Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome (IBMFS) that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. Seventy-five to ninety percent of patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. Using trio whole-exome sequencing (WES) in an SBDS-negative SDS family and candidate gene sequencing in additional SBDS-negative SDS cases or molecularly undiagnosed IBMFS cases, we identified 3 independent patients, each of whom carried a de novo missense variant in SRP54 (encoding signal recognition particle 54 kDa). These 3 patients shared congenital neutropenia linked with various other SDS phenotypes. 3D protein modeling revealed that the 3 variants affect highly conserved amino acids within the GTPase domain of the protein that are critical for GTP and receptor binding. Indeed, we observed that the GTPase activity of the mutated proteins was impaired. The level of SRP54 mRNA in the bone marrow was 3.6-fold lower in patients with SRP54-mutations than in healthy controls. Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype. In conclusion, autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond-like phenotype.

Several lines of evidence support the presence of dosage-sensitive genes on chromosome 21 that regulate leukemogenesis and hematopoiesis. We report a detailed clinical and molecular characterization of 3 patients with chronic thrombocytopenia caused by distinct constitutional microdeletions involving chromosomal region 21q22.12. The patients exhibited growth restriction, dysmorphic features, and developmental delays.One patient developed acute myelogenous leukemia (AML) at 6 years of age. All 3 deletions included the RUNX1, CLIC6, DSCR, and KCNE1 genes. Our data provide additional support for the role of RUNX1 haploinsufficiency in megakaryopoiesis and predisposition to AML. The leukemic clone had trisomy 21 resulting from duplication of chromosome 21 containing the RUNX1 deletion. This shows that genes other than RUNX1 must also play a role in AML associated with trisomy 21. We recommend that children with syndromic thrombocytopenia have clinical array-comparative genomic hybridization analysis and appropriate cytogenetic studies to facilitate our ability to provide a definitive diagnosis. (Blood. 2008; 112:1042-1047)

The cellular protooncogene, c-ski, is expressed in all cells of the developing mouse at low but detectable levels. In situ hybridization and Northern blot analyses reveal that some cells and tissues express this gene at higher levels at certain stages of embryonic and postnatal development. RT-PCR results indicate that alternative splicing of exon 2, known to occur in chickens (Sutrave and Hughes [1989] Mol. Cell. Biol. 9:4046-4051; Grimes et al. [1993] Oncogene 8:2863-2868) does not occur in adult mouse tissues. In the embryo, neural crest cells express the c-ski gene during migration at 8.5 to 9.5 days post coitum (p.c.). Neural crest derivatives such as dorsal root ganglia and melanocytes stain positively with an antibody to the ski protein. At 9 days p.c., the entire neural tube has high levels of c-ski gene expression. By 12-13.5 days only the ependymal layer expresses c-ski above background levels. At 14-16 days p.c., c-ski mRNAs are detected at high levels in the cortical layers of the brain and in the olfactory bulb. In 2 week and 6 week postnatal brains, c-ski gene transcripts are also detected in the hippocampus and in the granule cell layer of the cerebellum. The allantois and placenta exhibit high levels of c-ski mRNAs. Neonatal lung tissue increases c-ski gene expression approximately two-fold compared to prenatal levels. These results suggest that ski plays a role in both the proliferation and differentiation of specific cell populations of the central and peripheral nervous systems and of other tissues.