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Cambridge Institute for Medical Research


Ribosomopathies such as Shwachman-Diamond syndrome (SDS) are rare diseases caused by defects in ribosome assembly.  A new international study co-led by Prof. Alan Warren (CIMR) and Prof. Patrick Revy (University of Paris) has been published in Nature Communications which reveals indirect somatic genetic rescue in subpopulations of hematopoietic cells from the bone marrows of some people with inherited forms of SDS.  In multiple independent clones, acquired somatic mutations in the ribosome assembly factor eIF6 can compensate for the translational defects caused by the germline mutations in the SBDS gene which they are also carrying, and which drive the disease. The study included detailed structural and functional analyses towards a mechanism for how these eIF6 variants reduce the impact of pathological SBDS mutations on ribosome assembly and function - and a rationale for SDS treatment through therapeutic targeting of eIF6.  This new research also suggests that indirect somatic genetic rescue may also be more widespread in other rare inherited disorders than previously thought.