SRD5A3 – SRD5A3-CDG

SRD5A3 encodes steroid 5α-reductase type 3, an enzyme critical for polyprenol reduction in N-linked glycosylation. Bi-allelic pathogenic variants in SRD5A3 underlie SRD5A3-CDG (MONDO:0012885), an autosomal recessive disorder with multisystem involvement. To date, 43 affected individuals have been reported in the literature ([PMID:33403770]).

Genetic studies have identified homozygous truncating variants in 15 pediatric cases and two adult siblings carrying c.57G>A (p.Trp19Ter) ([PMID:24433453]), as well as a novel homozygous missense variant c.460C>A (p.Ser154Pro) in a consanguineous family ([PMID:33403770]). All reported alleles follow autosomal recessive inheritance, with no dominant presentations documented.

Segregation analysis across at least five consanguineous sibships, including the two adult brothers diagnosed by linkage and exome sequencing, confirms co-segregation of homozygous SRD5A3 variants with disease ([PMID:24433453]; [PMID:34925443]).

Clinically, SRD5A3-CDG presents with early-onset retinal dystrophy and optic atrophy, cerebellar ataxia, and variable neurological signs including dystonia and hypotonia. Dysmorphic facial features such as short nose, wide mouth, and highly arched eyebrows have also been reported ([PMID:34925443]; [PMID:24433453]).

Functional assays in patient-derived fibroblasts revealed 3,047 N-glycopeptides with 379 significantly decreased species (P<0.05), including high-mannose and complex glycans on key glycoproteins ([PMID:39360848]). Proteomic profiling identified 873 proteins with altered abundance, implicating disrupted glycosylation and energy metabolism pathways.

A cerebellum-specific Srd5a3 knockout mouse exhibited motor coordination defects, impaired granule cell development, and defective IgSF-CAM-mediated neurite outgrowth, linking high N-glycan multiplicity to neural adhesion in vivo ([PMID:30311906]).

Together, robust genetic and functional data support a Strong clinical validity classification for SRD5A3 and SRD5A3-CDG. Key take-home: consider SRD5A3 sequencing in patients with ataxia, retinal dystrophy, and characteristic dysmorphic features to enable accurate diagnosis and guide management.

References

• BMC medical genetics • 2014 • Adult phenotype and further phenotypic variability in SRD5A3-CDG. PMID:24433453
• American journal of medical genetics. Part A • 2021 • SRD5A3-CDG: 3D structure modeling, clinical spectrum, and computer-based dysmorphic facial recognition. PMID:33403770
• Frontiers in genetics • 2021 • SRD5A3-CDG: Emerging Phenotypic Features of an Ultrarare CDG Subtype. PMID:34925443
• Glycobiology • 2024 • N-glycoproteomic and proteomic alterations in SRD5A3-deficient fibroblasts. PMID:39360848
• eLife • 2018 • High N-glycan multiplicity is critical for neuronal adhesion and sensitizes the developing cerebellum to N-glycosylation defect. PMID:30311906

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