Abstract
Ciliopathies—are widely recognized and associated with a wide variety of developmental and degenerative disorders. Most cilia-related diseases have renal manifestation, and there is a cross- overlapping relationship between gene mutations and cilia disease. Here, we investigated the clinical and pathological manifestation of a rare disease patient. We present the case of a 15-year-old child with dysplasia and multiple-organ damage who was initially diagnosed with nephrotic syndrome. The patient’s kidney disease progressed to renal failure and received hemodialysis 10 months after renal biopsy. The individual presented primary ciliary dyskinesia (PCD) and additional symptoms including sensorineural deafness, kidney dysplasia, severe kidney function loss, and congenital heart disease which potentially linked to primary cilia deficiency. Cilia immunofluorescence of renal tissue showed a decrease in the number of cilium of the patient compared to the normal kidney. We identified a site mutation in CCDC114 (NM_144577 exon7 c. 596Cå T p. Ala199Val) by whole-exon sequences. We found that CCDC114 located at the basal body at cilia and the knockdown of CCDC114 could affect the occurrence of cilia in hRPE1 cells. The previous study of CCDC114 mainly lies in the motile cilia, and this study found that its impact on primary cilia thus broadened the understanding of overlapping function of different types of cilia.
Introduction
The surprising discoveries of cilia and the development of genetic sequencing have confirmed that both defective primary cilia and motile cilia are causative to a wide spectrum of human genetic disorders [1, 2]. Such disorders now have been recognized as ciliopathies, which are often serious and with invariably complex clinical conditions. Each ciliopathy was taken as a discrete clinical entity, but together they have overlapping pathological characteristics [3]. Cilia are highly conserved and consist of a microtubule-based ciliary axoneme, assembled from a basal body, which represents one of the centrioles of the centrosome [4]. Ciliopathies can affect multiple organs (like Alström syndrome, Bardet–Biedl syndrome, and Joubert syndrome) or a single organ (like Leber congenital amaurosis and polycystic kidney disease), and also they can be monogenic (Alström syndrome and polycystic kidney disease) or multigenic (Bardet–Biedl syndrome) [5, 6]. Defective motile cilia can result in primary ciliary dyskinesia (PCD; MIM244400) characterized clinically mainly by retinitis pigmentosa, situs inversus [7]. Primary (immotile) cilia are thought to function mainly as sensory organelles regulating the signal transduction pathways, similar in structure to the motile cilia but without the central pair [8, 9]. Defective primary cilia can cause polydactyly, learning difficulties, kidney, liver, and pancreatic diseases, which can be seen among motile cilia deficiency too [7, 10]. So, ciliopathies are a kind of disease with high heterogeneity. The basic ciliary biology underlying disease has raised an explosion of interest in the spectrum of ciliopathy disease since 2002 [11,12,13]. More than 30 genes have been identified to be causative to PCD [14]. Mutations in CCDC114 have been shown to cause primary ciliary dyskinesia, which two papers published and mutations in CCDC114 (c.742G > A) may account for 6% of the individuals with PCD [15, 16]. One of the studies was from unrelated families in the United States and the other was from Volendam families, a fishing village in North Holland. But all patients with mutations of CCDC114 did not show situs inversus. CCDC114 is an ortholog of DCC2 which is an outer dynein arm (ODA) protein of Chlamydomonas reinhardtii and causes motility defect in mutants [17]. CCDC114 locates at the entire cilia of motile cilia but its function has not been well illustrated [16]. Notably, one individual presenting PCD also presented with additional manifestations not classically reported in other PCD conditions. These included sensorineural deafness, kidney dysplasia, severe kidney function loss, and congenital heart disease, which potentially linked to primary cilia deficiency. We identified a site mutation in CCDC114 by whole-exon sequences of the family members. The aim of the study was to investigate the contributions of CCDC114 to primary cilia assembly.
Materials and methods
Patient and family members
The patient did not come from consanguineous families. Medical history interviews, physical examination, sight, and hearing tests were performed. Kidney biopsy and other tests including serum chemistry analysis, blood count, urinalysis, and an ECG were performed. Genomic DNA was extracted from peripheral blood using a blood DNA extraction kit according to the manufacturer’s instructions (TianGen, Beijing, China).
