Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss and reduced male fertility

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Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss and reduced male fertility. / Ascari, Giulia; Peelman, Frank; Farinelli, Pietro; Rosseel, Toon; Lambrechts, Nina; Wunderlich, Kirsten A; Wagner, Matias; Nikopoulos, Konstantinos; Martens, Pernille; Balikova, Irina; Derycke, Lara; Holtappels, Gabriële; Krysko, Olga; Van Laethem, Thalia; De Jaegere, Sarah; Guillemyn, Brecht; De Rycke, Riet; De Bleecker, Jan; Creytens, David; Van Dorpe, Jo; Gerris, Jan; Bachert, Claus; Neuhofer, Christiane; Walraedt, Sophie; Bischoff, Almut; Pedersen, Lotte B.; Klopstock, Thomas; Rivolta, Carlo; Leroy, Bart P; De Baere, Elfride; Coppieters, Frauke.

In: Human Mutation, Vol. 41, No. 5, 2020, p. 998-1011.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Ascari, G, Peelman, F, Farinelli, P, Rosseel, T, Lambrechts, N, Wunderlich, KA, Wagner, M, Nikopoulos, K, Martens, P, Balikova, I, Derycke, L, Holtappels, G, Krysko, O, Van Laethem, T, De Jaegere, S, Guillemyn, B, De Rycke, R, De Bleecker, J, Creytens, D, Van Dorpe, J, Gerris, J, Bachert, C, Neuhofer, C, Walraedt, S, Bischoff, A, Pedersen, LB, Klopstock, T, Rivolta, C, Leroy, BP, De Baere, E & Coppieters, F 2020, 'Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss and reduced male fertility', Human Mutation, vol. 41, no. 5, pp. 998-1011. https://doi.org/10.1002/humu.23993

APA

Ascari, G., Peelman, F., Farinelli, P., Rosseel, T., Lambrechts, N., Wunderlich, K. A., Wagner, M., Nikopoulos, K., Martens, P., Balikova, I., Derycke, L., Holtappels, G., Krysko, O., Van Laethem, T., De Jaegere, S., Guillemyn, B., De Rycke, R., De Bleecker, J., Creytens, D., ... Coppieters, F. (2020). Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss and reduced male fertility. Human Mutation, 41(5), 998-1011. https://doi.org/10.1002/humu.23993

Vancouver

Ascari G, Peelman F, Farinelli P, Rosseel T, Lambrechts N, Wunderlich KA et al. Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss and reduced male fertility. Human Mutation. 2020;41(5):998-1011. https://doi.org/10.1002/humu.23993

Author

Ascari, Giulia ; Peelman, Frank ; Farinelli, Pietro ; Rosseel, Toon ; Lambrechts, Nina ; Wunderlich, Kirsten A ; Wagner, Matias ; Nikopoulos, Konstantinos ; Martens, Pernille ; Balikova, Irina ; Derycke, Lara ; Holtappels, Gabriële ; Krysko, Olga ; Van Laethem, Thalia ; De Jaegere, Sarah ; Guillemyn, Brecht ; De Rycke, Riet ; De Bleecker, Jan ; Creytens, David ; Van Dorpe, Jo ; Gerris, Jan ; Bachert, Claus ; Neuhofer, Christiane ; Walraedt, Sophie ; Bischoff, Almut ; Pedersen, Lotte B. ; Klopstock, Thomas ; Rivolta, Carlo ; Leroy, Bart P ; De Baere, Elfride ; Coppieters, Frauke. / Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss and reduced male fertility. In: Human Mutation. 2020 ; Vol. 41, No. 5. pp. 998-1011.

Bibtex

@article{28d708e6c4b14f658899e247c0d9b274,
title = "Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss and reduced male fertility",
abstract = "Inactivating variants in the centrosomal CEP78 gene have been found in cone-rod dystrophy with hearing loss (CRDHL), a particular phenotype distinct from Usher syndrome. Here, we identified and functionally characterized the first CEP78 missense variant c.449T>C, p.(Leu150Ser) in three CRDHL families. The variant was found in a biallelic state in two Belgian families and in a compound heterozygous state - in trans with c.1462-1G>T - in a third German family. Haplotype reconstruction showed a founder effect. Homology modeling revealed a detrimental effect of p.(Leu150Ser) on protein stability, which was corroborated in patients' fibroblasts. Elongated primary cilia without clear ultrastructural abnormalities in sperm or nasal brushes suggests impaired cilia assembly. Two affected males from different families displayed sperm abnormalities causing infertility. One of these is a heterozygous carrier of a complex allele in SPAG17, a ciliary gene previously associated with autosomal recessive male infertility. Taken together, our data indicate that a missense founder allele in CEP78 underlies the same sensorineural CRDHL phenotype previously associated with inactivating variants. Interestingly, the CEP78 phenotype has been possibly expanded with male infertility. Finally, CEP78 loss-of-function variants may have an underestimated role in misdiagnosed Usher syndrome, with or without sperm abnormalities. This article is protected by copyright. All rights reserved.",
author = "Giulia Ascari and Frank Peelman and Pietro Farinelli and Toon Rosseel and Nina Lambrechts and Wunderlich, {Kirsten A} and Matias Wagner and Konstantinos Nikopoulos and Pernille Martens and Irina Balikova and Lara Derycke and Gabri{\"e}le Holtappels and Olga Krysko and {Van Laethem}, Thalia and {De Jaegere}, Sarah and Brecht Guillemyn and {De Rycke}, Riet and {De Bleecker}, Jan and David Creytens and {Van Dorpe}, Jo and Jan Gerris and Claus Bachert and Christiane Neuhofer and Sophie Walraedt and Almut Bischoff and Pedersen, {Lotte B.} and Thomas Klopstock and Carlo Rivolta and Leroy, {Bart P} and {De Baere}, Elfride and Frauke Coppieters",
note = "This article is protected by copyright. All rights reserved.",
year = "2020",
doi = "10.1002/humu.23993",
language = "English",
volume = "41",
pages = "998--1011",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "JohnWiley & Sons, Inc.",
number = "5",

