Abstract
Biallelic pathogenic variants in the gene CC2D2A cause a spectrum of ciliopathies, including Joubert and Meckel syndrome, which frequently involve the kidney; however, no cases of isolated renal disease (i.e., nephronophthisis) have yet been reported. In an adult with a clinical presentation consistent with nephronophthisis, next-generation sequencing identified a rare homozygous nonsense variant in CC2D2A (c.100 C > T; p.(Arg34*)). Tissue-specific expression data and promoter activity analysis demonstrates that this variant primarily affects a transcript isoform predominant in the kidneys but does not affect the transcript isoforms predominant in other tissues typically involved in CC2D2A-related ciliopathies (e.g., cerebellum, liver). Expression analysis of patient-specific cDNA in MDCK cells demonstrates partial translation re-initiation downstream of p.(Arg34*) as a possible escape mechanism from nonsense mediated decay. These data provide mechanistic insights in support of this novel genotype-phenotype association.
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Data availability
The data supporting this study are described in the supplementary materials.
References
Barroso-Gil M, Olinger E, Sayer JA. Molecular genetics of renal ciliopathies. Biochem Soc Trans. 2021;49:1205–20.
Snoek R, van Setten J, Keating BJ, Israni AK, Jacobson PA, Oetting WS, et al. NPHP1 (Nephrocystin-1) Gene Deletions Cause Adult-Onset ESRD. J Am Soc Nephrol JASN. 2018;29:1772–9.
Veleri S, Manjunath SH, Fariss RN, May-Simera H, Brooks M, Foskett TA, et al. Ciliopathy-associated gene Cc2d2a promotes assembly of subdistal appendages on the mother centriole during cilia biogenesis. Nat Commun. 2014;5:4207.
Barroso‐Gil M, Olinger E, Ramsbottom SA, Molinari E, Miles CG, Sayer JA. Update of genetic variants in CEP120 and CC2D2A—With an emphasis on genotype‐phenotype correlations, tissue specific transcripts and exploring mutation specific exon skipping therapies. Mol Genet Genomic Med. 2021;9:e1603.
Gorden NT, Arts HH, Parisi MA, Coene KLM, Letteboer SJF, van Beersum SEC, et al. CC2D2A Is Mutated in Joubert Syndrome and Interacts with the Ciliopathy-Associated Basal Body Protein CEP290. Am J Hum Genet. 2008;83:559–71.
Noor A, Windpassinger C, Patel M, Stachowiak B, Mikhailov A, Azam M, et al. CC2D2A, Encoding A Coiled-Coil and C2 Domain Protein, Causes Autosomal-Recessive Mental Retardation with Retinitis Pigmentosa. Am J Hum Genet. 2008;82:1011–8.
Tallila J, Jakkula E, Peltonen L, Salonen R, Kestilä M. Identification of CC2D2A as a Meckel Syndrome Gene Adds an Important Piece to the Ciliopathy Puzzle. Am J Hum Genet. 2008;82:1361–7.
Méjécase C, Hummel A, Mohand-Saïd S, Andrieu C, El Shamieh S, Antonio A, et al. Whole exome sequencing resolves complex phenotype and identifies CC2D2A mutations underlying non-syndromic rod-cone dystrophy. Clin Genet. 2019;95:329–33.
Doherty D, Parisi MA, Finn LS, Gunay-Aygun M, Al-Mateen M, Bates D, et al. Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis). J Med Genet. 2010;47:8–21.
Bachmann-Gagescu R, Ishak GE, Dempsey JC, Adkins J, O’Day D, Phelps IG, et al. Genotype–phenotype correlation in CC2D2A-related Joubert syndrome reveals an association with ventriculomegaly and seizures. J Med Genet. 2012;49:126–37.
Harion M, Qebibo L, Riquet A, Rougeot C, Afenjar A, Garel C, et al. New insights into CC2D2A-related Joubert syndrome. J Med Genet. 2023;60:578–86.
Mougou-Zerelli S, Thomas S, Szenker E, Audollent S, Elkhartoufi N, Babarit C, et al. CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation. Hum Mutat. 2009;30:1574–82.
Lindeboom RGH, Vermeulen M, Lehner B, Supek F. The impact of nonsense-mediated mRNA decay on genetic disease, gene editing and cancer immunotherapy. Nat Genet. 2019;51:1645–51.
Kozak M. The scanning model for translation: an update. J Cell Biol. 1989;108:229–41.
Dyle MC, Kolakada D, Cortazar MA, Jagannathan S. How to get away with nonsense: Mechanisms and consequences of escape from nonsense-mediated RNA decay. WIREs RNA. 2020;11:e1560.
Gleason AC, Ghadge G, Chen J, Sonobe Y, Roos RP. Machine learning predicts translation initiation sites in neurologic diseases with nucleotide repeat expansions. PLOS ONE. 2022;17:e0256411.
Puel A, Reichenbach J, Bustamante J, Ku CL, Feinberg J, Döffinger R, et al. The NEMO Mutation Creating the Most-Upstream Premature Stop Codon Is Hypomorphic Because of a Reinitiation of Translation. Am J Hum Genet. 2006;78:691–701.
Stump MR, Gong Q, Packer JD, Zhou Z. Early LQT2 nonsense mutation generates N-terminally truncated hERG channels with altered gating properties by the reinitiation of translation. J Mol Cell Cardiol. 2012;53:725–33.
Al-Hamed MH, Hussein MH, Shah Y, Al-Mojalli H, Alsabban E, Alshareef T, et al. Exome sequencing unravels genetic variants associated with chronic kidney disease in Saudi Arabian patients. Hum Mutat. 2022;43:e24–37.
Awazu M, Yamada M, Asada N, Hashiguchi A, Kosaki K, Matsumura K. A girl with a mutation of the ciliary gene CC2D2A presenting with FSGS and nephronophthisis. CEN Case Rep. 2021;11:116–9.
Acknowledgements
We would like to thank the patient for their participation.
Funding
T.K. is funded through support by the Fonds de recherche du Québec en Santé (FRQS) Salary Grant and the SickKids New Investigator Research Grant. Z.S. is funded through support of the Canadian Institutes of Health Research (CIHR).
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Z.S. contributed to research conceptualization, performed in silico analyses and in vitro experiments, drafted the manuscript and approved the final version. N.A. and J.R. performed clinical variant interpretation and approved the final manuscript version. Z.N. contributed to the analysis of results, contributed to manuscript drafting and approved the final version. L.M. contributed to experimental design and contributed to manuscript drafting and approved the final version. S.B. contributed to experimental design and approved the final manuscript version. P.G. and E.T. contributed to the experimental design and manuscript review and approved the final manuscript version. T.K. contributed to the research conceptualization, recruited and consented participants, collected and interpreted clinical and genetic data, interpreted the results, contributed to the manuscript drafting and approved the final version.
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Given the retrospective nature of the study, and informed consent for the use of clinical information was verbally obtained from the participant and documented in the participant’s medical chart, approval by the McGill University Health Centre Research Ethics Board was not required for this case report. The study was conducted in accordance with the ethical principles enshrined in the Helsinki Declaration.
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Sentell, Z.T., Nurcombe, Z.W., Mougharbel, L. et al. Expanding the phenotypic spectrum of CC2D2A-related ciliopathies: a rare homozygous nonsense variant in a patient with suspected nephronophthisis. Eur J Hum Genet (2024). https://doi.org/10.1038/s41431-024-01668-x
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DOI: https://doi.org/10.1038/s41431-024-01668-x
