NDST1 – NDST1-related autosomal recessive intellectual disability

NDST1 mutations cause autosomal recessive non-syndromic intellectual disability ([PMID:25125150]). Affected individuals present global developmental delay and intellectual disability (HP:0001249), muscular hypotonia (HP:0001252), seizures (HP:0001250), and postnatal growth retardation (HP:0008897). Five unrelated families—four reported in 2014 and one in 2020—harbor homozygous NDST1 variants supporting recessive inheritance ([PMID:25125150]; [PMID:32878022]). Consistent homozygosity in probands and heterozygosity in parents across families confirms segregation with disease.

Six homozygous variants have been identified in five unrelated probands: c.1926G>T (p.Glu642Asp), c.2126G>A (p.Arg709Gln), c.1918T>C (p.Phe640Leu), c.1831G>A (p.Gly611Ser), c.340G>T (p.Glu114Ter), and c.1966G>A (p.Asp656Asn). All predict substitution of conserved residues within the sulfotransferase domain, with segregation demonstrated by Sanger sequencing in four families ([PMID:25125150]; [PMID:32878022]).

The variant spectrum comprises five missense changes and one nonsense allele. The recurrent p.Gly611Ser variant has been observed in four alleles across distinct families and is absent from population databases, consistent with a rare autosomal recessive disorder ([PMID:25125150]; [PMID:38129107]).

Functional assays show that knockdown of the NDST1 ortholog sulfateless in Drosophila impairs long-term memory, mirroring the cognitive phenotype ([PMID:25125150]). Enzymatic characterization of the p.Gly611Ser protein reveals complete loss of N-sulfotransferase activity with preserved deacetylase function, establishing a loss-of-function mechanism ([PMID:38129107]).

Mechanistic studies in Xenopus embryos demonstrate that NDST1-mediated N-sulfation is required for Wnt8 localization and canonical signaling; mutants lacking sulfotransferase activity fail to accumulate Wnt8 on the cell surface, linking HS under-sulfation to developmental signaling deficits ([PMID:38326088]).

Integration of genetic and experimental data supports a Strong gene–disease association. While mouse Ndst1 knockout is perinatally lethal, the hypomorphic alleles described recapitulate key features of non-syndromic intellectual disability without lethality. Key take-home: NDST1 should be included in diagnostic gene panels for autosomal recessive intellectual disability with hypotonia, seizures, and growth retardation.

References

• American journal of medical genetics. Part A • 2014 • NDST1 missense mutations in autosomal recessive intellectual disability. PMID:25125150
• Genes • 2020 • Two Cases of Recessive Intellectual Disability Caused by NDST1 and METTL23 Variants. PMID:32878022
• Human molecular genetics • 2024 • Loss of NDST1 N-sulfotransferase activity is associated with autosomal recessive intellectual disability. PMID:38129107
• Development, growth & differentiation • 2024 • Dissection of N-deacetylase and N-sulfotransferase activities of NDST1 and their effects on Wnt8 distribution and signaling in Xenopus embryos. PMID:38326088

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