Whole-exome sequencing
Whole-exome capture sequencing was performed (II:1, II:2, III:1, and III:2, Fig. 1b). DNA quality was measured by ultraviolet spectrometry (A260/280 ratios between 1.8 and 2.0 and the concentrations of DNA were above 1.0 μg for all samples) and gel electrophoresis. All samples did not have obvious degradation and were acceptable for use. Approximately 3 mg of genomic DNA was sheared to 180−280 bp by sonication (Covaris). End repair and dA-tails were used for the preparation of DNA library. The Agilent Sure Select Human All Exon V6 kit (Agilent Technologies, Inc.) was used to capture exons. Fragments were subjected to Illumina Exome Enrichment preparation and enriched for target sequences. After the construction of the prepped library, Qubit 2.0 was used for preliminary quantitative analysis at first, and then the library’s insert size was tested by Agilent 2100. Confirming the insert size in line with expectations, we used the qPCR method for accurate quantitative concentration (3 nM) to ensure the quality of the library. Each captured library was loaded onto the Illumina Hiseq4000 platform (PE150, pair end 150 bp) for sequencing. The effective sequencing depth was more than 100×. After filtering out low-quality and duplicate reads, clean data were mapped with Burrows−Wheeler Aligner (http://bio-bwa.sourceforge.net/bwa.shtml) tools to the human reference genome (hg19, http://hgdownload.soe.ucsc.edu/goldenPath/hg19/bigZips/). After alignment, sequence variants were called by SAM tools and Picard Tools were used to mark duplicate reads following documented best practices [18]. More than 10.0 GB of sequence was generated per sample. Different filters including dbSNP database, 1000 Genome Projects were applied to exclude all variants located in nonexonic regions, pseudogenes, UTRs, or known polymorphic variants with a frequency ~1%. Indels that were absent or observed <10 times in the other exomes sequenced at the University of Washington were considered further. The functional consequence of variants was predicted using the SIFT (http://sift.jcvi.org/www/SIFT_enst_submit.html), PolyPhen2 (http://genetics.bwh.harvard.edu/pph2/) MutationTaster (www.mutationtaster.org/), and CADD (http://cadd.gs.washington.edu/) programs. Under an autosomal-recessive model, only genes with biallelic variants (homozygous or compound heterozygous) were considered further. Phenolyzer (http://phenolyzer.wglab.org/) was used for analyzing the relationship between phenotype and genotype. Candidate genes were validated by Sanger sequencing.
Model building and multiple-sequence alignment
Three-dimensional modeling of p.Ala199Val was performed using SWISS-MODEL (https://swissmodel.expasy.org/interactive, Q96M63) [19]. Multiple-sequence alignment was performed according to a Homologene program.
Immunohistochemistry and immunofluorescence
Kidney tissue from the patient and nonneoplastic kidney tissues (considered as controlled) from ten patients with renal carcinoma were stained. The tissues were fixed with 4% paraformaldehyde, dehydrated with a graded series of ethanol, and paraffin embedded; serial sections were cut at 8-μm thickness. Sodium citrate buffer (10 mM sodium citrate, 0.05% Tween 20, pH 6.0) was used for antigen retrieval. Blocking solution (PBS + 3% NGS + 0.1% Triton) was used to block nonspecific binding sites. An anti-ARL13B antibody was diluted (1:100 rabbit polyclonal antibody; Proteintech, Cat 17711-1-AP) and added for cilia staining followed by an Alexa Fluor 568-conjugated secondary antibody (1:200; Invitrogen). FITC-conjugated lotus tetragonolobus lectin (LTL) (#FL-1321; LTL, 1:200; Vector Laboratories) was mixed with secondary antibody for renal proximal tubules staining. Both primary and secondary antibodies were incubated at room temperature for 1 h. After staining with Hoechst 33342 (1:1000, H3570; Invitrogen) to visualize the nuclei, images were obtained using an LSM880 confocal microscope (Carl Zeiss Microscopy GmbH, Göttingen, Germany). Cilia and nuclei were quantified; the percentage of cells with primary cilia (% cilia) was calculated as ciliated cells/total cells (n > 200 cells per patient and controls). Cells were stored on ice for 10 min and fixed with 4% paraformaldehyde for 10 min; then methanol for 5 min, permeabilized with 1% Triton X-100 in PBS, blocked at room temperature for 1 h (PBS + 3% NGS + 0.1% Triton), and incubated with antibodies using standard protocols. Primary antibodies included rabbit polyclonal coiled-coil domain-containing protein 114 (HPA042524; Sigma), rabbit polyclonal anti-ARL13B (17711-1-AP; Proteintech), rabbit polyclonal anti-γ-tubulin (T5192; Sigma), mouse polyclonal anti-γ-tubulin (T6557; Sigma), mouse polyclonal anti-acetylation-α-tubulin (T6793; Sigma), and mouse polyclonal anti-Centrin 2 (1:400, 04-1624; Millipore). Secondary antibodies labeled with Alexa-488 and Alexa-568 were were from Jackson Lab. Visualization of the nuclei, image obtaining, and the calculation of ciliated cells percentage were the same as tissue. All data are presented as mean ± SEM. Statistical analysis and graphical representations of the data were performed using GraphPad Prism 5.0 (GraphPad Software, San Diego, California, USA). Statistical significance was calculated using Student’s t test, one-way ANOVA, or chi-squared test, as appropriate.
