Schmidt, Albrecht Extended Abstracts of the 2023 CHI Conference on Human Factors in Computing Systems New York,NY,United States : Association for Computing Machinery, 2023 (2023), Artikel-ID 477, Seite 1-5
von Tim Van Damme ; Thatjana Gardeitchik ; Miski Mohamed ; Sergio Guerrero-Castillo ; Peter Freisinger ; Brecht Guillemyn ; Ariana Kariminejad ; Daisy Dalloyaux ; Sannevan Kraaij ; Dirk J. Lefeber ; Delfien Syx ; Wouter Steyaert ; Riet De Rycke ; Alexander Hoischen ; Erik-Jan Kamsteeg ; Sunnie Y. Wong ; Monique van Scherpenzeel ; Payman Jamili ; Ulrich Brandt ; Leo Nijtmans ; Christoph Korenke ; Brian H.Y. Chung ; Christopher C.Y. Mak ; Ingrid Hausser ; Uwe Kornak ; Björn Fischer-Zirnsak ; Tim M. Strom ; Thomas Meitinger ; Yasemin Alanay ; Gulem E. Utine ; Peter K.C. Leung ; Siavash Ghaderi-Sohi ; Paul Coucke ; Sofie Symoens ; Anne De Paepe ; Christian Thiel ; Tobias B. Haack ; Fransiska Malfait ; Eva Morava ; Bert Callewaert ; Ron A. Wevers
1-deoxy-sphingolipids; Charcot-Marie-Tooth disease; hereditary neuropathy; next generation sequencing; small fiber neuropathy
Hereditary neuropathies comprise a wide variety of chronic diseases associated to more than 80 genes identified to date. We herein examined 612 index patients with either a Charcot-Marie-Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a customized multigene panel based on the next generation sequencing technique. In 121 cases (19.8%), we identified at least one putative pathogenic mutation. Of these, 54.4% showed an autosomal dominant, 33.9% an autosomal recessive, and 11.6% an X-linked inheritance. The most frequently affected genes were PMP22 (16.4%), GJB1 (10.7%), MPZ, and SH3TC2 (both 9.9%), and MFN2 (8.3%). We further detected likely or known pathogenic variants in HINT1, HSPB1, NEFL, PRX, IGHMBP2, NDRG1, TTR, EGR2, FIG4, GDAP1, LMNA, LRSAM1, POLG, TRPV4, AARS, BIC2, DHTKD1, FGD4, HK1, INF2, KIF5A, PDK3, REEP1, SBF1, SBF2, SCN9A, and SPTLC2 with a declining frequency. Thirty-four novel variants were considered likely pathogenic not having previously been described in association with any disorder in the literature. In one patient, two homozygous mutations in HK1 were detected in the multigene panel, but not by whole exome sequencing. A novel missense mutation in KIF5A was considered pathogenic because of the highly compatible phenotype. In one patient, the plasma sphingolipid profile could functionally prove the pathogenicity of a mutation in SPTLC2. One pathogenic mutation in MPZ was identified after being previously missed by Sanger sequencing. We conclude that panel based next generation sequencing is a useful, time- and cost-effective approach to assist clinicians in identifying the correct diagnosis and enable causative treatment considerations.
Journal of neurochemistry Oxford : Wiley-Blackwell, 1956 143(2017), 5, Seite 507-522 Online-Ressource
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 E1 and A subunits, respectively, of the V1 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.
The American journal of human genetics New York, NY [u.a.] : Cell Press, 1949 100(2017), 2, Seite 216-227
