Cep78 is a new centriolar protein involved in Plk4-induced centriole overduplication

Brunk, Kathrin; Zhu, Mo; Bärenz, Felix; Kratz, Anne-Sophie; Haselmann-Weiß, Uta; Antony, Claude; Hoffmann, Ingrid

doi:10.1242/jcs.184093

Cited by 24 publications

(40 citation statements)

References 29 publications

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“…The splice site substitution is predicted to cause skipping of exon 13. This figure has been adapted from material from Brunk et al (2016). RP, retinitis pigmentosa…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…CEP78 (UniProt: Q5JTW2, 4 isoforms reported—http://www.uniprot.org) is a component of the centrosome and localizes to the mature centrioles (Brunk et al, 2016). The human full‐length protein of 722 amino acids (Q5JTW2‐2) contains an N‐terminal leucine‐rich repeat (LRR) domain with five consecutive LRR domains, and a C‐terminal coiled‐coil domain (Brunk et al, 2016; Hossain, Javadi Esfehani, Das, & Tsang, 2017). Centrioles are the main components of centrosomes, key microtubule‐organizing centers in eukaryotic cells, with the mother centriole acting as the basal body during cilia formation (Gönczy & Hatzopoulos, 2019).…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2020

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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractInactivating 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. K E Y W O R D S CEP78, cilia, cone-rod dystrophy with hearing loss (CRDHL), founder, male infertility, missense 1000 |

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“…The splice site substitution is predicted to cause skipping of exon 13. This figure has been adapted from material from Brunk et al (2016). RP, retinitis pigmentosa…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

et al. 2020

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“…Upon filtering, 397 and 411 variants were remained and 9 biallelic variants were shared by both patients (see online supplementary table S1). After variant exclusion and prioritisation, one CEP78 homozygous variant was identified as the top candidate due to its possible loss-of-function nature and the functional link between CEP78 and cilia14 24 25 (see online supplementary table S1). This variant (NM_032171, c.1254+5G>A, p.?)…”

Section: Resultsmentioning

confidence: 99%

“…In this study, by whole exome sequencing (WES) and whole genome sequencing (WGS), we identified mutations in CEP78 , a ciliary gene,14 in two independent consanguineous families presenting a distinct Usher syndrome phenotype featured by cone–rod dystrophy and progressive sensorineural hearing loss. One allele affects the canonical splicing acceptor site of exon 14 and the other allele locates adjacent to the exon 10 splicing donor site.…”

Section: Introductionmentioning

confidence: 99%

CEP78is mutated in a distinct type of Usher syndrome

Xue

et al. 2016

J Med Genet

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Background Usher syndrome is a genetically heterogeneous disorder featured by combined visual impairment and hearing loss. Despite a dozen of genes involved in Usher syndrome having been identified, the genetic basis remains unknown in 20–30% of patients. In this study, we aimed to identify the novel disease-causing gene of a distinct subtype of Usher syndrome. Methods Ophthalmic examinations and hearing tests were performed on patients with Usher syndrome in two consanguineous families. Target capture sequencing was initially performed to screen causative mutations in known retinal disease-causing loci. Whole exome sequencing (WES) and whole genome sequencing (WGS) were applied for identifying novel disease-causing genes. RT-PCR and Sanger sequencing were performed to evaluate the splicing-altering effect of identified CEP78 variants. Results Patients from the two independent families show a mild Usher syndrome phenotype featured by juvenile or adult-onset cone–rod dystrophy and sensorineural hearing loss. WES and WGS identified two homozygous rare variants that affect mRNA splicing of a ciliary gene CEP78. RT-PCR confirmed that the two variants indeed lead to abnormal splicing, resulting in premature stop of protein translation due to frameshift. Conclusions Our results provide evidence that CEP78 is a novel disease-causing gene for Usher syndrome, demonstrating an additional link between ciliopathy and Usher protein network in photoreceptor cells and inner ear hair cells.

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The genetic and phenotypic landscapes of Usher syndrome: from disease mechanisms to a new classification

Delmaghani

El-Amraoui

2022

Hum Genet

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Usher syndrome (USH) is the most common cause of deaf–blindness in humans, with a prevalence of about 1/10,000 (~ 400,000 people worldwide). Cochlear implants are currently used to reduce the burden of hearing loss in severe-to-profoundly deaf patients, but many promising treatments including gene, cell, and drug therapies to restore the native function of the inner ear and retinal sensory cells are under investigation. The traditional clinical classification of Usher syndrome defines three major subtypes—USH1, 2 and 3—according to hearing loss severity and onset, the presence or absence of vestibular dysfunction, and age at onset of retinitis pigmentosa. Pathogenic variants of nine USH genes have been initially reported: MYO7A, USH1C, PCDH15, CDH23, and USH1G for USH1, USH2A, ADGRV1, and WHRN for USH2, and CLRN1 for USH3. Based on the co-occurrence of hearing and vision deficits, the list of USH genes has been extended to few other genes, but with limited supporting information. A consensus on combined criteria for Usher syndrome is crucial for the development of accurate diagnosis and to improve patient management. In recent years, a wealth of information has been obtained concerning the properties of the Usher proteins, related molecular networks, potential genotype–phenotype correlations, and the pathogenic mechanisms underlying the impairment or loss of hearing, balance and vision. The advent of precision medicine calls for a clear and more precise diagnosis of Usher syndrome, exploiting all the existing data to develop a combined clinical/genetic/network/functional classification for Usher syndrome.

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Cep78 is a new centriolar protein involved in Plk4-induced centriole overduplication

Cited by 24 publications

References 29 publications

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

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

CEP78is mutated in a distinct type of Usher syndrome

The genetic and phenotypic landscapes of Usher syndrome: from disease mechanisms to a new classification

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