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Rare Diseases

Su Yang, Xiao-Jiang Li, Shihua Li
Spinocerebellar ataxia 17 (SCA17) belongs to the family of 9 genetically inherited, late-onset neurodegenerative diseases, which are caused by polyglutamine (polyQ) expansion in different proteins. In SCA17, the polyQ expansion occurs in the TATA box binding protein (TBP), which functions as a general transcription factor. Patients with SCA17 suffer from a broad array of motor and non-motor defects, and their life expectancy is normally within 20 y after the initial appearance of symptoms. Currently there is no effective treatment, but remarkable efforts have been devoted to tackle this devastating disorder...
2016: Rare Diseases
Matthew D Rannals, Stephanie Cerceo Page, Morganne N Campbell, Ryan A Gallo, Brent Mayfield, Brady J Maher
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...
2016: Rare Diseases
Elizabeth M Turner, Christian Schlieker
Lamin B Receptor (LBR) is an inner nuclear membrane protein associated with the rare human diseases Pelger-Huët anomaly and Greenberg skeletal dysplasia. A new study has used CRISPR/Cas9-mediated genetic manipulations in a human cell system to determine that the molecular etiology of these previously poorly understood disorders is a defect in cholesterol synthesis due to loss of LBR-associated sterol C14 reductase activity. The study furthermore determined that disease-associated LBR point mutations reduce sterol C14 reductase activity by decreasing the affinity of LBR for the reducing agent NADPH...
2016: Rare Diseases
Marjo K Hytönen, Hannes Lohi
Millions of children worldwide are born with rare and debilitating developmental disorders each year. Although an increasing number of these conditions are being recognized at the molecular level, the characterization of the underlying pathophysiology remains a grand challenge. This is often due to the lack of appropriate patient material or relevant animal models. Dogs are coming to the rescue as physiologically relevant large animal models. Hundreds of spontaneous genetic conditions have been described in dogs, most with close counterparts to human rare disorders...
2016: Rare Diseases
Christina Spilker, Katarzyna M Grochowska, Michael R Kreutz
Mutations in the NSMF gene have been related to Kallmann syndrome. Conflicting results have been reported on the subcellular localization of Jacob/NELF, the protein encoded by the NSMF gene. Some reports indicate an extracellular localization and a function as a guidance molecule for migration of GnRH-positive neurons from the olfactory placode to the hypothalamus. Other studies have shown protein transport of Jacob from synapse-to-nucleus and indicate a role of the protein in neuronal activity-dependent gene expression...
2016: Rare Diseases
Emma Bondy-Chorney, Tara E Crawford Parks, Aymeric Ravel-Chapuis, Bernard J Jasmin, Jocelyn Côté
In a recent issue of PLOS Genetics, we reported that the double-stranded RNA-binding protein, Staufen1, functions as a disease modifier in the neuromuscular disorder Myotonic Dystrophy Type I (DM1). In this work, we demonstrated that Staufen1 regulates the alternative splicing of exon 11 of the human Insulin Receptor, a highly studied missplicing event in DM1, through Alu elements located in an intronic region. Furthermore, we found that Staufen1 overexpression regulates numerous alternative splicing events, potentially resulting in both positive and negative effects in DM1...
2016: Rare Diseases
Glenn S Belinsky, Leanne Ward, Chuhan Chung
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...
2016: Rare Diseases
Moones Heidari, Sam H Gerami, Brianna Bassett, Ross M Graham, Anita C G Chua, Ritambhara Aryal, Michael J House, Joanna F Collingwood, Conceição Bettencourt, Henry Houlden, Mina Ryten, John K Olynyk, Debbie Trinder, Daniel M Johnstone, Elizabeth A Milward
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...
2016: Rare Diseases
Jean-Loup Duband, Sophie Escot, Claire Fournier-Thibault
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...
2016: Rare Diseases
Ola Abdelhadi, Daniela Iancu, Horia Stanescu, Robert Kleta, Detlef Bockenhauer
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...
2016: Rare Diseases
Yoichiro Hamamoto, Shinjiro Takeoka, Atsuto Mouri, Munehisa Fukusumi, Kazushige Wakuda, Tatsuya Ibe, Chie Honma, Yoshihito Arimoto, Kazuaki Yamada, Miyuki Wagatsuma, Akito Tashiro, Shingo Kamoshida, Mitsuhiro Kamimura
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...
