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

被引：14

作者：

Ascari, Giulia ^{[1
]}

Peelman, Frank ^{[2
]}

Farinelli, Pietro ^{[3
,4
]}

Rosseel, Toon ^{[1
]}

Lambrechts, Nina ^{[1
]}

Wunderlich, Kirsten A. ^{[3
,5
]}

Wagner, Matias ^{[6
,7
,8
]}

Nikopoulos, Konstantinos ^{[9
]}

Martens, Pernille ^{[4
]}

Balikova, Irina ^{[10
,11
]}

Derycke, Lara ^{[12
]}

Holtappels, Gabriele ^{[12
]}

Krysko, Olga ^{[12
]}

Van Laethem, Thalia ^{[1
]}

De Jaegere, Sarah ^{[1
]}

Guillemyn, Brecht ^{[1
]}

De Rycke, Riet ^{[13
,14
,15
]}

De Bleecker, Jan ^{[16
]}

Creytens, David ^{[17
]}

Van Dorpe, Jo ^{[17
]}

Gerris, Jan ^{[18
]}

Bachert, Claus ^{[12
]}

Neuhofer, Christiane ^{[19
]}

Walraedt, Sophie ^{[10
]}

Bischoff, Almut ^{[20
]}

Pedersen, Lotte B. ^{[4
]}

Klopstock, Thomas ^{[20
,21
,22
]}

Rivolta, Carlo ^{[3
,23
,24
,25
]}

Leroy, Bart P. ^{[1
,10
,26
,27
]}

De Baere, Elfride ^{[1
]}

Coppieters, Frauke ^{[1
]}

机构：

[1] Univ Ghent, Ghent Univ Hosp, Ctr Med Genet Ghent, Dept Biomol Med, Ghent, Belgium

[2] Univ Ghent, Flanders Inst Biotechnol VIB, Fac Med & Hlth Sci, Dept Med Prot Res, Ghent, Belgium

[3] Univ Lausanne, Unit Med Genet, Dept Computat Biol, Lausanne, Switzerland

[4] Univ Copenhagen, Dept Biol, Copenhagen, Denmark

[5] Ludwig Maximilians Univ Munchen, BMC, Dept Phys Genom, Planegg, Germany

[6] Tech Univ Munich, Fac Med, Inst Human Genet, Munich, Germany

[7] Deutsch Forschungszentrum Gesundheit & Umwelt Gmb, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany

[8] Deutsch Forschungszentrum Gesundheit & Umwelt Gmb, Helmholtz Zentrum Munchen, Inst Neurogenom, Neuherberg, Germany

[9] Lausanne Univ Hosp CHUV, Dept Hematol, Oncogenom Lab, Lausanne, Switzerland

[10] Ghent Univ Hosp, Dept Ophthalmol, Ghent, Belgium

[11] Univ Hosp Leuven, Dept Ophthalmol, Leuven, Belgium

[12] Ghent Univ Hosp, Dept Otorhinolaryngol, Upper Airways Res Lab, Ghent, Belgium

[13] Univ Ghent, Dept Biomed Mol Biol, Ghent, Belgium

[14] Univ Ghent, Expertise Ctr Transmiss Electron Microscopy, Ghent, Belgium

[15] VIB, VIB Ctr Inflammat Res & BioImaging Core, Ghent, Belgium

[16] Ghent Univ Hosp, Dept Neurol, Ghent, Belgium

[17] Ghent Univ Hosp, Dept Pathol, Ghent, Belgium

[18] Ghent Univ Hosp, Dept Human Struct & Repair, Ghent, Belgium

[19] Univ Med Ctr Gottingen UMG, Inst Human Genet, Gottingen, Germany

[20] Ludwig Maximilians Univ Munchen, Friedrich Baur Inst, Dept Neurol, Munich, Germany

[21] German Ctr Neurodegenerat Dis DZNE, Munich, Germany

[22] Munich Cluster Syst Neurol SyNergy, Munich, Germany

[23] Clin Res Ctr, Inst Mol & Clin Ophthalmol Basel IOB, Basel, Switzerland

[24] Univ Hosp Basel, Dept Ophthalmol, Basel, Switzerland

[25] Univ Leicester, Dept Genet & Genome Biol, Leicester, Leics, England

[26] Childrens Hosp Philadelphia, Div Ophthalmol, Philadelphia, PA 19104 USA

[27] Childrens Hosp Philadelphia, Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA

来源：

HUMAN MUTATION | 2020年 / 41卷 / 05期

基金：

瑞士国家科学基金会;

关键词：

CEP78; cilia; cone-rod dystrophy with hearing loss (CRDHL); founder; male infertility; missense; CILIA; MUTATIONS; CENTROSOMES; PROTEINS; COMPLEX; SPAG17; GENES; MODEL;

D O I：

10.1002/humu.23993

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 suggest 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.

引用

页码：998 / 1011

页数：14

共 59 条

[1] Genomic profiling supports the diagnosis of primary ciliary dyskinesia and reveals novel candidate genes and genetic variants [J].