Browsing by Author "Hoischen, Alexander"

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    Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa
    (CELL PRESS, 2017-01-01) Van Damme, Tim; Gardeitchik, Thatjana; Mohamed, Miski; Guerrero-Castillo, Sergio; Freisinger, Peter; Guillemyn, Brecht; Kariminejad, Ariana; Dalloyaux, Daisy; Van Kraaij, Sanne; Lefeber, Dirk J.; Syx, Delfien; Steyaert, Wouter; De Rycke, Riet; Hoischen, Alexander; Kamsteeg, Erik-Jan; Wong, Sunnie Y.; van Scherpenzeel, Monique; Jamali, Payman; Brandt, Ulrich; Nijtmans, Leo; Korenke, G. Christoph; Chung, Brian H. Y.; Mak, Christopher C. Y.; Hausser, Ingrid; Kornak, Uwe; Fischer-Zirnsak, Bjorn; Strom, Tim M.; Meitinger, Thomas; Alanay, Yasemin; Utine, Gulen E.; Leung, Peter K. C.; Ghaderi-Sohi, Siavash; Coucke, Paul; Symoens, Sofie; De Paepe, Anne; Thiel, Christian; Haack, Tobias B.; Malfait, Fransiska; Morava, Eva; Callewaert, Bert; Wevers, Ron A.
    Defects of the V-type proton (H+) ATPase (V-ATPase) impair acidification and intracellular trafficking of membrane-enclosed compartments, including secretory granules, endosomes, and lysosomes. Whole-exome sequencing in five families affected by mild to severe cutis laxa, dysmorphic facial features, and cardiopulmonary involvement identified biallelic missense mutations in ATP6V1E1 and ATP6V1A, which encode the El and A subunits, respectively, of the V-1 domain of the heteromultimeric V-ATPase complex. Structural modeling indicated that all substitutions affect critical residues and inter- or intrasubunit interactions. Furthermore, complexome profiling, a method combining blue-native gel electrophoresis and liquid chromatography tandem mass spectrometry, showed that they disturb either the assembly or the stability of the V-ATPase complex. Protein glycosylation was variably affected. Abnormal vesicular trafficking was evidenced by delayed retrograde transport after brefeldin A treatment and abnormal swelling and fragmentation of the Golgi apparatus. In addition to showing reduced and fragmented elastic fibers, the histopathological hallmark of cutis laxa, transmission electron microscopy of the dermis also showed pronounced changes in the structure and organization of the collagen fibers. Our findings expand the clinical and molecular spectrum of metabolic cutis laxa syndromes and further link defective extracellular matrix assembly to faulty protein processing and cellular trafficking caused by genetic defects in the V-ATPase complex.
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    Mutations in the interleukin receptor IL11RA cause autosomal recessive Crouzon-like craniosynostosis
    (WILEY, 2013-01-01) Keupp, Katharina; Li, Yun; Vargel, Ibrahim; Hoischen, Alexander; Richardson, Rebecca; Neveling, Kornelia; Alanay, Yasemin; Uz, Elif; Elcioglu, Nursel; Rachwalski, Martin; Kamaci, Soner; Tuncbilek, Gokhan; Akin, Burcu; Grotzinger, Joachim; Konas, Ersoy; Mavili, Emin; Muller-Newen, Gerhard; Collmann, Hartmut; Roscioli, Tony; Buckley, Michael F.; Yigit, Gokhan; Gilissen, Christian; Kress, Wolfram; Veltman, Joris; Hammerschmidt, Matthias; Akarsu, Nurten A.; Wollnik, Bernd
    We have characterized a novel autosomal recessive Crouzon-like craniosynostosis syndrome in a 12-affected member family from Antakya, Turkey, the presenting features of which include: multiple suture synostosis, midface hypoplasia, variable degree of exophthalmos, relative prognathism, a beaked nose, and conductive hearing loss. Homozygosity mapping followed by targeted next-generation sequencing identified a c.479+6T>G mutation in the interleukin 11 receptor alpha gene (IL11RA) on chromosome 9p21. This donor splice-site mutation leads to a high percentage of aberrant IL11RA mRNA transcripts in an affected individual and altered mRNA splicing determined by in vitro exon trapping. An extended IL11RA mutation screen was performed in a cohort of 79 patients with an initial clinical diagnosis of Crouzon syndrome, pansynostosis, or unclassified syndromic craniosynostosis. We identified mutations segregating with the disease in five families: a German patient of Turkish origin and a Turkish family with three affected sibs all of whom were homozygous for the previously identified IL11RA c.479+6T>G mutation