2016: Rare Diseases
Nicolas Pilon
Neurocristopathies form a specific group of rare genetic diseases in which a defect in neural crest cell development is causal. Because of the large number of neural crest cell derivatives, distinct structures/cell types (isolated or in combination) are affected in each neurocristopathy. The most important issues in this research field is that the underlying genetic cause and associated pathogenic mechanism of most cases of neurocristopathy are poorly understood. This article describes how a relatively simple insertional mutagenesis approach in the mouse has proved useful for identifying new candidate genes and pathogenic mechanisms for diverse neurocristopathies...
2016: Rare Diseases
Nicholas P Whitehead, Min Jeong Kim, Kenneth L Bible, Marvin E Adams, Stanley C Froehner
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...
2016: Rare Diseases
Jonasz J Weber, Midea M Ortiz Rios, Olaf Riess, Laura E Clemens, Huu P Nguyen
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...
2016: Rare Diseases
Dariusz C Górecki
Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease leading to severe disability and death of young men. Current interventions are palliative as no treatment improves the long-term outcome. Therefore, new therapeutic modalities with translational potential are urgently needed and abnormalities downstream from the absence of dystrophin are realistic targets. It has been shown that DMD mutations alter extracellular ATP (eATP) signaling via P2RX7 purinoceptor upregulation, which leads to autophagic death of dystrophic muscle cells...
2016: Rare Diseases
Saverio Marchi, Eliana Trapani, Mariangela Corricelli, Luca Goitre, Paolo Pinton, Saverio Francesco Retta
Cerebral Cavernous Malformation (CCM) is a major cerebrovascular disease of proven genetic origin affecting 0.3-0.5% of the general population. It is characterized by abnormally enlarged and leaky capillaries, which predispose to seizures, focal neurological deficits and intracerebral hemorrhage. Causative loss-of-function mutations have been identified in 3 genes, KRIT1 (CCM1), CCM2 and PDCD10 (CCM3). While providing new options for the development of pharmacological therapies, recent advances in knowledge of the functions of these genes have clearly indicated that they exert pleiotropic effects on several biological pathways...
2016: Rare Diseases
Helen Budworth, Cynthia T McMurray
Huntington's Disease is caused by inheritance of a single disease-length allele harboring an expanded CAG repeat, which continues to expand in somatic tissues with age. Whether somatic expansion contributed to toxicity was unknown. From extensive work from multiple laboratories, it has been made clear that toxicity depended on length of the inherited allele, but whether preventing or delaying somatic repeat expansion in vivo would be beneficial was unknown, since the inherited disease allele was still expressed...
2016: Rare Diseases
Christopher Patzke, Thomas C Südhof
The use of human pluripotent stem cells to model human diseases has become a new standard in biomedical sciences. To this end, patient-derived somatic cells are studied in vitro to mimic human pathological conditions. Here, we describe an alternative experimental strategy, the 'conditional KO approach', which allows engineering disease-relevant mutations in pluripotent stem cells from healthy donors. In combination with the Cre/Lox technology, this strategy enables us to study the molecular causes of human diseases independent of the genetic background or of genetic alterations induced by clonal selection...
2016: Rare Diseases
Kerri J Kinghorn, Jorge Iván Castillo-Quan
The PLA2G6 gene encodes a group VIA calcium independent phospholipase A2 (iPLA2β), which hydrolyses glycerophospholipids to release fatty acids and lysophospholipids. Mutations in PLA2G6 are associated with a number of neurodegenerative disorders including neurodegeneration with brain iron accumulation (NBIA), infantile neuroaxonal dystrophy (INAD), and dystonia parkinsonism, collectively known as PLA2G6-associated neurodegeneration (PLAN). Recently Kinghorn et al. demonstrated in Drosophila and PLA2G6 mutant fibroblasts that loss of normal PLA2G6 activity is associated with mitochondrial dysfunction and mitochondrial lipid peroxidation...
2016: Rare Diseases
Samuel J Rose, Ellen J Hess
In a recent issue of Brain, we reported on the generation and characterization of a mouse model of the rare disease L-DOPA-responsive dystonia (DRD). Here, we discuss the utility of these mice for understanding broader disease processes and treatment strategies. Using specific experimental designs that either work "forward" from genetic etiology or "backward" from the symptomatic presentation, we discuss how our data and future work can be used to understand broader themes.
2016: Rare Diseases
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