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

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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.


  • Nicola Bedoni
  • Lonneke Haer-Wigman
  • Veronika Vaclavik
  • Viet H. Tran
  • Pietro Farinelli
  • Sara Balzano
  • Beryl Royer-Bertrand
  • Mohammed E. El-Asrag
  • Olivier Bonny
  • Christos Ikonomidis
  • Yan Litzistorf
  • Konstantinos Nikopoulos
  • Georgia G. Yioti
  • Maria I. Stefaniotou
  • Martin McKibbin
  • Adam P. Booth
  • Jamie M. Ellingford
  • Graeme C. M. Black
  • Carmel Toomes
  • Chris F. Inglehearn
  • Carel B. Hoyng
  • Nathalie Bax
  • Caroline C. W. Klaver
  • Alberta A. Thiadens
  • Fabien Murisier
  • Daniel F. Schorderet
  • Manir Ali
  • Frans P M Cremers
  • Francis L. Munier
  • Carlo Rivolta
Enheter & grupper
Externa organisationer
  • Jules Gonin Ophthalmic Hospital
  • Lausanne University Hospital
  • University of Lausanne
  • Radboud University Nijmegen
  • University of Leeds

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Medicinsk genetik
Sidor (från-till)4546-4555
Antal sidor10
TidskriftHuman Molecular Genetics
StatusPublished - 2016
Peer review utfördJa