Cell culture and siRNA
Human retinal pigment epithelial (RPE1) cells were grown in DMEM with 10% fetal bovine serum (FBS). For analysis of ciliary disassembly, cells were plated at 30% confluence in plates containing glass cover slips and starved for 48 h (in Opti-MEM, without added serum) to induce cilia formation, followed by treatments described in Results. Human renal mesangial cells were from Sciencell (Catalog #4200) and human renal proximal tubular epithelial cells were from ATCC (ATCC® Number: PCS-400-010™), and they were cultured as the company instructed. Details of siRNAs used for depletion of CCDC114 and control siRNAs (Invitrogen) are available on request. For siRNA treatment, cells were initially plated in DMEM/10% FBS in plates containing cover slips, and 12 h later, siRNA transfection was performed in Opti-MEM with Oligofectamine (Invitrogen) according to the manufacturer’s recommendations, and fixed 48 h after transfection, following treatments indicated in Results. The remaining cells on the plate were lysed, and then directly analyzed by western blot analysis.
pEZ-M55-CCDC114 recombinant vector construction
The CCDC114 cDNA was reverse transcribed from mRNA from human white blood cells. The complete CCDC114 cDNA (CCDS12714.2, 2013 nt) was subcloned into pEZ-M55 to construct the recombinant vector pEZ-M55-CCDC114. The vector was tagged with m-cherry and Ampicillin antibiotic. The identified variation was introduced by site-directed mutagenesis using Pfu Turbo RNA polymerase (Agilent). The presence of the mutations was verified by Sanger sequencing.
Results
An individual presenting with ciliopathy and decreased cilia in kidney
The affected individual is 15 years old and the first daughter of healthy parents of Chinese origin (see family pedigree in Fig. 1b). The patient has a wider pupillary distance (Fig. 1a). The diagnosis of primary ciliary dyskinesia was made based on the combination of her clinical features. She presents with sinusitis and bronchiectasis. The MRI of her brain showed brain atrophy and abnormal signals in the bilateral parietal lobes, the FLAIR sequence which indicated slow local flow of cerebrospinal fluid (Fig. 1c). The case also presents additional phenotypes that were not classically described in PCD. The patient has multiple-organ dysplasia, including patent ductus arteriosus for which she received an operation when she was 10 years old, pulmonary artery stenosis, sensorineural deafness, decreased visual acuity, and right kidney repeated. She also has renal fibrosis throughout the renal parenchyma. She received hemodialysis treatment at the age of 16. In conclusion, the affected individual presented with ciliopathy, both primary cilia deficiency and PCD. These manifestations are evocative of both primary and motile ciliary defects and present an association of manifestations not described previously. The pathological changes in kidney showed that most glomeruli are globally obsolescent or focal global and segmental glomerulosclerosis, and also show severe interstitial fibrosis and tubular atrophy (Fig. 1d) Then we decided to check the patient’s ciliogenesis in kidney. We found that the number of ciliated cells of the patient is significantly lower than that of controls (Fig. 1e–g).
