Browsing by Author "Gissen, Paul"

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The calcium-independent phospholipase A2 gene, PLA2G6, is mutated in a spectrum of childhood neurodegenerative disorders with high brain iron
(Bmj Publishing Group, 2006-09) Morgan, Neil; Westaway, Shawn K.; Morton, Jenny; Gregory, Allison; Gissen, Paul; Sonek, S.; Coryell, Jessi L.; Canham, N.; Nardocci, Nardo; Zorzi, Giovanna; Pasha, Shanaz; Rodriguez, D.; Desguerre, Isabelle; Mubaidin, A.; Bertini, Enrico; Trembath, Richard C.; Simonati, A.; Schanen, Carolyn; Johnson, Colin A.; Levinson, B.; Woods, Christopherg; Wilmot, Brett; Kramer, P.; Gitschier, J.; Hayflick, Susan J.; Maher, E. R.; Cangül, H.; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Genetik Anabilim Dalı.
Molecular investigations to improve diagnostic accuracy in patients with ARC syndrome.
(Wiley, 2009-02) Cullinane, Andrew R.; Straatman, Anna Iwanowska; Seo, Jeong K.; Ko, Jae S.; Song, Kyung S.; Gizewska, Maria; Gruszfeld, Dariusz; Gliwicz, Dorota; Tüysüz, Beyhan; Sougrat, Rachid; Wakabayashi, Yoshiyuki; Hinds, Rupert; Barnicoat, Angela; Mandel, Hanna; Chitayat, David; Fischler, Bjorn; Garcia, Angels Cazorla; Knisely, A. S.; Kelly, Deirdre A.; Maher, Eamonn R.; Gissen, Paul; Erdemir, Gülin; Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Sağlığı ve Hastalıkları Anabilim Dalı/Çocuk Gastroenteroloji Hepatoloji ve Beslenme Bilim Dalı.; 0000-0002-9726-8219; 36015044400
Arthrogryposis, Renal dysfunction and Cholestasis (ARC) syndrome is a multi-system autosomal recessive disorder caused by germline mutations in VPS33B. The detection of germline VPS33B mutations removes the need for diagnostic organ biopsies (these carry a >50% risk of life-threatening haemorrhage due to platelet dysfunction); however, VPS33B mutations are not detectable in similar to 25% of patients. In order further to define the molecular basis of ARC we performed mutation analysis and mRNA and protein studies in patients with a clinical diagnosis of ARC. Here we report novel mutations in VPS33B in patients from Eastern Europe and South East Asia. One of the mutations was present in 7 unrelated Korean patients. Reduced expression of VPS33B and cellular phenotype was detected in fibroblasts from patients clinically diagnosed with ARC with and without known VPS33B mutations. One mutation-negative patient was found to have normal mRNA and protein levels. This patient's clinical condition improved and he is alive at the age of 2.5 years. Thus we show that all patients with a classical clinical course of ARC had decreased expression of VPS33B whereas normal VPS33B expression was associated with good prognosis despite initial diagnosis of ARC.
