Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype

Gene discovery using massively parallel sequencing has focused on phenotypes diagnosed postnatally such as well‐characterized syndromes or intellectual disability, but is rarely reported for fetal disorders. We used family‐based whole‐exome sequencing in order to identify causal variants for a recurrent pattern of an undescribed lethal fetal congenital anomaly syndrome. The clinical signs included intrauterine growth restriction (IUGR), severe microcephaly, renal cystic dysplasia/agenesis and complex brain and genitourinary malformations. The phenotype was compatible with a ciliopathy, but not diagnostic of any known condition. We hypothesized biallelic disruption of a gene leading to a defect related to the primary cilium. We identified novel autosomal recessive truncating mutations in KIF14 that segregated with the phenotype. Mice with autosomal recessive mutations in the same gene have recently been shown to have a strikingly similar phenotype. Genotype–phenotype correlations indicate that the function of KIF14 in cell division and cytokinesis can be linked to a role in primary cilia, supported by previous cellular and model organism studies of proteins that interact with KIF14. We describe the first human phenotype, a novel lethal ciliary disorder, associated with biallelic inactivating mutations in KIF14. KIF14 may also be considered a candidate gene for allelic viable ciliary and/or microcephaly phenotypes.     

Licensed human natural killer cells aid dendritic cell maturation via TNFSF14/LIGHT

Interactions between natural killer (NK) cells and dendritic cells (DCs) aid DC maturation and promote T-cell responses. Here, we have analyzed the response of human NK cells to tumor cells, and we identify a pathway by which NK–DC interactions occur. Gene expression profiling of tumor-responsive NK cells identified the very rapid induction of TNF superfamily member 14 [TNFSF14; also known as homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT)], a cytokine implicated in the enhancement of antitumor responses. TNFSF14 protein expression was induced by three primary mechanisms of NK cell activation, namely, via the engagement of CD16, by the synergistic activity of multiple target cell-sensing NK-cell activation receptors, and by the cytokines IL-2 and IL-15. For antitumor responses, TNFSF14 was preferentially produced by the licensed NK-cell population, defined by the expression of inhibitory receptors specific for self-MHC class I molecules. In contrast, IL-2 and IL-15 treatment induced TNFSF14 production by both licensed and unlicensed NK cells, reflecting the ability of proinflammatory conditions to override the licensing mechanism. Importantly, both tumor- and cytokine-activated NK cells induced DC maturation in a TNFSF14-dependent manner. The coupling of TNFSF14 production to tumor-sensing NK-cell activation receptors links the tumor immune surveillance function of NK cells to DC maturation and adaptive immunity. Furthermore, regulation by NK cell licensing helps to safeguard against TNFSF14 production in response to healthy tissues.Natural killer (NK) cells play an important role in protecting the host against viral infection and cancer. As well as having potent cytotoxic activity, NK cells are endowed with immunoregulatory activity (1, 2). For example, NK cell activation induces the production of chemokines, such as macrophage inflammatory protein-1α (MIP-1α) and IL-8, and proinflammatory cytokines, such as IFN-γ, GM-CSF, and TNF-α. These molecules regulate the recruitment and activity of numerous immune cell types (1, 2). Importantly, NK cells can promote development of T-cell responses via NK–dendritic cell (DC) interactions that favor both DC maturation and NK-cell activation (3–5), with NK cell-derived IFN-γ skewing T-cell differentiation toward the Th1 phenotype (6, 7).Cytotoxic activity and cytokine production are coupled to signaling pathways downstream of a repertoire of activating and inhibitory receptors; signals from activating receptors (including NKG2D, DNAM-1, and 2B4, as well as the natural cytotoxicity receptors NKp30, NKp44, and NKp46) compete with signals from inhibitory receptors such as the killer cell immunoglobulin-like receptors (KIRs) and CD94/NKG2A heterodimers to regulate activation. In addition, NK cells express CD16, the low-affinity receptor for IgG, conferring antibody-dependent cellular cytotoxicity (8–10). Activation thus coordinates the killing of target cells, the induction of inflammation, and the promotion of adaptive immunity. This potent cytotoxicity and proinflammatory activity must be strictly controlled to minimize damage to healthy tissue. Functional competency of unstimulated NK cells is achieved via a process termed “licensing” or “education” (11–14). Licensing ensures that only those NK cells expressing inhibitory receptors for self-MHC class I can respond to target cells and NK cells that lack inhibitory receptors for self-MHC class I molecules are rendered hyporesponsive, preventing them from attacking healthy cells expressing normal levels of MHC class I molecules.We have analyzed the consequences of human NK cell activation by tumor cells. Our results reveal induction of the TNF superfamily member 14 (TNFSF14), also known as homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT) (15). We show that activated NK cells produce TNFSF14 in response to different stimuli, that tumor cells induce TNFSF14 production by licensed NK cells, and that TNFSF14-producing NK cells aid DC maturation during NK–DC cross-talk.     

Concurrent rearrangements of BCL2, BCL3, and BCL11A genes in atypical chronic lymphocytic leukemia

The most frequent chromosomal aberrations with the well established prognostic meaning in chronic lymphocytic leukemia (CLL) are +12, del(11q), del(13q), and del(17p). Less common translocations lead to deregulation of genes primarily due to juxtaposition with IGH gene.

We present a case of CLL patient with atypical morphology and an aggressive course of disease. In spite of aggressive treatment including allogeneic hematopoietic stem cell transplantation disease progressed into a rare cutaneous Richter's syndrome. Trisomy 12 was found as a sole chromosomal change at initial cytogenetic analysis of lymphoma cells. At progression, besides trisomy 12 three concomitant balanced translocations t(2;14)(p13;q32), t(14;19)(q32;q13), and t(18;22)(q21;q11) were found. The same karyotype was confirmed in cells aspirated from skin infiltrates at Richter transformation.

Atypical cytological features, trisomy 12, and a progressive course of disease observed in our case are typical for CLL with each of particular Ig translocations that were concomitantly found in CLL for the first time. Similar to “double hit” lymphoma concurrent rearrangements may be relevant also in CLL.     

The combination of bortezomib and dexamethasone is an efficient therapy for relapsed/refractory scleromyxedema: a rare disease with new clinical insights

Scleromyxedema (SM) is a rare primary cutaneous inflammatory mucinosis characterised by papular mucinosis, monoclonal gammopathy and extracutaneous involvement. Most therapeutic options have failed in SM but high-dose therapy followed by autologous peripheral blood stem cell transplantation (APBSCT) appears to be highly effective, although SM normally relapses. We report the case of a 29-yr-old patient with severe SM who achieved stringent complete response with Bortezomib plus Dexamethasone after an early relapse subsequent to a high-dose melphalan regimen followed APBSCT. It is of particular note that dermatological lesions responded to both therapies before M-component modifications, suggesting that SM is independent of M-component characteristics. However, treatment should be directed towards the underlying plasma cell malignancy with typical anti-myeloma agents.