What causes Shwachman-Diamond syndrome (SDS)?

Updated: Nov 17, 2020
  • Author: Antoinette C Spoto-Cannons, MD, FAAP; Chief Editor: Hassan M Yaish, MD  more...
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Shwachman-Diamond syndrome is inherited in an autosomal recessive fashion. [46] See the image below.

Autosomal recessive inheritance. Autosomal recessive inheritance.

In 90% of patients with Shwachman-Diamond syndrome, mutations have been found in the SBDS gene located on chromosome 7q11. The most frequent mutations are due to gene conversion between the SBDS gene and its pseudogene (SBDSP). The SBDS gene contains 5 exons, which encode a 250-amino-acid protein of unknown function. [47] SBDS is a highly conserved protein [48] which is known to play a role in ribosome biosynthesis, mitotic spindle assembly, chemotaxis, and regulation of reactive oxygen species generation. [49, 50, 51, 52, 53]

Experiments reveal that SBDS knockdown affects expression of critical genes involved in brain development and function, bone morphogenesis, blood cell proliferation and differentiation, and cell adhesion. [54] This may be due to its role in ribosome biogenesis or RNA processing, which has been shown in yeast [55] and mammalian cells. [56] One of the SBDS-binding proteins, nucleophosmin (NPM, B23), has a role in ribosome biogenesis and control of cell cycle, [57] and the SBDS proteins facilitate the release of eIF-6 which impairs the association of the 40S and 60S subunits. [51] Interestingly, mutations that affect ribosome assembly or function are associated with other inherited bone marrow failure syndromes, [58] and models of how impairment of ribosomal pathways might affect hematopoiesis and tumorigenesis are currently under investigation. [57]

Burwick et al found that knockdown of eIF-6 expression showed improvement of ribosomal subunit association but did not improve the hematopoietic deficits noted in Shwachman-Diamond syndrome. [59]

A study by Joyce et al indicated that in Shwachman-Diamond syndrome, increased activity in the transforming growth factor-β (TGFβ) pathway triggers hematopoietic dysfunction and bone marrow failure. The investigators found a rise in hematopoietic stem cells and multipotent progenitors in Shwachman-Diamond syndrome patient bone marrow in connection with TGFβ inhibitors. The study also reported higher levels of TGFβ pathway members in the blood plasma of patients with the syndrome. [60]

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