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2. Molecular characterization of WFS1 in patients with Wolfram syndrome

Author

Van den Ouweland, JMW, Cryns, K, Pennings, RJE, Walraven, [No Value], Janssen, GMC, Maassen, JA, Veldhuijzen, BFE, Arntzenius, AB, Lindhout, D, Cremers, CWRJ, Van Camp, G, Dikkeschei, LD, and University of Groningen

Subjects
TRANSMEMBRANE PROTEIN, endocrine system diseases, TRANSLATION EFFICIENCY, MITOCHONDRIAL-DNA, MUTATIONS, OPTIC ATROPHY, HEARING-LOSS, DELETION, otorhinolaryngologic diseases, nutritional and metabolic diseases, DIABETES-MELLITUS, SYNDROME GENE, DEAFNESS
Abstract

Wolfram (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is a rare autosomal-recessive neurodegenerative disorder that is characterized by juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing impairment. A gene responsible for Wolfram syndrome (WTS1) has been identified on the short arm of chromosome 4 and subsequently mutations in WFS1 have been described. We have screened 12 patients with Wolfram syndrome from nine Dutch families for mutations in the WFS1-coding region by single-strand conformation polymorphism analysis and direct sequencing. Furthermore, we analyzed the mitochondrial genome for gross abnormalities and the A3243G point mutation in the leucyl-tRNA gene, because Wolfram syndrome shows phenotypic similarities with mitochondrial disease. Seven mutations in WTS1 were identified in six of nine families: two missense mutations, one frameshift mutation, one splice donor site mutation, and three deletions. in addition, a splice variant near the 5'UTR of WFS1 was identified, present in patient as well as control RNA samples in various percentages, alternating the translation initiation consensus sequence. Whether this WTS1 splice variant displays impaired translation efficiency remains to be deter mined. No MtDNA lesions were identified in any of the Wolfram patients. Our results demonstrate the usefulness of molecular analysis of WFS1 in the refinement of clinical diagnostic criteria for Wolfram syndrome that helps to dissect the clinically overlapping syndromes sharing diabetes mellitus and optic atrophy.

Published
2003

4. A common ancestor for COCH related cochleovestibular (DFNA9) patients in Belgium and The Netherlands bearing the P51S mutation

Author

UCL, Fransen, E, Verstreken, M, Bom, SJH, Lemaire, F, Kemperman, MH, De Kok, YJM, Wuyts, FL, Verhagen, WIM, Huygen, PLM, McGuirt, WT, Smith, RJH, Van Maldergem, L., Declau, F, Cremers, CWRJ, Van de Heyning, PH, Cremers, FPM, Van Camp, G., UCL, Fransen, E, Verstreken, M, Bom, SJH, Lemaire, F, Kemperman, MH, De Kok, YJM, Wuyts, FL, Verhagen, WIM, Huygen, PLM, McGuirt, WT, Smith, RJH, Van Maldergem, L., Declau, F, Cremers, CWRJ, Van de Heyning, PH, Cremers, FPM, and Van Camp, G.

Published
2001

6. A RIPOR2 in-frame deletion is a frequent and highly penetrant cause of adult-onset hearing loss.

Author

de Bruijn SE, Smits JJ, Liu C, Lanting CP, Beynon AJ, Blankevoort J, Oostrik J, Koole W, de Vrieze E, Cremers CWRJ, Cremers FPM, Roosing S, Yntema HG, Kunst HPM, Zhao B, Pennings RJE, and Kremer H

Abstract

Background: Hearing loss is one of the most prevalent disabilities worldwide, and has a significant impact on quality of life. The adult-onset type of the condition is highly heritable but the genetic causes are largely unknown, which is in contrast to childhood-onset hearing loss., Methods: Family and cohort studies included exome sequencing and characterisation of the hearing phenotype. Ex vivo protein expression addressed the functional effect of a DNA variant., Results: An in-frame deletion of 12 nucleotides in RIPOR2 was identified as a highly penetrant cause of adult-onset progressive hearing loss that segregated as an autosomal dominant trait in 12 families from the Netherlands. Hearing loss associated with the deletion in 63 subjects displayed variable audiometric characteristics and an average (SD) age of onset of 30.6 (14.9) years (range 0-70 years). A functional effect of the RIPOR2 variant was demonstrated by aberrant localisation of the mutant RIPOR2 in the stereocilia of cochlear hair cells and failure to rescue morphological defects in RIPOR2-deficient hair cells, in contrast to the wild-type protein. Strikingly, the RIPOR2 variant is present in 18 of 22 952 individuals not selected for hearing loss in the Southeast Netherlands., Conclusion: Collectively, the presented data demonstrate that an inherited form of adult-onset hearing loss is relatively common, with potentially thousands of individuals at risk in the Netherlands and beyond, which makes it an attractive target for developing a (genetic) therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2020
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