SRP54 – Shwachman-Diamond Syndrome

Shwachman-Diamond syndrome (SDS) is an autosomal recessive inherited bone marrow failure disorder characterized by persistent neutropenia, exocrine pancreatic insufficiency, and skeletal abnormalities. While biallelic SBDS variants account for ~90% of cases, heterozygous mutations in SRP54 have emerged as a cause of an SDS-like phenotype. Initial trio whole-exome sequencing uncovered three independent de novo SRP54 missense variants in SBDS-negative SDS patients, each presenting congenital neutropenia and pancreatic dysfunction ([PMID:28972538]). Subsequent screening of 66 SBDS-negative congenital neutropenia probands identified 23 individuals (16 sporadic, 7 familial) with heterozygous SRP54 mutations ([PMID:29914977]). These genetic findings, combined with supporting functional data, establish a robust link between SRP54 and SDS.

Clinical Validity

The gene–disease association meets a Strong level of evidence based on ClinGen criteria. Twenty-six unrelated probands (3 de novo in trio sequencing ([PMID:28972538]); 23 registry cases ([PMID:29914977])) and segregation in 7 families ([PMID:29914977]) support pathogenicity. Dominant inheritance is demonstrated by de novo occurrence and familial transmission. Functional concordance across structural, cellular, and animal models further strengthens this classification.

Genetic Evidence

SRP54 mutations act in an autosomal dominant manner, with affected individuals exhibiting neutropenia, exocrine pancreatic insufficiency, and skeletal defects. Segregation analysis in seven multiplex families confirmed co-segregation of heterozygous variants with disease ([PMID:29914977]). Twenty-six probands have been reported, including 16 sporadic and 7 familial cases. The variant spectrum comprises seven distinct alleles, notably the recurrent in-frame deletion c.343ACA[2] (p.Thr117del) observed in 14 patients ([PMID:29914977]). One exemplar variant is c.677G>A (p.Gly226Glu).

Functional Evidence

Structural studies using X-ray crystallography and hydrogen–deuterium exchange mass spectrometry reveal that SDS-associated SRP54 variants disrupt the GTPase core and abolish SRP–receptor complex formation ([PMID:33053321]). In zebrafish, SRP54 knockdown leads to severe neutropenia, exocrine pancreatic hypoplasia, and developmental defects mirroring human SDS, while injection of patient-derived mRNAs exacerbates the phenotype ([PMID:28972538]). Further, mutant SRP54 exerts dominant-negative effects by impairing XBP1 splicing; spliced XBP1 mRNA rescues neutropenia in srp54+/- fish ([PMID:33227812]). These complementary assays confirm a dominant-negative mechanism underlying SDS-like disease.

Integration and Conclusion

Collectively, genetic and experimental data provide compelling evidence for SRP54 as a novel autosomal dominant cause of Shwachman-Diamond syndrome. The identification of recurrent and de novo mutations in multiple families, robust segregation, and mechanistic validation in structural, cellular, and animal models fulfill ClinGen criteria for a Strong gene–disease relationship. Additional large-scale studies may expand the variant spectrum and refine genotype–phenotype correlations. Key Take-home: Heterozygous SRP54 variants cause an SDS-like syndrome via a dominant-negative mechanism, guiding molecular diagnosis and informing therapeutic targeting of the SRP pathway.

References

• The Journal of clinical investigation • 2017 • Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features. PMID:28972538
• Blood • 2018 • Mutations in the SRP54 gene cause severe congenital neutropenia as well as Shwachman-Diamond-like syndrome. PMID:29914977
• Structure (London, England : 1993) • 2021 • Structural and Functional Impact of SRP54 Mutations Causing Severe Congenital Neutropenia. PMID:33053321
• Blood • 2021 • SRP54 mutations induce congenital neutropenia via dominant-negative effects on XBP1 splicing. PMID:33227812

Evidence Based Scoring (AI generated)