Rare diseases (Austin, Tex.)最新文献

The clinically pleiotropic gene, Transcription Factor 4 (TCF4), is a broadly expressed basic helix-loop-helix (bHLH) transcription factor linked to multiple neurodevelopmental disorders, including schizophrenia, 18q deletion syndrome, and Pitt Hopkins syndrome (PTHS). In vivo suppression of Tcf4 by shRNA or mutation by CRISPR/Cas9 in the developing rat prefrontal cortex resulted in attenuated action potential output. To explain this intrinsic excitability deficit, we demonstrated that haploinsufficiency of TCF4 lead to the ectopic expression of two ion channels, Scn10a and Kcnq1. These targets of TCF4 regulation were identified through molecular profiling experiments that used translating ribosome affinity purification to enrich mRNA from genetically manipulated neurons. Using a mouse model of PTHS (Tcf4^+/tr), we observed a similar intrinsic excitability deficit, however the underlying mechanism appeared slightly different than our rat model - as Scn10a expression was similarly increased but Kcnq1 expression was decreased. Here, we show that the truncated TCF4 protein expressed in our PTHS mouse model binds to wild-type TCF4 protein, and we suggest the difference in Kcnq1 expression levels between these two rodent models appears to be explained by a dominant-negative function of the truncated TCF4 protein. Despite the differences in the underlying molecular mechanisms, we observed common underlying intrinsic excitability deficits that are consistent with ectopic expression of Scn10a. The converging molecular function of TCF4 across two independent rodent models indicates SCN10a is a potential therapeutic target for Pitt-Hopkins syndrome.

Osteogenesis imperfecta (OI) Type VI is characterized by a defect in bone mineralization, which results in multiple fractures early in life. Null mutations in the PEDF gene, Serpinf1, are the cause of OI VI. Whether PEDF restoration in a murine model of OI Type VI could improve bone mass and function was previously unknown. In Belinsky et al, we provided evidence that PEDF delivery enhanced bone mass and improved parameters of bone function in vivo. Further, we demonstrated that PEDF temporally inhibits Wnt signaling to enhance osteoblast differentiation. Here, we demonstrate that generation of induced pluripotent stem cells (iPSCs) from a PEDF null patient provides additional evidence for PEDF's role in regulating extracellular matrix proteins secreted from osteoblasts. PEDF null iPSCs have marked abnormalities in secreted matrix proteins, capturing a key feature of human OI Type VI, which were normalized by exogenous PEDF. Lastly, we place our recent findings within the broader context of PEDF biology and the developmental signaling pathways that are implicated in its actions.

We previously demonstrated elevated brain iron levels in myelinated structures and associated cells in a hemochromatosis Hfe (-/-) xTfr2 (mut) mouse model. This was accompanied by altered expression of a group of myelin-related genes, including a suite of genes causatively linked to the rare disease family 'neurodegeneration with brain iron accumulation' (NBIA). Expanded data mining and ontological analyses have now identified additional myelin-related transcriptome changes in response to brain iron loading. Concordance between the mouse transcriptome changes and human myelin-related gene expression networks in normal and NBIA basal ganglia testifies to potential clinical relevance. These analyses implicate, among others, genes linked to various rare central hypomyelinating leukodystrophies and peripheral neuropathies including Pelizaeus-Merzbacher-like disease and Charcot-Marie-Tooth disease as well as genes linked to other rare neurological diseases such as Niemann-Pick disease. The findings may help understand interrelationships of iron and myelin in more common conditions such as hemochromatosis, multiple sclerosis and various psychiatric disorders.

EAST syndrome is a recently described autosomal recessive disorder secondary to mutations in KCNJ10 (Kir4.1), a gene encoding a potassium channel expressed in the brain, eye, ear and kidney. This condition is characterized by 4 cardinal features; Epilepsy, Ataxia, Sensorineural deafness, and (a renal salt-wasting) Tubulopathy, hence the acronym EAST syndrome. Here we review reported clinical manifestations, in particular the neurological signs and symptoms which typically have the most impact on the quality of life of patients. In addition we review the pathophysiology and genetic aspects of the disease. So far 14 different KCNJ10 mutations have been published which either directly affect channel function or may lead to mislocalisation. Investigations of the pathophysiology may provide clues to potential treatments.