The affected individual carries a homozygous variation in CCDC114
In order to identify the genetic cause of this complex ciliopathy spectrum, we applied whole-exome sequencing to find all the possible causative genes including ciliopathy genes, genes encoding known ciliary proteins, and genes encoding paralogs or ciliary protein family members [3]. We consequently identified variations in only one gene CCDC114. Homozygous variation was identified in CCDC114 encoding coiled-coil domain-containing protein 114 that has not previously been involved in ciliopathies but was considered a good candidate gene for motile cilia defects. The affected individual is a homozygous variant corresponding to a rare missense SNV (c. 596C > T [p.A199V]) inherited from her parents and her sister is also a heterozygous variant (Fig. 2a, b). This variation causes an anion acid change in the coiled-coil domain of CCDC114 that is predicted to be a functional change of the protein (Fig. 2c, d). Since the functional effects of CCDC114 in motile cilia have been investigated [15, 16], we therefore explore the locations and its functional effect in primary cilia.
CCDC114 locates at the ciliary base and is required for ciliogenesis
To illustrate the function of CCDC114 in primary cilia, we first investigated the subcellular localization of CCDC114 in the ciliated cells using a validated anti-CCDC114 antibody [20]. Figure 3a shows that CCDC114 was visualized at the ciliary base in human retinal pigment epithelial (RPE-1) cells, but not in cells treated with CCDC114-specific siRNAs. CCDC114 locates at the basal body in the RPE-1 cells with or without cilia; and both at the interphase state and the mitosis phase (Fig. 3d). We further confirmed this basal body localization of CCDC114 in other types of cells, including human renal mesangial cells and human renal proximal tubular epithelial cells (Fig. 3e, f). We next attempted to determine the physiological importance of CCDC114 at the ciliary base. Interfering by the specific siRNAs, we found that knockdown of CCDC114 significantly inhibited ciliogenesis in RPE-1 cells (Fig. 3c).
Rescue experiments indicate causation of the CCDC114 mutation to reduce occurrence of primary cilia
The human RPE1 cells transfected with pEZ-M55-CCDC114 showing exogenous CCDC114 also locate at the basal body of the cilia (Fig. 4c). Plasmid-containing human CCDC114 open-reading frame (pEZ-M55-CCDC114) and site mutation CCDC114 (c. 596C > T) open-reading frame were injected into human RPE1 cells transfected with control siRNA or CCDC114 siRNAs. Cilia defects induced by CCDC114 knockdown in human RPE1 cells were largely rescued by expressing an M-cherry-tagged, RNAi-resistant form of CCDC114, but not in cells transfected with plasmid-containing site mutation CCDC114 (c. 596C > T) (Fig. 4d, e).
Discussion
Ciliopathies contain a variety of diseases related to primary cilia and motile cilia, and both formation and function, as cilia almost exist in various cells of the human body, so various organs may have lesions in ciliopathies [2]. Each ciliopathy was long recognized as a discrete disease in its own manifestation, but together they have overlapping pathological elements [21]. In this study, we found a decline in the number of cilia in a patient’s renal tissue with rare ciliopathies, and identified CCDC114 as the main target gene by whole-exon sequencing. We found that CCDC114 located at the basal body of cilia affected primary cilia formation in hRPE1 cells. The previous study of CCDC114 mainly lies in the ODA of motile cilia, and this study found its impact on primary cilia.
