TY - JOUR A1 - Vona, Barbara A1 - Mazaheri, Neda A1 - Lin, Sheng-Jia A1 - Dunbar, Lucy A. A1 - Maroofian, Reza A1 - Azaiez, Hela A1 - Booth, Kevin T. A1 - Vitry, Sandrine A1 - Rad, Aboulfazl A1 - Rüschendorf, Franz A1 - Varshney, Pratishtha A1 - Fowler, Ben A1 - Beetz, Christian A1 - Alagramam, Kumar N. A1 - Murphy, David A1 - Shariati, Gholamreza A1 - Sedaghat, Alireza A1 - Houlden, Henry A1 - Petree, Cassidy A1 - VijayKumar, Shruthi A1 - Smith, Richard J. H. A1 - Haaf, Thomas A1 - El-Amraoui, Aziz A1 - Bowl, Michael R. A1 - Varshney, Gaurav K. A1 - Galehdari, Hamid T1 - A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans JF - Human Genetics N2 - Deafness, the most frequent sensory deficit in humans, is extremely heterogeneous with hundreds of genes involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein, as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 14.96 Mb locus on chromosome 4p15.32p15.1 containing a likely pathogenic missense variant in CLRN2 (c.494C > A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C > A variant leads to two events: (1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and (2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients. KW - deafness KW - CLRN2 KW - gene Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267740 SN - 1432-1203 VL - 140 IS - 6 ER - TY - JOUR A1 - Böhm, Johann A1 - Vasli, Nasim A1 - Maurer, Marie A1 - Cowling, Belinda A1 - Shelton, G. Diane A1 - Kress, Wolfram A1 - Toussaint, Anne A1 - Prokic, Ivana A1 - Schara, Ulrike A1 - Anderson, Thomas James A1 - Weis, Joachim A1 - Tiret, Laurent A1 - Laporte, Jocelyn T1 - Altered Splicing of the BIN1 Muscle-Specific Exon in Humans and Dogs with Highly Progressive Centronuclear Myopathy JF - PLOS Genetics N2 - Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies. KW - linked myotubular myopathy KW - skeletal muscle KW - inherited myopathy KW - SH3 domain KW - amphiphysin-2 BIN1 KW - membrane curvature KW - tumor-suppressor KW - great dane KW - mutation KW - gene Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127590 SN - 1553-7404 VL - 9 IS - 6 ER - TY - JOUR A1 - Rickman, Kimberly A. A1 - Lach, Francis P. A1 - Abhyankar, Avinash A1 - Donovan, Frank X. A1 - Sanborn, Erica M. A1 - Kennedy, Jennifer A. A1 - Sougnez, Carrie A1 - Gabriel, Stacey B. A1 - Elemento, Olivier A1 - Chandrasekharappa, Settara C. A1 - Schindler, Detlev A1 - Auerbach, Arleen D. A1 - Smogorzewska, Agata T1 - Deficiency of UBE2T, the E2 Ubiquitin Ligase Necessary for FANCD2 and FANCI Ubiquitination, Causes FA-T Subtype of Fanconi Anemia JF - Cell Reports N2 - Fanconi anemia (FA) is a rare bone marrow failure and cancer predisposition syndrome resulting from pathogenic mutations in genes encoding proteins participating in the repair of DNA interstrand crosslinks (ICLs). Mutations in 17 genes (FANCA-FANCS) have been identified in FA patients, defining 17 complementation groups. Here, we describe an individual presenting with typical FA features who is deficient for the ubiquitin-conjugating enzyme (E2), UBE2T. UBE2T is known to interact with FANCL, the E3 ubiquitin-ligase component of the multiprotein FA core complex, and is necessary for the monoubiquitination of FANCD2 and FANCI. Proband fibroblasts do not display FANCD2 and FANCI monoubiquitination, do not form FANCD2 foci following treatment with mitomycin C, and are hypersensitive to crosslinking agents. These cellular defects are complemented by expression of wild-type UBE2T, demonstrating that deficiency of the protein UBE2T can lead to Fanconi anemia. UBE2T gene gains an alias of FANCT. KW - cross-link repair KW - DNA repair KW - gene KW - mutations KW - aldehydes KW - somatic mosaicism KW - pathway KW - monoubiquitination KW - diagnosis KW - proteins Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151525 VL - 12 SP - 35 EP - 41 ER - TY - JOUR A1 - Walter, Maggie C. A1 - Reilich, Peter A1 - Thiele, Simone A1 - Schessl, Joachim A1 - Schreiber, Herbert A1 - Reiners, Karlheinz A1 - Kress, Wolfram A1 - Müller-Reible, Clemens A1 - Vorgerd, Matthias A1 - Urban, Peter A1 - Schrank, Bertold A1 - Deschauer, Marcus A1 - Schlotter-Weigel, Beate A1 - Kohnen, Ralf A1 - Lochmüller, Hans T1 - Treatment of dysferlinopathy with deflazacort: a double-blind, placebo-controlled clinical trial JF - Orphanet Journal of Rare Diseases N2 - Background: Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with the most prominent being Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B). Methods: We assessed the one-year-natural course of dysferlinopathy, and the safety and efficacy of deflazacort treatment in a double-blind, placebo-controlled cross-over trial. After one year of natural course without intervention, 25 patients with genetically defined dysferlinopathy were randomized to receive deflazacort and placebo for six months each (1 mg/kg/day in month one, 1 mg/kg every 2nd day during months two to six) in one of two treatment sequences. Results: During one year of natural course, muscle strength declined about 2% as measured by CIDD (Clinical Investigation of Duchenne Dystrophy) score, and 76 Newton as measured by hand-held dynamometry. Deflazacort did not improve muscle strength. In contrast, there is a trend of worsening muscle strength under deflazacort treatment, which recovers after discontinuation of the study drug. During deflazacort treatment, patients showed a broad spectrum of steroid side effects. Conclusion: Deflazacort is not an effective therapy for dysferlinopathies, and off-label use is not warranted. This is an important finding, since steroid treatment should not be administered in patients with dysferlinopathy, who may be often misdiagnosed as polymyositis. KW - Deflazacort KW - muscle strength KW - gridle muscular-dystrophy KW - Duchenne dystrphy KW - Miyoshi myopathy KW - mutation KW - prednisone KW - gene KW - 2B KW - children KW - design KW - steroids KW - therapy KW - dysferlinopathy KW - Limb girdle muscular dystrophy (LGMD) Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125663 SN - 1750-1172 VL - 8 IS - 26 ER -