• PMID: 28173158
• Gene Name: TTLL5
• Condition: Male subfertility
• Association: Associated
• Mutation: p.(Asp594fs), p.(Gln117*), p.(Met712fs), p.(Ile756Phe), and p.(Glu543Lys)
• Population size: 8
• Population details: 8 patients from 6 families
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Male subfertility, cone-dominated retinopathy

Mutations in the polyglutamylase gene TTLL5, expressed in photoreceptor cells and spermatozoa, are associated with cone-rod degeneration and reduced male fertility

Bedoni N, Haer-Wigman L, Vaclavik V, Tran VH, Farinelli P, Balzano S, Royer-Bertrand B, El-Asrag ME, Bonny O, Ikonomidis C, Litzistorf Y, Nikopoulos K, Yioti GG, Stefaniotou MI, McKibbin M, Booth AP, Ellingford JM, Black GC, Toomes C, Inglehearn CF, Hoyng CB, Bax N, Klaver CC, Thiadens AA, Murisier F, Schorderet DF, Ali M, Cremers FP, Andréasson S, Munier FL, Rivolta C.

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 displayed 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. FAU - Bedoni, Nicola AU - Bedoni N AD - Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, Lausanne, Switzerland. FAU - Haer-Wigman, Lonneke AU - Haer-Wigman L AD - Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands. AD - Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands. FAU - Vaclavik, Veronika AU - Vaclavik V AD - Jules Gonin Eye Hospital, Lausanne, Switzerland. AD - Fertas Andrology Laboratory, Lausanne, Switzerland. FAU - Tran, Viet H AU - Tran VH AD - Jules Gonin Eye Hospital, Lausanne, Switzerland. FAU - Farinelli, Pietro AU - Farinelli P AD - Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, Lausanne, Switzerland. FAU - Balzano, Sara AU - Balzano S AD - Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, Lausanne, Switzerland. FAU - Royer-Bertrand, Beryl AU - Royer-Bertrand B AD - Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, Lausanne, Switzerland. AD - Institute for Research in Ophtalmology, University of Lausanne and Ecole Polytechnique Federale de Lausanne, Switzerland. FAU - El-Asrag, Mohammed E AU - El-Asrag ME AD - Section of Ophthalmology & Neuroscience, Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, UK. FAU - Bonny, Olivier AU - Bonny O AD - Service of Nephrology, Lausanne University Hospital (CHUV), Lausanne, Switzerland. FAU - Ikonomidis, Christos AU - Ikonomidis C AD - Department of Otorhinolaryngology, Head and Neck Surgery, Lausanne University Hospital (CHUV), Lausanne, Switzerland. FAU - Litzistorf, Yan AU - Litzistorf Y AD - Department of Otorhinolaryngology, Head and Neck Surgery, Lausanne University Hospital (CHUV), Lausanne, Switzerland. FAU - Nikopoulos, Konstantinos AU - Nikopoulos K AD - Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, Lausanne, Switzerland. FAU - Yioti, Georgia G AU - Yioti GG AD - Department of Ophthalmology, University of Ioannina School of Medicine, Ioannina, Greece. FAU - Stefaniotou, Maria I AU - Stefaniotou MI AD - Department of Ophthalmology, University of Ioannina School of Medicine, Ioannina, Greece. FAU - McKibbin, Martin AU - McKibbin M AD - The Eye Department, St. James's University Hospital, Leeds, UK. FAU - Booth, Adam P AU - Booth AP AD - Royal Eye Infirmary, Derriford Hospital, Plymouth, UK. FAU - Ellingford, Jamie M AU - Ellingford JM AD - Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK. FAU - Black, Graeme C AU - Black GC AD - Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK. FAU - Toomes, Carmel AU - Toomes C AD - Section of Ophthalmology & Neuroscience, Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, UK. FAU - Inglehearn, Chris F AU - Inglehearn CF AD - Section of Ophthalmology & Neuroscience, Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, UK. FAU - Hoyng, Carel B AU - Hoyng CB AD - Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands. FAU - Bax, Nathalie AU - Bax N AD - Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands. FAU - Klaver, Caroline C W AU - Klaver CC AD - Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands. AD - Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands. FAU - Thiadens, Alberta A AU - Thiadens AA AD - Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands. FAU - Murisier, Fabien AU - Murisier F AD - Fertas Andrology Laboratory, Lausanne, Switzerland. FAU - Schorderet, Daniel F AU - Schorderet DF AD - Institute for Research in Ophtalmology, University of Lausanne and Ecole Polytechnique Federale de Lausanne, Switzerland. FAU - Ali, Manir AU - Ali M AD - Section of Ophthalmology & Neuroscience, Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, UK. FAU - Cremers, Frans P M AU - Cremers FP AD - Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands. AD - Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands. FAU - Andréasson, Sten AU - Andréasson S AD - Department of Ophthalmology, Lund University, Lund, Sweden. FAU - Munier, Francis L AU - Munier FL AD - Jules Gonin Eye Hospital, Lausanne, Switzerland.