Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond–like features

Abstract

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.

Receptor compaction and GTPase movements drive cotranslational protein translocation

“…4d and 4f, brown). Contrary to a previous report 7 , we found that SRP(G226E) displays basal GTPase activity and stimulated GTPase reactions with SR as efficiently as wildtype SRP (Extended Data Fig. 4d and 4f).…”

“…Notably, mutant SRP(G226E), which causes severe congenital neutropenia 7,8 , strongly impaired pPL translocation ( Fig. 4d and 4f, brown).…”

“…A special GTPase domain in SRP54, termed NG, forms a GTP-dependent complex with a homologous NG-domain in SR, and the two NG-domains reciprocally stimulate each other's GTPase activity 4,5 . SRP is essential 1,6 , and mutations in SRP54-NG cause severe congenital neutropenia with Shwachman-Diamond-like features 7,8 , but the molecular basis of the defect is unknown. Previous works have primarily focused on how SRP recognizes its cargo and assembles with SR 4,5,9,10 .…”

“…ALEX measurements suggest that these mutants block the conformational rearrangements in the targeting complex at distinct steps. SRP54(G226E), which causes congenital neutropenia 7 and SR(D371) ( Fig. 2h and 2i; summarized in Fig.…”

Shwachman‐Diamond syndrome with clonal interstitial deletion of the long arm of chromosome 20 in bone marrow: haematological features, prognosis and genomic instability

“…In a small proportion of cases, biallelic mutations of two other genes involved in ribosome biogenesis may cause SDS, or an SDS-like condition: DNAJC21 (Dhanraj et al, 2017;D'Amours et al, 2018) and EFL1 (Stepensky et al, 2017). Further, an SDS-like phenotype may be caused by monoallelic mutations of the gene SRP54, which produces a protein that is a key member of the cotranslational protein-targeting pathway (Carapito et al, 2017).…”