SRD5A3 and Congenital Disorder of Glycosylation

SRD5A3, a gene implicated in the biosynthesis of dolichol‐linked oligosaccharides, is robustly associated with congenital disorders of glycosylation (CDG). Multiple independent case reports and multi‐patient studies have documented patients with biallelic pathogenic variants in SRD5A3 presenting with a spectrum of clinical features including psychomotor retardation, nystagmus, visual impairment, and microcephaly. This evidence consolidates SRD5A3’s role in defective protein glycosylation, a critical process for normal cellular function (PMID:22240719).

The genetic evidence is underscored by several reports where patients show autosomal recessive inheritance of loss‑of‑function mutations. In particular, recurrent detection of the c.57G>A (p.Trp19Ter) variant in independent families has been a hallmark, with additional cases demonstrating segregation of the variant with disease phenotypes across affected relatives (PMID:22304929). Furthermore, segregation analysis in these families, including affected sibling pairs, supports the pathogenicity of these variants (PMID:30019980).

The variant spectrum in SRD5A3 reported among CDG patients predominantly includes truncating mutations, most notably the c.57G>A (p.Trp19Ter) change. This variant, identified in multiple studies, satisfies the complete coding and protein change description criteria, making it a reliable genetic marker for diagnostic assessments. Its recurrence reinforces the gene–disease association and provides a clear target for genetic testing.

Functional studies further contribute to validating this association. Experimental evidence from knock‑out mouse models, glycoproteomic analyses, and 3D protein structural modeling has demonstrated that loss of SRD5A3 function impairs N‑linked glycosylation. These assays consistently mimic the human phenotype and highlight disrupted glycosylation pathways as the primary pathogenic mechanism, lending substantial support to a loss-of-function etiology (PMID:24433453, PMID:39360848).

Integration of the genetic and functional findings indicates that SRD5A3 mutations result in a clinically significant impairment of glycoprotein biosynthesis. The convergence of multiple lines of evidence—from recurrent pathogenic variants to robust functional assays—establishes a strong gene-disease connection. This comprehensive evidence has direct implications for diagnostics, genetic counseling, and potential future therapeutic interventions.

Key take‑home sentence: The strong association between biallelic loss‑of‑function mutations in SRD5A3 and congenital disorders of glycosylation underscores its clinical utility as a diagnostic marker and highlights the need for integrated genetic and functional testing in suspected cases.

References

• European journal of paediatric neurology • 2012 • SRD5A3-CDG: a patient with a novel mutation PMID:22240719
• Molecular genetics and metabolism • 2012 • Life with too much polyprenol: polyprenol reductase deficiency PMID:22304929
• Ophthalmic genetics • 2018 • Early-onset retinal dystrophy and chronic dermatitis in a girl with an undiagnosed congenital disorder of glycosylation (SRD5A3-CDG) PMID:30019980
• BMC medical genetics • 2014 • Adult phenotype and further phenotypic variability in SRD5A3-CDG PMID:24433453
• Glycobiology • 2024 • N-glycoproteomic and proteomic alterations in SRD5A3-deficient fibroblasts PMID:39360848

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