Journal of Clinical Investigation -- Current IssueJournal of Clinical Investigation RSS feed -- Current issueDecreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice- (Found August 15, 2008 ) Idiopathic hypogonadotropic hypogonadism (IHH) with anosmia (Kallmann syndrome; KS) or with a normal sense of smell (normosmic IHH; nIHH) are heterogeneous genetic disorders associated with deficiency of gonadotropin-releasing hormone (GnRH). While loss-of-function mutations in FGF receptor 1 (FGFR1) cause human GnRH deficiency, to date no specific ligand for FGFR1 has been identified in GnRH neuron ontogeny. Using a candidate gene approach, we identified 6 missense mutations in FGF8 in IHH...http://www.jci.org/articles/view/34538 Lnk controls mouse hematopoietic stem cell self-renewal and quiescence through direct interactions with JAK2- (Found August 15, 2008 ) In addition to its role in megakaryocyte production, signaling initiated by thrombopoietin (TPO) activation of its receptor, myeloproliferative leukemia virus protooncogene (c-Mpl, or Mpl), controls HSC homeostasis and self-renewal. Under steady-state conditions, mice lacking the inhibitory adaptor protein Lnk harbor an expanded HSC pool with enhanced self-renewal. We found that HSCs from Lnk&x02013;&x02013; mice have an increased quiescent fraction, decelerated cell cycle kinetics, and...http://www.jci.org/articles/view/35808 Using transcriptional profiling to develop a diagnostic test of operational tolerance in liver transplant recipients- (Found August 15, 2008 ) A fraction of liver transplant recipients are able to discontinue all immunosuppressive therapies without rejecting their grafts and are said to be operationally tolerant to the transplant. However, accurate identification of these recipients remains a challenge. To design a clinically applicable molecular test of operational tolerance in liver transplantation, we studied transcriptional patterns in the peripheral blood of 80 liver transplant recipients and 16 nontransplanted healthy...http://www.jci.org/articles/view/35342 Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria- (Found August 15, 2008 ) Phenylketonuria (PKU) is an inborn error of metabolism caused by mutations in phenylalanine hydroxylase (PAH). Over 500 disease-causing mutations have been identified in humans, most of which result in PAH protein misfolding and increased turnover in vivo. The use of pharmacological chaperones to stabilize or promote correct folding of mutant proteins represents a promising new direction in the treatment of misfolding diseases. We performed a high-throughput ligand screen of over 1,000...http://www.jci.org/articles/view/34355 Immune tolerance improves the efficacy of enzyme replacement therapy in canine mucopolysaccharidosis I- (Found August 15, 2008 ) Mucopolysaccharidoses (MPSs) are lysosomal storage diseases caused by a deficit in the enzymes needed for glycosaminoglycan (GAG) degradation. Enzyme replacement therapy with recombinant human &x003b1;-l-iduronidase successfully reduces lysosomal storage in canines and humans with iduronidase-deficient MPS I, but therapy usually also induces antibodies specific for the recombinant enzyme that could reduce its efficacy. To understand the potential impact of &x003b1;-l-iduronidase&x02013;specific.http://www.jci.org/articles/view/34676 Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations- (Found August 15, 2008 ) Congenital hyperinsulinism is a condition of dysregulated insulin secretion often caused by inactivating mutations of the ATP-sensitive K+ (KATP) channel in the pancreatic &x003b2; cell. Though most disease-causing mutations of the 2 genes encoding KATP subunits, ABCC8 (SUR1) and KCNJ11 (Kir6.2), are recessively inherited, some cases of dominantly inherited inactivating mutations have been reported. To better understand the differences between dominantly and recessively inherited inactivating...http://www.jci.org/articles/view/35414 APRIL secreted by neutrophils binds to heparan sulfate proteoglycans to create plasma cell niches in human mucosa- (Found August 15, 2008 ) The bone marrow constitutes a favorable environment for long-lived antibody-secreting plasma cells, providing blood-circulating antibody. Plasma cells are also present in mucosa-associated lymphoid tissue (MALT) to mediate local frontline immunity, but how plasma cell survival there is regulated is not known. Here we report that a proliferation-inducing ligand (APRIL) promoted survival of human upper and lower MALT plasma cells by upregulating expression of the antiapoptotic proteins bcl-2,...http://www.jci.org/articles/view/33760 B cell receptor revision diminishes the autoreactive B cell response after antigen activation in mice- (Found August 15, 2008 ) Autoreactive B cells are regulated in the BM during development through mechanisms, including editing of the B cell receptor (BCR), clonal deletion, and anergy. Peripheral B cell tolerance is also important for protection from autoimmune damage, although the mechanisms are less well defined. Here we demonstrated, using a mouse model of SLE-like serology, that during an autoimmune response, RAG was reinduced in antigen-activated early memory or preplasma B cells. Expression of RAG was specific...http://www.jci.org/articles/view/35618 Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice- (Found August 15, 2008 ) Familial macular degeneration is a clinically and genetically heterogeneous group of disorders characterized by progressive central vision loss. Here we show that an R373C missense mutation in the prominin 1 gene (PROM1) causes 3 forms of autosomal-dominant macular degeneration. In transgenic mice expressing R373C mutant human PROM1, both mutant and endogenous PROM1 were found throughout the layers of the photoreceptors, rather than at the base of the photoreceptor outer segments, where PROM1...http://www.jci.org/articles/view/35891 |