Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome.

The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann-like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development.

Molecular cytogenetic characterization of four commonly used cell lines derived from Hodgkin lymphoma.

Hodgkin lymphoma (HL) is a malignant lymphoma composed of a minority of neoplastic cells-the Hodgkin and Reed-Sternberg (HRS) cells-and a majority of nonneoplastic inflammatory cells. The low proportion of tumor cells makes genetic studies of primary neoplasia difficult. Therefore, established HL-derived cell lines are commonly used as model systems. Here we have characterized the chromosomal composition of four such cell lines: L-540, DEV, HDLM-2, and CO. Using spectral karyotyping (SKY), reversed DAPI banding, and comparative genomic hybridization (CGH), the karyotypes were characterized and previously unidentified marker chromosomes were resolved. The karyotype for CO was incompatible with the original description but showed striking similarities with the T-ALL-derived cell line CCRF-CEM, suggesting that CO had been cross-contaminated and overgrown prior to arrival at our laboratory. Multiple numerical and structural abnormalities were identified in DEV and HDLM-2, as well as in L-540. Refined composed karyotypes are suggested for the cell lines studied, to be used as references for further studies of lymphoma.