Somatic genetic rescue of a germline ribosome assembly defect

Abstract

Indirect somatic genetic rescue (SGR) of a germline mutation is thought to be rare in inherited Mendelian disorders. Here, we establish that acquired mutations in the EIF6 gene are a frequent mechanism of SGR in Shwachman-Diamond syndrome (SDS), a leukemia predisposition disorder caused by a germline defect in ribosome assembly. Biallelic mutations in the SBDS or EFL1 genes in SDS impair release of the anti-association factor eIF6 from the 60S ribosomal subunit, a key step in the translational activation of ribosomes. Here, we identify diverse mosaic somatic genetic events (point mutations, interstitial deletion, reciprocal chromosomal translocation) in SDS hematopoietic cells that reduce eIF6 expression or disrupt its interaction with the 60S subunit, thereby conferring a selective advantage over non-modified cells. SDS-related somatic EIF6 missense mutations that reduce eIF6 dosage or eIF6 binding to the 60S subunit suppress the defects in ribosome assembly and protein synthesis across multiple SBDS-deficient species including yeast, Dictyostelium and Drosophila. Our data suggest that SGR is a universal phenomenon that may influence the clinical evolution of diverse Mendelian disorders and support eIF6 suppressor mimics as a therapeutic strategy in SDS.

The frequent and clinically benign anomalies of chromosomes 7 and 20 in Shwachman-diamond syndrome may be subject to further clonal variations

“…In 1/6 cases, the patient with the i(7)(q) rearranged independently the normal chromosome 7 in a different clone. These findings strongly indicate that in SDS patients there is a peculiar karyotype instability, depending upon a mechanism/s not yet identified, that, through a striking and specific selective pressure, acts mainly on chromosomes 7 and 20 and drives to a somatic rescue of the clone, as recently shown by Tan and coworkers for del(20)(q) [16].…”

“…Both these anomalies are predicted to result in more efficient ribosome biogenesis in the BM abnormal clone which may lower the risk of MDS/AML [ 10 , 11 ] and result in a milder haematological condition compared to SDS patients with other chromosome changes or with normal karyotype [ 13 – 15 ]. These conclusions were further supported by a recent paper concerning the benign effects of somatic mutations of EIF6 [ 16 ].…”

“…We confirm that in all patients with SDS, the del(20)(q) in BM imply the loss of the EIF6 gene: the analysis of the cases presented here and of those already reported leads to a total of 24 patients. This change has specific prognostic benign implications, playing a role as BM rescue mechanisms as previously postulated [ 13 , 15 , 16 , 20 ].…”

“…It has been postulated that del(20)(q), with consistent loss of the EIF6 gene in all cases analysed, imply a good prognosis, with lower risk of MDS/AML and milder haematological conditions [ 11 , 13 , 15 ]. The relevance of EIF6 protein in ribosome biogenesis [ 4 ] may explain the benign effects in BM of the deletion del(20)(q) [ 16 ]. In a study on gene expression in BM of SDS patients with del(20)(q), with i(7)(q10), with other clonal anomalies or with normal karyotype, the transcription pattern of the patients with acquired del(20)(q) was similar to that of healthy subjects, at least in cases with a high proportion of abnormal cells, thus supporting the potential positive role of this anomaly [ 20 ].…”

Translational research for bone marrow failure patients

“…Hematopoietic colony-forming assays showed that EIF6 I13N and EIF6 A194T (EIF6 destabilization) and EIF6 N106S (disrupt EIF6 −60S ribosomal protein RPL23 interaction) mutations expressed in SBDS-deficient human CD34 + cells increased their myeloid and erythroid colony output, suggesting that EIF6 mutations increased their hematopoietic function. A subsequent study also reported similar loss of function EIF6 mutations in patients with SDS [28].…”