Tuesday, December 9, 2008

Growth Hormone in Shwachman-Diamond Syndrome

I cut and pasted from the eMedicine article. Such a shame that medical professionals still cannot SPELL the disease. SIGH.


Growth hormone has been used to treat children with Schwachman-Diamond syndrome who have growth hormone deficiency. The initial response is good; however, long-term therapy with growth hormone is unsuccessful.

It comes from the eMedicine article on SDS found here: http://www.emedicine.com/ped/topic2060.htm

The reference is gives is: Marseglia GL, Bozzola M, Marchi A, et al. Response to long-term hGH therapy in two children with Schwachman- Diamond syndrome associated with GH deficiency. Horm Res. 1998;50(1):42-5




For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America

Shwachman-Diamond Syndrome Registry

You can contact the SDS registry for info on how to register. Melissa Alvendia malvendi@fhcrc.org Questionnaires are available, but the website is not up and running yet. It will hopefully be on-line soon. They also have pamphlets in PDF…but the margins are off when they are printed. They are working on getting all the supporting organizations a flyer that is easier to print. I just got an email about the flyer last night—so hopefully it will be soon.

The website for the registry will be located at www.SDSRegistry.org



For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America

Monday, December 8, 2008

SBDS-deficiency results in specific hypersensitivity to Fas stimulation and accumulation of Fas at the plasma membrane.

Apoptosis. 2008 Nov 14.

SBDS-deficiency results in specific hypersensitivity to Fas stimulation and accumulation of Fas at the plasma membrane.
Watanabe KI, Ambekar C, Wang H, Ciccolini A, Schimmer AD, Dror Y.

Shwachman-Diamond syndrome (SDS) is an inherited disorder characterized by reduced cellularity in the bone marrow and exocrine pancreas. Most patients have mutations in the SBDS gene, whose functions are unknown. We previously showed that cells deficient in the SBDS protein are characterized by accelerated apoptosis and Fas hypersensitivity, suggesting that the protein might play an important role in Fas-mediated apoptosis. To study the mechanism of Fas hypersensitivity, we compared shRNA-mediated SBDS-knockdown HeLa cells and SDS marrow CD34+ cells for their sensitivity to several groups of apoptosis inducers. Marked hypersensitivity was noticed in response to Fas stimulation, but not to tumor necrosis factor-alpha, DNA-damaging agents, transcription inhibition or protein synthesis inhibition. To identify the Fas signaling factors that cause hypersensitivity, we analyzed the expression of the pathway's proteins. We found that Fas accumulated at the plasma membrane in SBDS-knockdown cells with corresponding expression of Fas transcript 1, the main Fas transcript which contains both the transmembrane domain and the death domain. However, the total levels of Fas protein and mRNA were comparable to controls, and Fas internalization occurred normally. Expression of FADD, caspase-8 and -3 were not elevated and the pathway inhibitors: ERK, c-FLIP and XIAP were not decreased. These results suggest that SBDS loss results in abnormal accumulation of Fas at the plasma membrane, where it sensitizes the cells to stimulation by Fas ligand.


For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America

Depletion of the Shwachman-Diamond syndrome gene product, SBDS, leads to growth inhibition and increased expression of OPG and VEGF-A.

I have the full-text of this one-- very interesting article!

Blood Cells Mol Dis. 2008 Nov 15.

Depletion of the Shwachman-Diamond syndrome gene product, SBDS, leads to growth inhibition and increased expression of OPG and VEGF-A.
Nihrane A, Sezgin G, Dsilva S, Dellorusso P, Yamamoto K, Ellis SR, Liu JM.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by bone marrow failure and leukemia predisposition, pancreatic exocrine dysfunction, and skeletal abnormalities, manifesting as skeletal dysplasia and osteoporosis. Mutations in SBDS have been shown to cause SDS, but the function of the SBDS gene product is unclear. Accelerated angiogenesis has recently been described in bone marrow cells from SDS patients. To clarify the unknown function of SBDS, we performed experiments analyzing the cellular effects of depleting SBDS by RNA interference. The growth of HeLa cells constitutively depleted of SBDS was markedly hindered when compared to cells stably transfected with siRNA against an irrelevant control gene. Similarly, growth of HeLa cells induced to express siRNA against SBDS was specifically inhibited. Inducible SBDS knockdown was associated with modestly increased levels of apoptosis, suggesting a partial contribution of this process to growth inhibition. By microarray analysis of knockdown cells, we found marked differences in expression of genes in multiple pathways, and we chose to examine a selected subset more closely using quantitative PCR arrays. In constitutive and inducible SBDS-depleted HeLa cell clones, we found 3- to 6-fold elevated mRNA levels of osteoprotegerin (OPG or TNFRSF11B) and vascular endothelial growth factor-A (VEGF-A). We confirmed significant overexpression of both secreted proteins by ELISA from supernatants of SBDS-depleted HeLa cells. Osteoprotegerin and VEGF-A are known to have diverse effects on osteoclast differentiation, angiogenesis, and monocyte/macrophage migration, all processes that may be aberrant in SDS, and we propose that overexpression of these factors may contribute to its pathology.

For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America

Totipotent stem cells bearing del(20q) maintain multipotential differentiation in Shwachman Diamond syndrome.

Br J Haematol. 2008 Nov 11.
Totipotent stem cells bearing del(20q) maintain multipotential differentiation in Shwachman Diamond syndrome.

Crescenzi B, La Starza R, Sambani C, Parcharidou A, Pierini V, Nofrini V, Brandimarte L, Matteucci C, Aversa F, Martelli MF, Mecucci C.

Summary SBDS/7q11 gene mutations underlie the congenital Shwachman Diamond syndrome (SDS), characterized by bone marrow failure and high risk of haematological malignancies. In two cases of SDS with bone marrow failure and isolated del(20q) interphase fluorescence in situ hybridization (I-FISH) found no abnormalities in FHIT/3p14.2, IKZF1/7p13, D7S486/7q31, PTEN/10q23.3, WT1/11p13, ATM/11q23, D13S25/13q14, TP53/17p13, NF1/17q11, SMAD2/18q21, RUNX1/21q22. Fluorescence immunophenotype combined with I-FISH found del(20q) in a totipotent haematopoietic stem cell (CD34(+), CD133(+)) and downstream myelocyte (CD33(+), CD14(+), CD13(+)), erythrocyte (Glycophorin A(+)) and lymphocyte lineages (CD19(+), CD20(+), CD3(+), CD7(+)). These findings and clinical follow-ups confirm the benign course of SDS with isolated del(20q).


For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America