Mutations in the polyglutamylase gene TTLL5, expressed in photoreceptor cells and spermatozoa, are associated with cone-rod degeneration and reduced male fertility
| Autor: | Francis L. Munier, Georgia G. Yioti, Carel B. Hoyng, Pietro Farinelli, Sara Balzano, Jamie M Ellingford, Viet H. Tran, Olivier Bonny, Christos Ikonomidis, Sten Andréasson, Veronika Vaclavik, Chris F. Inglehearn, Nicola Bedoni, Lonneke Haer-Wigman, Daniel F. Schorderet, Maria Stefaniotou, Fabien Murisier, Adam P. Booth, Mohammed E El-Asrag, Carlo Rivolta, Konstantinos Nikopoulos, Nathalie M. Bax, Yan Litzistorf, Frans P.M. Cremers, Carmel Toomes, Beryl Royer-Bertrand, Graeme C.M. Black, Caroline C W Klaver, Martin McKibbin, Manir Ali, Alberta A H J Thiadens |
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| Přispěvatelé: | Ophthalmology |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Retinal degeneration Male DNA Mutational Analysis Gene Expression medicine.disease_cause Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] Mice 0302 clinical medicine Testis Genetics (clinical) Genetics Mutation Homozygote Genetic disorder General Medicine Middle Aged Spermatozoa Pedigree medicine.anatomical_structure Organ Specificity Sperm Motility Female Photoreceptor Cells Vertebrate Gene isoform Adult Adolescent Biology 03 medical and health sciences All institutes and research themes of the Radboud University Medical Center medicine Animals Humans Allele Eye Proteins Molecular Biology Gene Infertility Male Aged Retina Dystrophy medicine.disease Molecular biology Rats Disease Models Animal 030104 developmental biology Carrier Proteins 030217 neurology & neurosurgery Cone-Rod Dystrophies |
| Zdroj: | Human Molecular Genetics, 25, 4546-4555 Scopus-Elsevier Human Molecular Genetics, 25(20), 4546-4555. Oxford University Press Human molecular genetics, vol. 25, no. 20, pp. 4546-4555 Human Molecular Genetics, 25, 20, pp. 4546-4555 |
| ISSN: | 0964-6906 |
| DOI: | 10.5451/unibas-ep81699 |
| Popis: | Hereditary retinal degenerations encompass a group of genetic diseases characterized by extreme clinical variability. Following next-generation sequencing and autozygome-based screening of patients presenting with a peculiar, recessive form of cone-dominated retinopathy, we identified five homozygous variants [p.(Asp594fs), p.(Gln117*), p.(Met712fs), p.(Ile756Phe), and p.(Glu543Lys)] in the polyglutamylase-encoding gene TTLL5, in eight patients from six families. The two male patients carrying truncating TTLL5 variants also suffered from a substantial reduction in sperm motility and infertility, whereas those carrying missense changes were fertile. Defects in this polyglutamylase in humans have recently been associated with cone photoreceptor dystrophy, while mouse models carrying truncating mutations in the same gene also display reduced fertility in male animals. We examined the expression levels of TTLL5 in various human tissues and determined that this gene has multiple viable isoforms, being highly expressed in testis and retina. In addition, antibodies against TTLL5 stained the basal body of photoreceptor cells in rat and the centrosome of the spermatozoon flagellum in humans, suggesting a common mechanism of action in these two cell types. Taken together, our data indicate that mutations in TTLL5 delineate a novel, allele-specific syndrome causing defects in two as yet pathogenically unrelated functions, reproduction and vision. |
| Databáze: | OpenAIRE |
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