}

RIS

TY - JOUR

T1 - Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss and reduced male fertility

AU - Ascari, Giulia

AU - Peelman, Frank

AU - Farinelli, Pietro

AU - Rosseel, Toon

AU - Lambrechts, Nina

AU - Wunderlich, Kirsten A

AU - Wagner, Matias

AU - Nikopoulos, Konstantinos

AU - Martens, Pernille

AU - Balikova, Irina

AU - Derycke, Lara

AU - Holtappels, Gabriële

AU - Krysko, Olga

AU - Van Laethem, Thalia

AU - De Jaegere, Sarah

AU - Guillemyn, Brecht

AU - De Rycke, Riet

AU - De Bleecker, Jan

AU - Creytens, David

AU - Van Dorpe, Jo

AU - Gerris, Jan

AU - Bachert, Claus

AU - Neuhofer, Christiane

AU - Walraedt, Sophie

AU - Bischoff, Almut

AU - Pedersen, Lotte B.

AU - Klopstock, Thomas

AU - Rivolta, Carlo

AU - Leroy, Bart P

AU - De Baere, Elfride

AU - Coppieters, Frauke

N1 - This article is protected by copyright. All rights reserved.

PY - 2020

Y1 - 2020

N2 - Inactivating variants in the centrosomal CEP78 gene have been found in cone-rod dystrophy with hearing loss (CRDHL), a particular phenotype distinct from Usher syndrome. Here, we identified and functionally characterized the first CEP78 missense variant c.449T>C, p.(Leu150Ser) in three CRDHL families. The variant was found in a biallelic state in two Belgian families and in a compound heterozygous state - in trans with c.1462-1G>T - in a third German family. Haplotype reconstruction showed a founder effect. Homology modeling revealed a detrimental effect of p.(Leu150Ser) on protein stability, which was corroborated in patients' fibroblasts. Elongated primary cilia without clear ultrastructural abnormalities in sperm or nasal brushes suggests impaired cilia assembly. Two affected males from different families displayed sperm abnormalities causing infertility. One of these is a heterozygous carrier of a complex allele in SPAG17, a ciliary gene previously associated with autosomal recessive male infertility. Taken together, our data indicate that a missense founder allele in CEP78 underlies the same sensorineural CRDHL phenotype previously associated with inactivating variants. Interestingly, the CEP78 phenotype has been possibly expanded with male infertility. Finally, CEP78 loss-of-function variants may have an underestimated role in misdiagnosed Usher syndrome, with or without sperm abnormalities. This article is protected by copyright. All rights reserved.

AB - Inactivating variants in the centrosomal CEP78 gene have been found in cone-rod dystrophy with hearing loss (CRDHL), a particular phenotype distinct from Usher syndrome. Here, we identified and functionally characterized the first CEP78 missense variant c.449T>C, p.(Leu150Ser) in three CRDHL families. The variant was found in a biallelic state in two Belgian families and in a compound heterozygous state - in trans with c.1462-1G>T - in a third German family. Haplotype reconstruction showed a founder effect. Homology modeling revealed a detrimental effect of p.(Leu150Ser) on protein stability, which was corroborated in patients' fibroblasts. Elongated primary cilia without clear ultrastructural abnormalities in sperm or nasal brushes suggests impaired cilia assembly. Two affected males from different families displayed sperm abnormalities causing infertility. One of these is a heterozygous carrier of a complex allele in SPAG17, a ciliary gene previously associated with autosomal recessive male infertility. Taken together, our data indicate that a missense founder allele in CEP78 underlies the same sensorineural CRDHL phenotype previously associated with inactivating variants. Interestingly, the CEP78 phenotype has been possibly expanded with male infertility. Finally, CEP78 loss-of-function variants may have an underestimated role in misdiagnosed Usher syndrome, with or without sperm abnormalities. This article is protected by copyright. All rights reserved.

U2 - 10.1002/humu.23993

DO - 10.1002/humu.23993

M3 - Journal article

C2 - 31999394

VL - 41

SP - 998

EP - 1011

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 5

ER -

ID: 235354923