Severe Shwachman-Diamond syndrome phenotype caused by compound heterozygous missense mutations in the SBDS gene

Melinda Erdos, Krisztina Alapi, István Balogh, György Oroszlán, Éva Rákóczi, Janos Sumegi, László Maródi

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Objective: A 5-month-old male infant presenting with recurrent respiratory tract infections, chronic diarrhea, and failure to thrive was found to be pancytopenic. Bone marrow and x-ray examinations were consistent with Shwachman-Diamond syndrome (SDS). Genomic DNA sequencing, restriction fragment analysis, and studies of the mutant proteins were performed to gain further knowledge on the molecular pathology of SDS. Materials and Methods: Exons 1 to 5 of the SBDS gene were amplified and sequenced. COS-7 cells were transfected with expression vectors containing wild-type cDNA or mutant cDNAs generated by site-directed mutagenesis. Protein expression of SBDS variants were examined by Western blotting. Pulse-chase assay and densitometry were used to study protein stability. Results: Two novel missense mutations (c.362A>C in exon 3, and c.523C>T in exon 4) of the SBDS gene were identified in the patient. These mutations result in p.N121T and p.R175W amino acid replacements and correspond to amino acid residues that are highly conserved in SBDS proteins. In vitro expression studies revealed a markedly decreased half-life of the p.R175W protein, whereas stability of the p.N121T mutant was not significantly reduced compared to that of the wild type. Conclusion: This is the first report of compound heterozygous missense mutations occurring in patients with SDS. These mutations may not eliminate SBDS expression but may result in impaired protein stability and protein function leading to severe disease.

Original languageEnglish (US)
Pages (from-to)1517-1521
Number of pages5
JournalExperimental Hematology
Volume34
Issue number11
DOIs
StatePublished - Nov 1 2006

Fingerprint

Protein Stability
Missense Mutation
Exons
Phenotype
Complementary DNA
Genes
Amino Acids
Failure to Thrive
Mutation
Proteins
Molecular Pathology
Densitometry
COS Cells
Mutant Proteins
Site-Directed Mutagenesis
DNA Sequence Analysis
Respiratory Tract Infections
Half-Life
Diarrhea
Bone Marrow

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

Cite this

Erdos, M., Alapi, K., Balogh, I., Oroszlán, G., Rákóczi, É., Sumegi, J., & Maródi, L. (2006). Severe Shwachman-Diamond syndrome phenotype caused by compound heterozygous missense mutations in the SBDS gene. Experimental Hematology, 34(11), 1517-1521. https://doi.org/10.1016/j.exphem.2006.06.009

Severe Shwachman-Diamond syndrome phenotype caused by compound heterozygous missense mutations in the SBDS gene. / Erdos, Melinda; Alapi, Krisztina; Balogh, István; Oroszlán, György; Rákóczi, Éva; Sumegi, Janos; Maródi, László.

In: Experimental Hematology, Vol. 34, No. 11, 01.11.2006, p. 1517-1521.

Research output: Contribution to journalArticle

Erdos, M, Alapi, K, Balogh, I, Oroszlán, G, Rákóczi, É, Sumegi, J & Maródi, L 2006, 'Severe Shwachman-Diamond syndrome phenotype caused by compound heterozygous missense mutations in the SBDS gene', Experimental Hematology, vol. 34, no. 11, pp. 1517-1521. https://doi.org/10.1016/j.exphem.2006.06.009
Erdos, Melinda ; Alapi, Krisztina ; Balogh, István ; Oroszlán, György ; Rákóczi, Éva ; Sumegi, Janos ; Maródi, László. / Severe Shwachman-Diamond syndrome phenotype caused by compound heterozygous missense mutations in the SBDS gene. In: Experimental Hematology. 2006 ; Vol. 34, No. 11. pp. 1517-1521.
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