TY - JOUR
T1 - Mutations in the polyglutamylase gene TTLL5, expressed in photoreceptor cells and spermatozoa, are associated with cone-rod degeneration and reduced male fertility
AU - Bedoni, Nicola
AU - Haer-Wigman, Lonneke
AU - Vaclavik, Veronika
AU - Tran, Viet H.
AU - Farinelli, Pietro
AU - Balzano, Sara
AU - Royer-Bertrand, Beryl
AU - El-Asrag, Mohammed E.
AU - Bonny, Olivier
AU - Ikonomidis, Christos
AU - Litzistorf, Yan
AU - Nikopoulos, Konstantinos
AU - Yioti, Georgia G.
AU - Stefaniotou, Maria I.
AU - McKibbin, Martin
AU - Booth, Adam P.
AU - Ellingford, Jamie M.
AU - Black, Graeme C.
AU - Toomes, Carmel
AU - Inglehearn, Chris F.
AU - Hoyng, Carel B.
AU - Bax, Nathalie
AU - Klaver, Caroline C. W.
AU - Thiadens, Alberta A.
AU - Murisier, Fabien
AU - Schorderet, Daniel F.
AU - Ali, Manir
AU - Cremers, Frans P. M.
AU - Andréasson, Sten
AU - Munier, Francis L.
AU - Rivolta, Carlo
PY - 2016/10/15
Y1 - 2016/10/15
N2 - 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.
AB - 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.
KW - Adolescent
KW - Adult
KW - Aged
KW - Animals
KW - Carrier Proteins/genetics
KW - Cone-Rod Dystrophies/enzymology
KW - DNA Mutational Analysis
KW - Disease Models, Animal
KW - Eye Proteins/genetics
KW - Female
KW - Gene Expression
KW - Homozygote
KW - Humans
KW - Infertility, Male/enzymology
KW - Male
KW - Mice
KW - Middle Aged
KW - Mutation
KW - Organ Specificity
KW - Pedigree
KW - Photoreceptor Cells, Vertebrate/enzymology
KW - Rats
KW - Sperm Motility
KW - Spermatozoa/enzymology
KW - Testis/enzymology
UR - https://academic.oup.com/hmg/article/25/20/4546/2525891
UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-85014402551&partnerID=MN8TOARS
U2 - 10.1093/hmg/ddw282
DO - 10.1093/hmg/ddw282
M3 - Article
C2 - 28173158
SN - 0964-6906
VL - 25
SP - 4546
EP - 4555
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 20
ER -