Mutations in the polyglutamylase gene TTLL5, expressed in photoreceptor cells and spermatozoa, are associated with cone-rod degeneration and reduced male fertility.
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.
Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
Nicola
N
Bedoni
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands.
Lonneke
L
Haer-Wigman
Jules Gonin Eye Hospital, Lausanne, Switzerland.|Fertas Andrology Laboratory, Lausanne, Switzerland.
Veronika
V
Vaclavik
Jules Gonin Eye Hospital, Lausanne, Switzerland.
Viet H
VH
Tran
Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
Pietro
P
Farinelli
Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
Sara
S
Balzano
Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, Lausanne, Switzerland.|Institute for Research in Ophtalmology, University of Lausanne and Ecole Polytechnique Federale de Lausanne, Switzerland.
Beryl
B
Royer-Bertrand
Section of Ophthalmology & Neuroscience, Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, UK.
Mohammed E
ME
El-Asrag
Service of Nephrology, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
Olivier
O
Bonny
Department of Otorhinolaryngology, Head and Neck Surgery, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
Christos
C
Ikonomidis
Department of Otorhinolaryngology, Head and Neck Surgery, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
Yan
Y
Litzistorf
Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
Konstantinos
K
Nikopoulos
Department of Ophthalmology, University of Ioannina School of Medicine, Ioannina, Greece.
Georgia G
GG
Yioti
Department of Ophthalmology, University of Ioannina School of Medicine, Ioannina, Greece.
Maria I
MI
Stefaniotou
The Eye Department, St. James's University Hospital, Leeds, UK.
Martin
M
McKibbin
Royal Eye Infirmary, Derriford Hospital, Plymouth, UK.
Adam P
AP
Booth
Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
Jamie M
JM
Ellingford
Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
Graeme C
GC
Black
Section of Ophthalmology & Neuroscience, Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, UK.
Carmel
C
Toomes
Section of Ophthalmology & Neuroscience, Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, UK.
Chris F
CF
Inglehearn
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.
Carel B
CB
Hoyng
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.
Nathalie
N
Bax
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands.
Caroline C W
CC
Klaver
Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands.
Alberta A
AA
Thiadens
Fertas Andrology Laboratory, Lausanne, Switzerland.
Fabien
F
Murisier
Institute for Research in Ophtalmology, University of Lausanne and Ecole Polytechnique Federale de Lausanne, Switzerland.
Daniel F
DF
Schorderet
Section of Ophthalmology & Neuroscience, Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, UK.
Manir
M
Ali
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands.
Frans P M
FP
Cremers
Department of Ophthalmology, Lund University, Lund, Sweden.
Sten
S
Andréasson
Jules Gonin Eye Hospital, Lausanne, Switzerland.
Francis L
FL
Munier
Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
Carlo
C
Rivolta
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D000071700:Cone-Rod Dystrophies / Q000201:enzymology* / Q000235:genetics; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006720:Homozygote; D006801:Humans; D007248:Infertility, Male / Q000201:enzymology* / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D009928:Organ Specificity; D010375:Pedigree; D020419:Photoreceptor Cells, Vertebrate / Q000201:enzymology; D051381:Rats; D013081:Sperm Motility; D013094:Spermatozoa / Q000201:enzymology; D013737:Testis / Q000201:enzymology
D002352:Carrier Proteins; D005136:Eye Proteins; C517816:TTLL5 protein, human