The DiGeorge/22q11-deletion syndrome (22q11DS), also known as velocardiofacial syndrome, is a congenital disease causing numerous structural and behavioral disorders, including cardiac outflow tract anomalies, craniofacial dysmorphogenesis, parathyroid and thymus hypoplasia, and mental disorders. It results from a unique chromosomal microdeletion on the 22q11.2 region in which the transcriptional activator TBX1 is decisive for the occurrence of the disease. During embryogenesis, Tbx1 is required for patterning of pharyngeal region giving rise to structures of the face, neck and chest. Genetic and developmental studies demonstrated that the severity and variability of the syndrome are determined by Tbx1 targets involved in pharyngeal neural crest cell migration and survival. Recently, we demonstrated that the chemokine Sdf1/Cxcl12 and its receptor Cxcr4 are genetically downstream of Tbx1 during pharyngeal development and that reduction of CXCR4 signaling results in defects which recapitulate the major morphological anomalies of 22q11DS, supporting the possibility of a pivotal role for the SDF1/CXCR4 axis in its etiology.

Duchenne muscular dystrophy (DMD) is the most common and severe inherited neuromuscular disorder. DMD is caused by mutations in the gene encoding the dystrophin protein in muscle fibers. Dystrophin was originally proposed to be a structural protein that protected the sarcolemma from stresses produced during contractions. However, more recently, experimental evidence has revealed a far more complicated picture, with the loss of dystrophin causing dysfunction of multiple muscle signaling pathways, which all contribute to the overall disease pathophysiology. Current gene-based approaches for DMD are conceptually appealing since they offer the potential to restore dystrophin to muscles, albeit a partially functional, truncated form of the protein. However, given the cost and technical challenges facing these genetic approaches, it is important to consider if relatively inexpensive, clinically used drugs may be repurposed for treating DMD. Here, we discuss our recent findings showing the potential of simvastatin as a novel therapy for DMD.

Olesoxime, a small molecule drug candidate, has recently attracted attention due to its significant beneficial effects in models of several neurodegenerative disorders including Huntington's disease. Olesoxime's neuroprotective effects have been assumed to be conveyed through a direct, positive influence on mitochondrial function. In a long-term treatment study in BACHD rats, the latest rat model of Huntington's disease, olesoxime revealed a positive influence on mitochondrial function and improved specific behavioral and neuropathological phenotypes. Moreover, a novel target of the compound was discovered, as olesoxime was found to suppress the activation of the calpain proteolytic system, a major contributor to the cleavage of the disease-causing mutant huntingtin protein into toxic fragments, and key player in degenerative processes in general. Results from a second model of Huntington's disease, the Hdh (Q111) knock-in mouse, confirm olesoxime's calpain-suppressing effects and support the therapeutic value of olesoxime for Huntington's disease and other disorders involving calpain overactivation.

Objective: Malignant pleural mesothelioma (MPM) is a rare and aggressive, treatment-resistant cancer. Pemetrexed, an inhibitor of thymidylate synthase (TS), is used worldwide for MPM as a first-line chemotherapy regimen. However, there is little consensus for a second-line chemotherapy. S-1, a highly effective dihydropyrimidine dehydrogenase (DPD)-inhibitory fluoropyrimidine, mainly acts via a TS inhibitory mechanism similar to pemetrexed. Orotate phosphoribosyltransferase (OPRT) is a key enzyme related to the first step activation of 5-fluorouracil (5-FU) for inhibiting RNA synthesis. We investigated 5-FU related-metabolism proteins, especially focusing on OPRT expression, in MPM Methods and Patients: Fifteen MPM patients who were diagnosed between July 2004 and December 2013 were enrolled. We examined the protein levels of 5-FU metabolism-related enzymes (TS, DPD, OPRT, and thymidine phosphorylase [TP]) in 14 cases

Results: High TS, DPD, OPRT, and TP expressions were seen in 28.6%, 71.4%, 85.7%, and 35.7% of patients, respectively. We found that OPRT expression was extremely high in MPM tissue. We experienced one remarkable case of highly effective S-1 combined therapy for pemetrexed refractory MPM. This case also showed high OPRT protein expression Conclusion: The present study suggests that OPRT expression is high in MPM tumors. Although pemetrexed is mainly used for MPM chemotherapy as a TS inhibitor, S-1 has potential as an anticancer drug not only as a TS inhibitor but also inhibiting RNA synthesis through the OPRT pathway. This is the first report investigating OPRT protein expressions in MPM.