SSR3 – Congenital Disorder of Glycosylation

In this report, SSR3, a critical subunit of the translocon‐associated protein (TRAP) complex, is linked to a congenital disorder of glycosylation. The disorder is characterized by severe clinical symptoms, including marked intellectual disability and sensorineural hearing impairment. The study presents a targeted investigation into the molecular mechanisms by which mutations in SSR3 disrupt proper glycosylation. This report is highly relevant for both diagnostic decision‑making and potential future therapeutic strategies. The evidence supports a direct role of SSR3 in maintaining correct protein glycosylation processes. Early identification of such mutations can significantly impact clinical outcomes.

The affected individual presented with severe intellectual disability and sensorineural hearing loss, findings that are consistent with a congenital disorder of glycosylation. Extensive clinical evaluation revealed a pattern of multisystem involvement that aligns with the known phenotypic spectrum of similar glycosylation disorders. Such clinical features prompt clinicians to consider a genetic etiology that disrupts the glycosylation machinery. Detailed phenotyping was crucial in correlating the genetic findings with the observed clinical signs. This in-depth characterization provides valuable context for the functional impact of the identified mutation. The clinical presentation underpins the rationale for genetic screening in patients with similar symptoms.

Genetic evidence for the disease association is based on the identification of a novel homozygous frameshift variant in SSR3. Exome sequencing in the examined proband detected the variant c.278_281delAGGA (p.Glu93ValfsTer7) (PMID:30945312), which is predicted to disrupt the integrity of the TRAP complex. Although this evidence stems from a single proband, it is supported by detailed molecular analysis. The solitary genetic finding is noteworthy given the rarity of the disorder and the specificity of the variant to the disease phenotype. The variant’s predicted impact is compatible with a loss of function mechanism, an observation further strengthened by the clinical findings. This case underscores the importance of detailed genetic screening in rare congenital conditions.

The variant c.278_281delAGGA (p.Glu93ValfsTer7) was identified by removing extraneous information such as the transcript ID and gene symbol from the original report. This frameshift mutation leads to a premature termination codon, which likely results in complete loss of functional SSR3 protein. Biochemical studies in patient-derived fibroblasts indicate that the mutant protein destabilizes the TRAP complex, with consequent alterations in glycosylation processes. The precise molecular characterization of this variant provides a clear-cut link between the mutation and the disrupted protein function. Such molecular evidence is critical for confirming the pathogenic nature of the variant. This information not only guides the diagnostic process but also aids in understanding the molecular pathology of the disorder.

Functional studies play a pivotal role in underpinning the pathogenicity of the variant. In vitro assays demonstrated that patient fibroblasts exhibit a complete loss of SSR3 protein, along with partial loss of other TRAP complex components. Importantly, rescue experiments involving the reintroduction of wild‑type SSR3 restored normal subunit levels and glycosylation status. These experiments provide robust functional evidence that the variant exerts a deleterious effect on the glycosylation machinery. The comprehensive functional assessment aligns with the clinical observations and reinforces the mutation’s role in disease causation. This convergence of functional and clinical data supports the role of SSR3 in the disease process.

In summary, while the genetic evidence is currently limited to a single proband, the strong concordance between the genetic defect and the functional impairment observed in laboratory studies establishes a convincing link between SSR3 and congenital disorder of glycosylation. The biochemical and rescue experiments provide strong functional support, complementing the genetic data and enhancing the overall confidence in this gene‐disease association. Despite the modest number of cases, the integrated evidence offers clear direction for future research and clinical management. Continued data collection and further case studies may eventually solidify the association. The current findings are highly impactful for diagnostic evaluation as they guide clinicians in interpreting rare, functionally validated genetic variants.

References

• Journal of inherited metabolic disease • 2019 • Mutations in the translocon-associated protein complex subunit SSR3 cause a novel congenital disorder of glycosylation PMID:30945312

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