👤 Margot Haun

We performed a molecular analysis of formalin-fixed paraffin embedded and decalcified bone marrow trephine biopsies of 41 patients with a B-cell disorder with lymphoplasmacytic differentiation to enable a more precise diagnosis and to describe potentially prognostic and therapeutic relevant mutations. Analysis was performed with a commercially available next-generation sequencing (NGS) lymphoma panel (Lymphoma Solution, SophiaGenetics). Results were correlated with clinical and pathological parameters. Our group covered a spectrum of B-cell disorders with plasmacytic differentiation ranging from Waldenstroem's macroglobulinemia (WM), to small-B-cell lymphomas with plasmacytic differentiation (SBCL-PC) to IgM myeloma (MM). The most helpful diagnostic criteria included morphology and immuno-phenotype as a prerequisite for the interpretation of molecular analysis. MYD88 mutation was present in nearly all WM, but also in 50% of SBCL-PCs, while MM were consistently negative. Driver mutations, such as TP53, were already detectable early in the course of the respective diseases indicating a higher risk of progression, transformation, and reduced progression-free survival. In addition, we report on a novel BIRC3 frameshift mutation in one case of a progressive WM. Our data indicate that patients with LPL/WM might benefit from thorough pathological work-up and detailed molecular analysis in terms of precise diagnosis and targeted treatment allocation. Show less

Osteogenesis imperfecta (OI) is a genetically and clinically heterogeneous disorder characterized by bone fragility and reduced bone mass generally caused by defects in type I collagen structure or defects in proteins interacting with collagen processing. We identified a homozygous missense mutation in SEC16B in a child with vertebral fractures, leg bowing, short stature, muscular hypotonia, and bone densitometric and histomorphometric features in keeping with OI with distinct ultrastructural features. In line with the putative function of SEC16B as a regulator of trafficking between the ER and the Golgi complex, we showed that patient fibroblasts accumulated type I procollagen in the ER and exhibited a general trafficking defect at the level of the ER. Consequently, patient fibroblasts exhibited ER stress, enhanced autophagosome formation, and higher levels of apoptosis. Transfection of wild-type SEC16B into patient cells rescued the collagen trafficking. Mechanistically, we show that the defect is a consequence of reduced SEC16B expression, rather than due to alterations in protein function. These data suggest SEC16B as a recessive candidate gene for OI. Show less

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD. Show less