Alt. symbols: SCN8

Approved name: signal recognition particle 54
Alt. names: signal recognition particle 54kDa

Location: 14q13.2: 34981957 - 35029686 (+)
Gene type: protein_coding, 23 transcripts.

Scores: LoFtool: 0.108000 | pLI: 0.99668972 | LOEUF: 0.219

HGNC: 11301

NCBI: 6729, RefSeq: .0

Ensembl: ENSG00000100883.13

LRG_ | Status: none

OMIM: 604857

Expression | ProteinAtlas

This gene encodes a 54-KDa peptide of the signal recognition particle (SRP), a ribonucleoprotein (RNP) complex that mediates the targeting of nascent signal sequence–carrying polypeptides to the translocon at the surface of the ER, is a major ribosome-associating partner during the biogenesis and initiation of protein translation. The mammalian SRP is composed of a single RNA molecule (the 7S RNA) and 6 polypeptides: SRP9, SRP14, SRP19, SRP54, SRP68, and SRP72. Thus far, SRP54 and SRP72 are the only SRP components to be associated with a monogenic disease; SRP72 mutations have been associated with bone marrow failure and aplastic anemia. SRP54 is a universally conserved SRP component and thus plays a central role in this RNP complex. SRP54 has 3 functional domains: The N-terminal domain (N-domain) is tightly connected to the central GTPase domain (G domain) and together they form the functional NG domain, implicated in GTP binding and dimerization with the SR receptor. The M domain plays a role in signal sequence binding. SRP54 binds (via its M domain) to the SRP19-bound 7S RNA and associates with the signal peptide of the nascent polypeptide chain. Then SRP54 binds to the SRP receptor (SR) on the ER membrane (via its N and G domains). Ultimately, SRP54 forms a link between the SRP and the ER membrane and allows insertion of the signal peptide-carrying polypeptide into the translocation channel (translocon). With regard to the immune system, it is involved in the granulocytic differentiation of myeloid precursor cells. The major Schwachman-Diamond syndrome gene SBDS is specifically required for the translation of key regulators of granulocyte differentiation including C/EBP α and ß. A similar mechanism may explain the selective effect of SRP54 mutations on neutrophils, because SRP54 expression levels influence genes like TRAIL that play a role in neutrophil apoptosis. It has been shown that SRP54 is specifically upregulated during in vitro granulocytic differentiation, and SRP54 mutations or knockdown have been shown to cause dramatically reduced proliferation of granulocytes. This, however, does not suffice to explain the extra-hematopoietic clinical manifestations. Another explanation that has been proposed is that nearly 40% of the almost 20,000 human protein–coding genes are predicted to be secreted or membrane bound, resulting in a de facto need for SRP54. Animal studies suggest that homozygous SRP54 mutations are likely to be lethal, while pathogenic heterozygous SRP54 mutations probably lead to quantitative and qualitative disruption of secreted and membrane-bound protein synthesis, with the potential to affect many organs. One would expect those organ systems most dependent on secreted proteins, such as pancreatic or hematopoietic cells, to be most significantly affected and show the most robustly penetrant phenotypes. Indeed, SRP54 knockdown in zebrafish embryos has been shown to cause reduced neutrophil count and neutrophil chemotaxis, as well as abnormal pancreatic development, in a manner that the identified pathogenic variants failed to rescue.

Monoallelic mutations in SRP54 have been shown to cause an autosomal dominant form of severe congenital neutropenia (SCN) with Shwachman-Diamond-like features (SDS) known as SCN type 8 [OMIM: 618752]. In 2017, Carapito et al. reported the first pathogenic heterozygous de novo missense variants in SRP54 in 3 unrelated patients with clinical features of SDS but without identifiable mutations in the known SDS genes or other inherited bone marrow failure syndrome (iBMFS) genes (PMID 28972538). Bella nné-Chantelot et al. (2018) additionally identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germline mutations. ). In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest noted within a few months of life. Many patients required long-term G-CSF therapy with variable responses. Neutropenia was sometimes associated with severe neurodevelopmental delay (n = 5) and/or exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The authors noted hallmarks of enhanced P53-dependent apoptosis, ER stress, and induction of autophagy in cells from the bone marrow of their SRP54-mutated patients and from SRP54 loss-of-function in vitro. These characteristics have also been observed in patients with SDS and Diamond Blackfan anemia. Activation of the unfolded protein response pathways has also been described in patients who have SCN with ELANE mutations. However, patients in the study from Carapito et al. presented with neutropenia associated with a host of other morphological abnormalities and/or bone marrow morphologies not typically observed in classical SDS. Among them is the finding of cytoplasmic vacuoles in myeloid precursors, suggesting that the mechanism leading to neutropenia may be different in patients with SRP54 mutations compared to the other SDS genotypes. Additionally, unlike SCN or SDS, none of the patients with SRP54 mutations (23 cases) transformed to leukemia, despite high doses of filgrastim, after a median follow-up of 15 years. After ELANE, mutations in SRP54 are the second most common cause of inherited neutropenia in the French Congenital Neutropenia Registry (Oyarbide, U. and Corey, S., Blood commentary, 2018). Reported pathogenic mutations in these studies include p.G113R, p.T115A, p.C118Y, p.C136Y, p.A223D, p.G226E, p.G274D, and the in-frame deletion p.T117del, which is the most commonly identified mutation identified thus far. All of the SRP54 mutations identified thus far are located in the G domain and predicted to affect either the catalytic function of SRP54 or the 3D structure of the NG domain. The Carapito study showed that all SRP54 mutants led to a global decrease in GTPase activity, and suggested potential genotype-phenotype correlations. With 2 exceptions, all 18 patients with G1 element mutations had only a hematological phenotype. Patients with G4 or G5 mutations presented with severe neurodevelopmental disorders, and some with exocrine pancreatic insufficiency as well. [Load More]