SBDS – Shwachman-Diamond syndrome

Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency and bone marrow failure, notably neutropenia and risk of hematologic malignancies. SDS is caused by biallelic pathogenic variants in the SBDS gene at 7q11, encoding a protein essential for 60S ribosomal subunit maturation.

Autosomal recessive inheritance of SDS is supported by identification of SBDS mutations in 141 of 158 unrelated SDS probands, with recurring gene conversion alleles (e.g., c.258+2T>C) across diverse populations ([PMID:12496757]). Consanguineous familial cases further confirm segregation; two affected siblings born to consanguineous parents both harbored biallelic SBDS mutations ([PMID:10975944]).

Variant spectrum includes recurrent gene conversion alleles c.183_184delinsCT (p.Lys62Ter) and c.258+2T>C, accounting for ~60% and ~29% of mutant alleles, respectively, as well as missense, splice-site, and structural variants. Compound heterozygous missense mutations (c.362A>C [p.Asn121Thr] and c.523C>T [p.Arg175Trp]) further illustrate allelic diversity and severe phenotype in infants ([PMID:17046571]).

Functional studies demonstrate that SDS-associated truncating and core-domain missense mutations abrogate SBDS function. Crystal structure of archaeal SBDS ortholog reveals critical FYSH domain folding disrupted by patient mutations; yeast complementation confirms non-functionality of p.Lys62Ter ([PMID:15701631]). SBDS localizes to the nucleolus in a cell-cycle–dependent manner, consistent with a role in rRNA processing ([PMID:15860664]).

Animal and cellular models recapitulate human SDS features: sbds knockdown in zebrafish impairs pancreatic progenitor proliferation and neutrophil development independent of p53, mirroring SDS clinical manifestations ([PMID:22872088]). These data support haploinsufficiency via defective ribosome assembly as the mechanism of pathogenesis.

Collectively, robust genetic, segregation, and functional concordance across >158 probands and multiple experimental systems establish SBDS as a definitive cause of Shwachman-Diamond syndrome. Genetic testing for common conversion alleles and rarer SBDS variants is critical for early diagnosis and management.

References

• Nature Genetics • 2003 • Mutations in SBDS are associated with Shwachman-Diamond syndrome PMID:12496757
• Archives of pathology & laboratory medicine • 2000 • Emergence of an unusual bone marrow precursor B-cell population in fatal Shwachman-Diamond syndrome PMID:10975944
• The Journal of biological chemistry • 2005 • Structural and mutational analysis of the SBDS protein family. Insight into the leukemia-associated Shwachman-Diamond Syndrome PMID:15701631
• Blood • 2005 • The Shwachman-Diamond SBDS protein localizes to the nucleolus PMID:15860664
• Experimental hematology • 2006 • Severe Shwachman-Diamond syndrome phenotype caused by compound heterozygous missense mutations in the SBDS gene PMID:17046571
• Development • 2012 • Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development PMID:22872088

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