Genetic and Phenotypic characterisation of a novel Efl1 mouse mutant of shwachman diamond syndrome

A novel mouse mutant was identified through an ENU (N-ethyl-N-nitrosourea) mutagenesis screen due to an abnormal gait. Next generation sequencing revealed the causative mutation to be in the gene Efl1 (K983R). The protein EFL1 is involved in ribosome maturation, a cellular process that is defective in diseases collectively known as ribosomopathies. More specifically, EFL1 is critical for the release of anti-association factor eIF6 from the 60S subunit, which allows subsequent joining with the 40S subunit to form a translationally active particle. ShwachmanDiamond syndrome (SDS) is a ribosomopathy in which this process is known to be defective. SDS is an autosomal recessive disorder typified by bone marrow failure, pancreatic insufficiency and various anaemias. 90% of patients with SDS have missense mutations in the gene SBDS. The protein SBDS, together with EFL1, binds to the 60S subunit and causes the release of the anti-association factor eIF6. Both SBDS and EFL1 are needed for this process to occur correctly. In patients with SDS, eIF6 release is impaired due to a deficiency of functional SBDS, thus causing a ribosomal joining defect. Current research into SDS focuses on yeast models or conditional knockout/embryonic mouse models. However, this gives a limited view of the disorder as it does not reflect the multi-system nature or temporal aspects of SDS. In depth phenotypic characterisation of the Efl1-K983R mouse-line has revealed many phenotypes that reflect human SDS symptoms, such as small size, various haematological abnormalities, reduced bone mass density, deafness secondary to otitis media and behavioural deviations. At the molecular level, impaired eIF6 release has been demonstrated in mouse embryonic fibroblasts and liver. Multiple tissues from mutant mice show severe EFL-1 deficiency, suggesting that these symptoms may be reflective of the SBDS deficiency seen in SDS patients. Approximately 10% of SDS patients do not have SBDS mutations, and these patients are referred to as having ‘genetically undefined’ SDS. The cause of patients symptoms in these cases are unclear, and no causative gene has been found. Here we present data that suggests that Efl1 may be a candidate gene for ‘genetically undefined’ SDS. The data presented here also suggests that this mouse represents an opportunity to study SDS-like processes in a long lived, multi-system mammalian model, which is otherwise unavailable for Sbds mutants.