The Shwachman-Diamond SBDS protein localizes to the nucleolus

Abstract

Shwachman-Diamond syndrome (SDS) is an autosomal recessively inherited disorder characterized by exocrine pancreatic insufficiency and bone marrow failure. The gene for this syndrome, SBDS, encodes a highly conserved novel protein. We characterized Shwachman-Bodian-Diamond syndrome (SBDS) protein expression and intracellular localization in 7 patients with SDS and healthy controls. As predicted by gene mutation, 4 patients with SDS exhibited no detectable full-length SBDS protein. Patient DF277, who was homozygous for the IVS2 + 2 T>C splice donor mutation, expressed scant levels of SBDS protein. Patient SD101 expressed low levels of SBDS protein harboring an R169C missense mutation. Patient DF269, who carried no detectable gene mutations, expressed wild-type levels of SBDS protein to add further support to the growing body of evidence for additional gene(s) that might contribute to the pathogenesis of the disease phenotype. The SBDS protein was detected in both the nucleus and the cytoplasm of normal control fibroblasts, but was particularly concentrated within the nucleolus. SBDS localization was cell-cycle dependent, with nucleolar localization during G1 and G2 and diffuse nuclear localization during S phase. SBDS nucleolar localization was intact in SD101 and DF269. The intranucleolar localization of SBDS provides further supportive evidence for its postulated role in rRNA processing.

The isochromosome i(7)(q10) carrying c.258+2t>c mutation of the SBDS gene does not promote development of myeloid malignancies in patients with Shwachman syndrome

“…2 However, the c.258 þ 2T4C mutation, either in homozygous condition or in association with a rare mutation such as c.505C4T (p.R169C), still allows the production of some amount of normal protein. 6 This observation was recently confirmed by Nicolis et al 7 who demonstrated the presence of some amount of normal mRNA in patients carrying the c.258 þ 2T4C mutation both as compound heterozygotes (258 þ 2T4C/183_184TA4CT) and as homozygotes (258 þ 2T4C/258 þ 2T4C). In fact, when the strength of the mutated and cryptic splice sites is compared, the scores obtained support the available evidence that the mutated splice site might be partially active.…”

“…5 A reduced but detectable quantity of the SBDS protein was shown to be present in fibroblasts of two SDS patients, this finding suggesting that the mutation found in these two cases, namely c.258 þ 2T4C, may lead to the presence of a small amount of alternatively spliced SBDS mRNA, encoding a functional protein. 6 Recently, Nicolis et al 7 demonstrated that wild-type (wt) mRNA can be found in patients carrying this mutation.…”

Defective ribosome biogenesis in myelodysplastic syndromes

“…This idea was supported by previous findings that genetic defects of ribosomal genes were implicated in congenital anemias including dyskeratosis congenita, 12 cartilage-hair hypoplasia, 13 DiamondBlackfan anemia 14 and Shwachman-Diamond syndrome. 15,16 The importance of RPS14 haplo-insufficency as a causative event in 5q-syndrome was then shown by Ebert et al using RNAi to selectively inhibit each of the 40 genes within the deleted region. 17 Suppression of RPS14 in normal CD34 + cells resulted in a 5q-syndrome like phenotype while forced expression in the hematopoietic cells of patients with 5q-syndrome rescued the phenotype.…”

Some cases of common variable immunodeficiency may be due to a mutation in the SBDS gene of Shwachman–Diamond syndrome

“…The SBDS gene located on chromosome 7q11 is highly conserved in archaea, plants and eukaryotes [3,16]. The protein is predicted to have 250 amino acids and gene conversion during meiosis with its neighbouring pseudogene, SBDSP (the duplicon of SBDS gene located 5·8Mb distally with nucleotide sequence homology of 97%), which results in the [17] and studies in yeast homologues suggest a role in ribosomal RNA processing [18,19]. Homozygous early truncating mutations result in complete loss in SDS function and are lethal at the embryo stage [18,20], explaining the absence of patients with such mutations.…”