Mutations in SLC29a3, encoding an equilibrative nucleoside transporter ENT3, cause a familial histiocytosis syndrome (Faisalabad histiocytosis) and familial Rosai-Dorfman disease
(Public Library Science, 2010-02) Morgan, Neil V.; Morris, Mark R.; Gleeson, Diane; Straatman-Iwanowska, Anna A.; Davies, Nicholas James; Keenan, Stephen J.; Pasha, Shanaz S.; Rahman, Fatimah; Gentle, Dean C.; Vreeswijk, Maaike P.G.; Devilee, Peter; Knowles, Margaret A.; Ceylaner, Serdar; Trembath, Richard C.; Dalence, Carlos; Kısmet, Erol; Köseoğlu, Vedat; Rossbach, Hans Christoph; Gissen, Paul; Tannahill, David; Mäher, Eamonn Richard; Cangül, Hakan; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Genetik Anabilim Dalı.; 8911611600
The histiocytoses are a heterogeneous group of disorders characterised by an excessive number of histiocytes. In most cases the pathophysiology is unclear and treatment is nonspecific. Faisalabad histiocytosis (FHC) (MIM 602782) has been classed as an autosomal recessively inherited form of histiocytosis with similarities to Rosai-Dorfman disease (RDD) (also known as sinus histiocytosis with massive lymphadenopathy (SHML)). To elucidate the molecular basis of FHC, we performed autozygosity mapping studies in a large consanguineous family and identified a novel locus at chromosome 10q22.1. Mutation analysis of candidate genes within the target interval identified biallelic germline mutations in SLC29A3 in the FHC kindred and in two families reported to have familial RDD. Analysis of SLC29A3 expression during mouse embryogenesis revealed widespread expression by e14.5 with prominent expression in the central nervous system, eye, inner ear, and epithelial tissues including the gastrointestinal tract. SLC29A3 encodes an intracellular equilibrative nucleoside transporter (hENT3) with affinity for adenosine. Recently germline mutations in SLC29A3 were also described in two rare autosomal recessive disorders with overlapping phenotypes: (a) H syndrome (MIM 612391) that is characterised by cutaneous hyperpigmentation and hypertrichosis, hepatomegaly, heart anomalies, hearing loss, and hypogonadism; and (b) PHID (pigmented hypertrichosis with insulin-dependent diabetes mellitus) syndrome. Our findings suggest that a variety of clinical diagnoses (H and PHID syndromes, FHC, and familial RDD) can be included in a new diagnostic category of SLC29A3 spectrum disorder.
Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization
(Nature Portfolio, 2010-04) Cullilane, Andrew Robert; Straatman-Iwanowska, Anna A.; Zaucker, Andreas; Wakabayashi, Yoshiyuki; Bruce, Christopher K.; Luo, Guanmei; Rahman, Fatimah; Gürakan, Figen; Ütine, Gülen Eda; Denecke, Jonas; Vukovic, Jurica; Di Rocco, Maja; Mandel, Hanna; Matthews, Randolph P.; Thomas, Steven G.; Rappoport, Joshua Zachary; Arias, Irwin M.; Wolburg, Hartwig; Knisely, Alexander S.; Kelly, Deirdre Anne K.; Ferenc Müller, Ferenc; Mäher, Eamonn Richard; Gissen, Paul; Özkan, Tanju Başarır; Cangül, Hakan; Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Sağlığı ve Hastalıkları Anabilim Dalı.; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Genetik Anabilim Dalı.; 35772174800; 8911611600
Arthrogryposis, renal dysfunction and cholestasis syndrome (ARC) is a multisystem disorder associated with abnormalities in polarized liver and kidney cells. Mutations in VPS33B account for most cases of ARC. We identified mutations in VIPAR (also called C14ORF133) in individuals with ARC without VPS33B defects. We show that VIPAR forms a functional complex with VPS33B that interacts with RAB11A. Knockdown of vipar in zebrafish resulted in biliary excretion and E-cadherin defects similar to those in individuals with ARC. Vipar-and Vps33b-deficient mouse inner medullary collecting duct (mIMDC-3) cells expressed membrane proteins abnormally and had structural and functional tight junction defects. Abnormal Ceacam5 expression was due to mis-sorting toward lysosomal degradation, but reduced E-cadherin levels were associated with transcriptional downregulation. The VPS33B-VIPAR complex thus has diverse functions in the pathways regulating apical-basolateral polarity in the liver and kidney.
PLA2G6, encoding a phospholipase A(2), is mutated in neurodegenerative disorders with high brain iron
(Nature Publishing Group, 2006) Morgan, Neil V.; Westaway, Shawn K; Morton, Jenny E. V.; Gregory, Allison; Gissen, Paul; Sonek, Scott; Coryell, Jason; Canham, Natalie; Nardocci, Nardo; Giovanna, Giovanna; Shanaz, Shanaz; Rodriguez, Diana; Desguerre, Isabelle; Mubaidin, Amar; Bertin, Enrico; Trembath, Richard C.; Simonati, Alessandro; Schanen, Carolyn; Johnson, Colin A.; Levinson, Barbara; Woods, C. Geoffrey; Wilmot, Beth; Kramer, Patricia; Gitschier, Jane; Maher, Eamonn R.; Hayflick, Susan J.; Cangül, Hakan; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Genetik Anabilim Dalı.; 8911611600
Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy ( INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A(2), in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis.