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Journal of Pediatric Neurology 2023; 21(01): 078-084
DOI: 10.1055/s-0042-1759533
Review Article

The Function and Role of the Cilium in the Development of Ciliopathies

Alessio Mancuso 
1   Department of Human Pathology of the Adult and Developmental Age “Gaetano Barresi,” Unit of Pediatric Emergency, University of Messina, Messina, Italy
,
Ida Ceravolo
2   Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
,
Caterina Cuppari
1   Department of Human Pathology of the Adult and Developmental Age “Gaetano Barresi,” Unit of Pediatric Emergency, University of Messina, Messina, Italy
,
Alessia Sallemi
1   Department of Human Pathology of the Adult and Developmental Age “Gaetano Barresi,” Unit of Pediatric Emergency, University of Messina, Messina, Italy
,
Monica Fusco
1   Department of Human Pathology of the Adult and Developmental Age “Gaetano Barresi,” Unit of Pediatric Emergency, University of Messina, Messina, Italy
,
Antonio Ceravolo
3   Pediatrician, Cinquefrondi (RC), Italy
,
Giovanni Farello
4   Pediatric Clinic–Department of Life, Health and Environmental Sciences–Piazzale Salvatore, Coppito (AQ), Italy
,
Giulia Iapadre
5   Department of Pediatrics, University of L'Aquila, Via Vetoio, 1. Coppito, 67100 L'Aquila, Italy
,
Luca Zagaroli
5   Department of Pediatrics, University of L'Aquila, Via Vetoio, 1. Coppito, 67100 L'Aquila, Italy
,
Giuliana Nanni
5   Department of Pediatrics, University of L'Aquila, Via Vetoio, 1. Coppito, 67100 L'Aquila, Italy
,
Giovanni Conti
6   Department of Human Pathology of the Adult and Developmental Age “Gaetano Barresi,” Unit of Pediatric Nephrology and Rheumatology, University of Messina, Messina, Italy
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Abstract

“Ciliopathies” are a group of genetic disorders described by the malformation or dysfunction of cilia. The disorders of ciliary proteins lead to a range of phenotype from organ-specific (e.g., cystic disease of the kidney, liver, and pancreas, neural tube defects, postaxial polydactyly, situs inversus, and retinal degeneration) to sketchily pleiotropic (e.g., Bardet-Biedl syndrome and Joubert syndrome). The mechanism below the disfunction of cilia to reach new therapeutic strategies.

Keywords

cilium - ciliopathies - Joubert syndrome

Authors' Contributions

A.M. and I.C. conceptualized the study. C.C. and A.C. contributed to investigation. G.C. provided resources. E.G. and A.S. helped in data curation. M.F. and L.Z. helped in writing-original draft preparation. G.F. and G.N. contributed to writing, review, and editing. G.C. and G.I. supervised the study.


All authors have read and agreed to the published version of the manuscript.


Data Availability Statement

The data presented in this study are available on request from the corresponding author.




Publication History

Received: 23 August 2022

Accepted: 27 October 2022

Article published online:
05 December 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Xie MH, Qiao WH, Cao H, Shi JW, Dong NG. [Progress in the role of mechanical stimulus in cardiac development]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2022; 44 (01) 164-172
    Search in Google Scholar
  • 2 Gerdes JM, Davis EE, Katsanis N. The vertebrate primary cilium in development, homeostasis, and disease. Cell 2009; 137 (01) 32-45
    Search in Google Scholar
  • 3 Singla V, Reiter JF. The primary cilium as the cell's antenna: signaling at a sensory organelle. Science 2006; 313 (5787): 629-633
    Search in Google Scholar
  • 4 Hoey DA, Downs ME, Jacobs CR. The mechanics of the primary cilium: an intricate structure with complex function. J Biomech 2012; 45 (01) 17-26
    Search in Google Scholar
  • 5 Madhivanan K, Aguilar RC. Ciliopathies: the trafficking connection. Traffic 2014; 15 (10) 1031-1056
    Search in Google Scholar
  • 6 Hildebrandt F, Otto E. Cilia and centrosomes: a unifying pathogenic concept for cystic kidney disease?. Nat Rev Genet 2005; 6 (12) 928-940
    Search in Google Scholar
  • 7 Accogli A, Iacomino M, Pinto F. et al. Novel AMPD2 mutation in pontocerebellar hypoplasia, dysmorphisms, and teeth abnormalities. Neurol Genet 2017; 3 (05) e179
    Search in Google Scholar
  • 8 Shaheen R, Mark P, Prevost CT. et al. Biallelic variants in CTU2 cause DREAM-PL syndrome and impair thiolation of tRNA wobble U34. [published correction appears in Hum Mutat. 2021 Feb;42(2):219] Hum Mutat 2019; 40 (11) 2108-2120
    Search in Google Scholar
  • 9 Fischer E, Legue E, Doyen A. et al. Defective planar cell polarity in polycystic kidney disease. Nat Genet 2006; 38 (01) 21-23
    Search in Google Scholar
  • 10 Salpietro V, Polizzi A, Granata F, Briuglia S, Mankad K, Ruggieri M. Upper respiratory tract infection and torticollis in children: differential diagnosis of Grisel's syndrome. Clin Neuroradiol 2012; 22 (04) 351-353
    Search in Google Scholar
  • 11 Casto C, Dipasquale V, Ceravolo I. et al. Prominent and regressive brain developmental disorders associated with Nance-Horan syndrome. Brain Sci 2021; 11 (09) 1150
    Search in Google Scholar
  • 12 Salpietro V, Malintan NT, Llano-Rivas I. et al; Deciphering Developmental Disorders Study, SYNAPS Study Group. Mutations in the neuronal vesicular SNARE VAMP2 affect synaptic membrane fusion and impair human neurodevelopment. Am J Hum Genet 2019; 104 (04) 721-730
    Search in Google Scholar
  • 13 Pedullà M, Miraglia Del Giudice M, Fierro V. et al. Atopy as a risk factor for thyroid autoimmunity in children. J Biol Regul Homeost Agents 2012; 26 (1, Suppl): S9-S14
    Search in Google Scholar
  • 14 Marseglia L, D'Angelo G, Manti S. et al. Sudden cardiac arrest in a child with nemaline myopathy. Ital J Pediatr 2015; 41: 20
    Search in Google Scholar
  • 15 Salpietro V, Ruggieri M, Sancetta F. et al. New insights on the relationship between pseudotumor cerebri and secondary hyperaldosteronism in children. J Hypertens 2012; 30 (03) 629-630
    Search in Google Scholar
  • 16 Salpietro V, Phadke R, Saggar A. et al. Zellweger syndrome and secondary mitochondrial myopathy. Eur J Pediatr 2015; 174 (04) 557-563
    Search in Google Scholar
  • 17 Nicita F, Ruggieri M, Polizzi A. et al. Seizures and epilepsy in Sotos syndrome: analysis of 19 Caucasian patients with long-term follow-up. Epilepsia 2012; 53 (06) e102-e105
    Search in Google Scholar
  • 18 Tassano E, Accogli A, Pavanello M. et al. Interstitial 9p24.3 deletion involving only DOCK8 and KANK1 genes in two patients with non-overlapping phenotypic traits. Eur J Med Genet 2016; 59 (01) 20-25
    Search in Google Scholar
  • 19 Chelban V, Wilson MP, Warman Chardon J. et al; Care4Rare Canada Consortium and the SYNaPS Study Group. PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation. Ann Neurol 2019; 86 (02) 225-240
    Search in Google Scholar
  • 20 Pavone P, Briuglia S, Falsaperla R. et al. Wide spectrum of congenital anomalies including choanal atresia, malformed extremities, and brain and spinal malformations in a girl with a de novo 5.6-Mb deletion of 13q12.11-13q12.13. Am J Med Genet A 2014; 164A (07) 1734-1743
    Search in Google Scholar
  • 21 Dias CM, Punetha J, Zheng C. et al. Homozygous missense variants in NTNG2, encoding a presynaptic Netrin-G2 adhesion protein, lead to a distinct neurodevelopmental disorder. Am J Hum Genet 2019; 105 (05) 1048-1056
    Search in Google Scholar
  • 22 Loddo I, Barbera F, Di Gesaro G. et al. Genetics and cardiovascular disease. J Biol Regul Homeost Agents 2020; 34 (4, Suppl. 2): 17-22
    Search in Google Scholar
  • 23 Ghosh SG, Becker K, Huang H. et al. Biallelic mutations in ADPRHL2, encoding ADP-Ribosylhydrolase 3, lead to a degenerative pediatric stress-induced epileptic ataxia syndrome. [published correction appears in Am J Hum Genet. 2018 Nov 1;103(5):826] [published correction appears in Am J Hum Genet. 2021 Dec 2;108(12):2385] Am J Hum Genet 2018; 103 (03) 431-439
    Search in Google Scholar
  • 24 Salpietro V, Manole A, Efthymiou S, Houlden H. A review of copy number variants in inherited neuropathies. Curr Genomics 2018; 19 (06) 412-419
    Search in Google Scholar
  • 25 Pavlidou E, Salpietro V, Phadke R. et al. Pontocerebellar hypoplasia type 2D and optic nerve atrophy further expand the spectrum associated with selenoprotein biosynthesis deficiency. Eur J Paediatr Neurol 2016; 20 (03) 483-488
    Search in Google Scholar
  • 26 Ruggieri M, Polizzi A, Schepis C. et al. Cutis tricolor: a literature review and report of five new cases. Quant Imaging Med Surg 2016; 6 (05) 525-534
    Search in Google Scholar
  • 27 Steel D, Salpietro V, Phadke R. et al. Whole exome sequencing reveals a MLL de novo mutation associated with mild developmental delay and without 'hairy elbows': expanding the phenotype of Wiedemann-Steiner syndrome. J Genet 2015; 94 (04) 755-758
    Search in Google Scholar
  • 28 Salpietro V, Zollo M, Vandrovcova J. et al; SYNAPS Study Group. The phenotypic and molecular spectrum of PEHO syndrome and PEHO-like disorders. Brain 2017; 140 (08) e49
    Search in Google Scholar
  • 29 Salpietro V, Efthymiou S, Manole A. et al. A loss-of-function homozygous mutation in DDX59 implicates a conserved DEAD-box RNA helicase in nervous system development and function. Hum Mutat 2018; 39 (02) 187-192
    Search in Google Scholar
  • 30 Oliverio GW, Ceravolo I, Bhatti A, Trombetta CJ. Foveal avascular zone analysis by optical coherence tomography angiography in patients with type 1 and 2 diabetes and without clinical signs of diabetic retinopathy. Int Ophthalmol 2021; 41 (02) 649-658
    Search in Google Scholar
  • 31 Bruno L, Ceravolo G, Ceravolo MD. et al. Genetic cardiac channelopathies and SIDS. J Biol Regul Homeost Agents 2020; 34 (4, Suppl. 2): 55-58
    Search in Google Scholar
  • 32 Riva A, Gambadauro A, Dipasquale V. et al. Biallelic variants in KIF17 associated with microphthalmia and Coloboma spectrum. Int J Mol Sci 2021; 22 (09) 4471
    Search in Google Scholar
  • 33 Efthymiou S, Salpietro V, Malintan N. et al; SYNAPS Study Group. Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination. Brain 2019; 142 (10) 2948-2964
    Search in Google Scholar
  • 34 Granata F, Morabito R, Mormina E. et al. 3T double inversion recovery magnetic resonance imaging: diagnostic advantages in the evaluation of cortical development anomalies. Eur J Radiol 2016; 85 (05) 906-914
    Search in Google Scholar
  • 35 Chirico V, Lacquaniti A, Salpietro V, Buemi M, Salpietro C, Arrigo T. Central precocious puberty: from physiopathological mechanisms to treatment. J Biol Regul Homeost Agents 2014; 28 (03) 367-375
    Search in Google Scholar
  • 36 Chimenz R, Manti S, Fede C. et al. Primary nocturnal enuresis in children with allergic rhinitis and severe adenotonsillar hypertrophy: a single center pilot study. J Biol Regul Homeost Agents 2015; 29 (2, Suppl 1): 73-79
    Search in Google Scholar
  • 37 Soliman NA, Hildebrandt F, Otto EA. et al. Clinical characterization and NPHP1 mutations in nephronophthisis and associated ciliopathies: a single center experience. Saudi J Kidney Dis Transpl 2012; 23 (05) 1090-1098
    Search in Google Scholar
  • 38 Hildebrandt F, Zhou W. Nephronophthisis-associated ciliopathies. J Am Soc Nephrol 2007; 18 (06) 1855-1871
    Search in Google Scholar
  • 39 Mollet G, Silbermann F, Delous M, Salomon R, Antignac C, Saunier S. Characterization of the nephrocystin/nephrocystin-4 complex and subcellular localization of nephrocystin-4 to primary cilia and centrosomes. Hum Mol Genet 2005; 14 (05) 645-656
    Search in Google Scholar
  • 40 Caspary T, Larkins CE, Anderson KV. The graded response to Sonic Hedgehog depends on cilia architecture. Dev Cell 2007; 12 (05) 767-778
    Search in Google Scholar
  • 41 Szakszon K, Salpietro C, Kakar N. et al. De novo mutations of the gene encoding the histone acetyltransferase KAT6B in two patients with Say-Barber/Biesecker/Young-Simpson syndrome. Am J Med Genet A 2013; 161A (04) 884-888
    Search in Google Scholar
  • 42 Ceravolo I, Oliverio GW, Alibrandi A. et al. The application of structural retinal biomarkers to evaluate the effect of intravitreal ranibizumab and dexamethasone intravitreal implant on treatment of diabetic macular edema. Diagnostics (Basel) 2020; 10 (06) 413
    Search in Google Scholar
  • 43 Marchetti M, Savorra M, Cenname G, Ceravolo I, Merra G. Childhood obesity: right diagnosis and treatment, a current challenge. Eur Rev Med Pharmacol Sci 2020; 24 (04) 1591-1592
    Search in Google Scholar
  • 44 Meo F, Salpietro A, Ceravolo G. et al. Cardiovascular complications in children with chronic kidney injury. J Biol Regul Homeost Agents 2020;34(4, Suppl. 2):43–46 www.scopus.com [Internet]
  • 45 Ceravolo G, Macchia T, Cuppari C. et al. Update on the classification and pathophysiological mechanisms of pediatric cardiorenal syndromes. Children (Basel) 2021; 8 (07) 528
    Search in Google Scholar
  • 46 Briguglio M, Pinelli L, Giordano L. et al; CBCD Study Group. Pontine tegmental cap dysplasia: developmental and cognitive outcome in three adolescent patients. Orphanet J Rare Dis 2011; 6: 36
    Search in Google Scholar
  • 47 Pinchefsky EF, Accogli A, Shevell MI, Saint-Martin C, Srour M. Developmental outcomes in children with congenital cerebellar malformations. Dev Med Child Neurol 2019; 61 (03) 350-358
    Search in Google Scholar
  • 48 Brancati F, Barrano G, Silhavy JL. et al; International JSRD Study Group. CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders. Am J Hum Genet 2007; 81 (01) 104-113
    Search in Google Scholar