The Ciliopathies: An Emerging Class of Human Genetic Disorders

Badano, José L.; Mitsuma, Norimasa; Beales, Phil; Katsanis, Nicholas

doi:10.1146/annurev.genom.7.080505.115610

Cited by 1,035 publications

(918 citation statements)

References 139 publications

Supporting

Mentioning

883

Contrasting

Unclassified

Order By: Relevance

“…These include the autosomal dominant and recessive forms of polycystic kidney disease and several other cystic kidney diseases, such as nephrophthisis, oral-facial-digital syndrome type 1, and Bardet-Biedl syndrome. 23 As primary cilia harbor pVHL 7 and renal cysts are present in about 60% of VHL patients, 24 this syndrome highly likely represents a ciliopathy. In fact, compared to normal tubular cells, pVHLdefective epithelial cells lining cysts of VHL patients display a reduced frequency of cilia.…”

Section: Discussionmentioning

confidence: 99%

Sporadic clear cell renal cell carcinoma but not the papillary type is characterized by severely reduced frequency of primary cilia

et al. 2009

View full text Add to dashboard Cite

Renal cysts and clear cell renal cell carcinoma are common clinical manifestations of people with germ-line mutations of the von Hippel-Lindau tumor suppressor gene, VHL. Recent cell biological evidence suggests that the VHL gene product, pVHL, functions to maintain the primary cilium, a microtubule-based antenna-like structure whose functional integrity is believed to have an important role in cell-cycle control. As VHL mutations are common in sporadic clear cell renal cell carcinoma, but not papillary renal cell carcinoma, we asked whether there is an association between VHL status and primary cilia in vivo. VHL status was assessed in 20 cases of clear cell renal cell carcinoma and 9 cases of papillary renal cell carcinoma by DNA sequencing and by immunohistochemical staining for the hypoxia-inducible factor-a target gene products CA9 and GLUT-1. Of 20, 18 clear cell renal cell carcinomas, but only 1 of 9 papillary renal cell carcinomas, displayed evidence of VHL inactivation. In clear cell renal cell carcinoma the frequency of ciliated tumor cells ranged from 0 to 22% (median value 7.8±6.0%), whereas cilia frequency was significantly higher (Po0.0001) in papillary renal cell carcinoma (range 12-83%, median value 43.3 ± 21.3%). There was no correlation between Ki-67 staining and cilia frequency, suggesting that the observed differences between the tumor types in cilia frequency are not accounted for by differences in cellular proliferation rates and that primary cilia degeneration in sporadic clear cell renal cell carcinoma depends on VHL inactivation. We propose that the different ciliation status of clear cell and papillary renal cell carcinoma may contribute, at least in part, to the different biological behaviors of these tumor types.

show abstract

Section: Discussionmentioning

confidence: 99%

Sporadic clear cell renal cell carcinoma but not the papillary type is characterized by severely reduced frequency of primary cilia

et al. 2009

View full text Add to dashboard Cite

show abstract

“…47,48 Supplemental Data Supplemental Data include seven figures and five tables and can be found with this article online at http://dx.doi.org/10.1016/j.ajhg. 2017.04.012.…”

Section: Semen Parametersmentioning

confidence: 99%

Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella

Tang¹,

Wang

Li³

et al. 2017

The American Journal of Human Genetics

254

212

View full text Add to dashboard Cite

Sperm motility is vital to human reproduction. Malformations of sperm flagella can cause male infertility. Men with multiple morphological abnormalities of the flagella (MMAF) have abnormal spermatozoa with absent, short, coiled, bent, and/or irregular-caliber flagella, which impair sperm motility. The known human MMAF-associated genes, such as DNAH1, only account for fewer than 45% of affected individuals. Pathogenic mechanisms in the genetically unexplained MMAF remain to be elucidated. Here, we conducted genetic analyses by using whole-exome sequencing and genome-wide comparative genomic hybridization microarrays in a multi-center cohort of 30 Han Chinese men affected by MMAF. Among them, 12 subjects could not be genetically explained by any known MMAFassociated genes. Intriguingly, we identified compound-heterozygous mutations in CFAP43 in three subjects and a homozygous frameshift mutation in CFAP44 in one subject. All of these recessive mutations were parentally inherited from heterozygous carriers but were absent in 984 individuals from three Han Chinese control populations. CFAP43 and CFAP44, encoding two cilia-and flagella-associated proteins (CFAPs), are specifically or preferentially expressed in the testis. Using CRISPR/Cas9 technology, we generated two knockout models each deficient in mouse ortholog Cfap43 or Cfap44. Notably, both Cfap43-and Cfap44-deficient male mice presented with MMAF phenotypes, whereas the corresponding female mice were fertile. Our experimental observations on human subjects and animal models strongly suggest that biallelic mutations in either CFAP43 or CFAP44 can cause sperm flagellar abnormalities and impair sperm motility. Further investigations on other CFAP-encoding genes in more genetically unexplained MMAF-affected individuals could uncover novel mechanisms underlying sperm flagellar formation.

show abstract

“…Primary cilia are known to play key roles in the development and functioning of several cell types, including retinal photoreceptors, neurons, and the epithelial cells comprising kidney tubules and bile ducts. 3 In the developing cerebellum and brainstem, primary cilia regulate major signal transduction pathways, and have been implicated in both neuronal cell proliferation and axonal migration. 4 In particular, primary cilia are required for Sonic Hedgehog (SHH) signaling and for SHHdependent cerebellar development, [5][6][7] including in humans.…”

mentioning

confidence: 99%

Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity

et al. 2014

View full text Add to dashboard Cite

Joubert syndrome (JS) is a genetically heterogeneous autosomal recessive ciliopathy with 22 genes implicated to date, including a small, ciliary GTPase, ARL13B. ARL13B is required for cilia formation in vertebrates. JS patients display multiple symptoms characterized by ataxia due to the cerebellar vermis hypoplasia, and that can also include ocular abnormalities, renal cysts, liver fibrosis or polydactyly. These symptoms are shared with other ciliopathies, some of which display additional phenotypes, such as obesity. Here we identified a novel homozygous missense variant in ARL13B/JBTS8 in a JS patient who displayed retinal defects and obesity. We demonstrate the variant disrupts ARL13B function, as its expression did not rescue the mutant phenotype either in Arl13b scorpion zebrafish or in Arl13b hennin mouse embryonic fibroblasts, while the wild-type ARL13B did. Finally, we show that ARL13B is localized within the primary cilia of neonatal mouse hypothalamic neurons consistent with the known link between hypothalamic ciliary function and obesity. Thus our data identify a novel ARL13B variant that causes JS and retinopathy and suggest an extension of the phenotypic spectrum of ARL13B mutations to obesity.

show abstract

The Ciliopathies: An Emerging Class of Human Genetic Disorders

Cited by 1,035 publications

References 139 publications

Sporadic clear cell renal cell carcinoma but not the papillary type is characterized by severely reduced frequency of primary cilia

Sporadic clear cell renal cell carcinoma but not the papillary type is characterized by severely reduced frequency of primary cilia

Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella

Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity

Contact Info

Product

Resources

About