During the progression of various kidney diseases, including acute kidney injury and chronic kidney disease, the length of primary cilia is dynamically changed, though we still do not know whether it is as a result and/or cause [22, 23]. In this case, we investigated a rare case of renal disease with multiple-organ dysfunctions and first determined the renal cilium abnormalities through immunofluorescence by one of the cilium markers Arl13b [24]. It has been reported that the number of cilia will decrease through aging, so by comparing the nonneoplastic kidney parenchyma of the patients with renal cancer whose age was 45−60 years old, we could prove that patient’s kidney cilia was significantly less than the normal renal tissue [25]. Although the most common ciliary-associated renal manifestations are renal cysts, abnormal cilia can cause renal sclerosis, while the mechanism of how the cilia abnormalities cause renal sclerosis remains unclear [6, 26]. This patient is the first reported case of PCD caused by CCDC114 mutation who developed kidney disease. We assume the reasons for that are wide-ranging and may include different race, different variations in the gene, and also can be the same reason as kidney dysfunction in Bardet–Biedl syndrome and Alström syndrome though they have not been rigorously studied [27]. The participant in our study had multiorgan dysplasia, but unfortunately, we were not able to have the patient’s birth weight. So, we still cannot exclude the focal segmental glomerulosclerosis induced by low birth weight [28]. Because the patient progressed to ESRD and the family refused to take any additional examinations, we were not able to have the pulmonary tissue to verify the motile cilium dysfunction. We confirmed the subcellular localization of CCDC114 at cilium basal body in various cell types and by overexpression of exogenous CCDC114 plasmid. The CCDC114 gene is located in 19q13.33, its encoding protein coiled-coil domain-containing protein 114, which has previously been studied involved in cilium movement. The mutation of CCDC114 can cause PCD [15]. The PCD caused by the CCDC114 gene mutation is named ciliary dyskinesia, primary, 20 (CILD20) [15]. Unlike other PCD characterized by fertility reduction, CILD20 patients still have a certain reproductive function [16]. Previous studies have confirmed the interaction of CCDC114 with CCCDC151 and TTC25, which can promote the recruitment and/or attachment of the external kinetic protein arm-docking complex protein (including CCDC114, CCDC151, and ARMC4) to the axis filaments [20]. The structure of CCDC114 protein contains a number of coiled-coil domains, and a coiled-coil domain is a two-stage structure consisting of two or more alpha helices, and its entanglement forms a cable structure. In proteins, helical cables play a mechanical role in forming hard fiber bundles [29]. In this case, the 596-base mutant of exon 7 of the 19th chromosome of the patient is harmful to the homozygous T base, which leads to the Alanine replaced by Valine at the 199 protein locus. The 199 protein locus is located in the coiled-coil domain. Both Valine and Alanine are neutral amino acids of the aliphatic amino acids, but the R-based side chains are different. We predicted that Valine instead of Alanine in CCDC114 affected the whole protein function and certified it by rescue experiment by site mutation of the same locus. By knocking down CCDC114, we have found the deficiency of ciliogenesis in RPE-1 cells. It is noteworthy that the affected PCD individual lacks certain symptoms classically observed in PCD [30, 31]. Furthermore, some clinical manifestations with PCD, such as atrial isomerism, may occur in patients without PCD as well, suggesting that ciliary dysfunction may present in different ways despite overlapping clinical presentations [32, 33]. It is clear that overlapping roles exist in ciliary dysfunction, implying that a single mutation may affect more than one cilia type in some cases. Usher’s syndrome, a so-called nonmotile ciliopathy, is associated with altered nasal ciliary function, suggesting an overlap in the terms “motile” and “nonmotile” ciliopathy [3, 34].
At present, the treatments for ciliopathies are limited. However, a clear and in-depth understanding of the disease can avoid misdiagnosis and inappropriate treatment; it can also apply birth guidance for the patients. Despite the fact that there are many aspects not clear of the functions of cilia and mechanisms of ciliopathies, the scope of ciliary-related renal diseases research is expanding and lots of studies have shown the vital role of cilia in kidney disease now [35]. The transformation from basic to clinical treatment needs a large span, by identifying the genes encoding the pathogenicity, studying the function of protein, and understanding the molecular basis of these pathologies, and will have a great advance in the diagnosis and treatment of diseases.
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Acknowledgements
We thank the patient and her family reported here for their willing and continued cooperation in this study. We thank Prof. Huiyan Li, Prof. Xuemin Zhang, and Haiqing Tu for their invaluable support for this research.
Funding
This study is funded by the Beijing Nova Program (Z161100004916129), National Natural Science Foundation of China (81570597), and National Key Research and Development Program of China (2016YFC1101400).
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Li, P., He, Y., Cai, G. et al. CCDC114 is mutated in patient with a complex phenotype combining primary ciliary dyskinesia, sensorineural deafness, and renal disease. J Hum Genet 64, 39–48 (2019). https://doi.org/10.1038/s10038-018-0514-z
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DOI: https://doi.org/10.1038/s10038-018-0514-z
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