr) ([PMID:32770643]). Segregation in multiple affected siblings (four additional relatives) and recurrence of hypomorphic alleles across distinct populations support a pathogenic role.

Functional assays demonstrate that RP-associated HGSNAT alleles yield intermediate enzyme activity in patient leukocytes—reduced relative to controls yet higher than classic MPS IIIC levels—and that HGSNAT is highly expressed in mouse retina, indicating tissue-specific activity thresholds ([PMID:25859010]). Moreover, protein folding studies reveal that missense variants cause misfolding and ER retention, which can be partially rescued by pharmacological chaperones ([PMID:19823584]).

Clinically, adult-onset HGSNAT-related RP manifests with nyctalopia, mid-peripheral bone spicules, and gradual concentric field constriction, often sparing neurologic and systemic function. Enzyme activity assays can aid in distinguishing hypomorphic retinal alleles from null mutations causing MPS IIIC.

Collectively, robust genetic and experimental evidence (25 probands, AR segregation, functional concordance) supports a strong gene–disease association. HGSNAT should be included in diagnostic retinal dystrophy panels, and leukocyte enzyme testing may resolve genotype–phenotype correlations.

Key Take-home: Biallelic HGSNAT variants cause autosomal recessive nonsyndromic retinitis pigmentosa through partial loss of enzyme function, warranting inclusion in genetic testing and functional diagnostics.

References

• Human molecular genetics • 2015 • Non-syndromic retinitis pigmentosa due to mutations in the mucopolysaccharidosis type IIIC gene, heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT). PMID:25859010
• Genetics in medicine • 2017 • arrEYE: a customized platform for high-resolution copy number analysis of coding and noncoding regions of known and candidate retinal dystrophy genes and retinal noncoding RNAs. PMID:27608171
• PloS one • 2009 • Protein misfolding as an underlying molecular defect in mucopolysaccharidosis III type C. PMID:19823584
• American journal of medical genetics. Part C, Seminars in medical genetics • 2020 • A genetic and clinical study of individuals with nonsyndromic retinopathy consequent upon sequence variants in HGSNAT, the gene associated with Sanfilippo C mucopolysaccharidosis. PMID:32770643

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