Pleiotropic Effects of CEP290 (NPHP6) Mutations Extend to Meckel Syndrome

Baala, Lekbir; Audollent, Sophie; Martinovic, Jéléna; Ozilou, Catherine; Babron, Marie‐Claude; Sivanandamoorthy, Sivanthiny; Saunier, Sophie; Salomon, Rémi; Gonzalès, Marie; Rattenberry, Eleanor; Esculpavit, Chantal; Toutain, Annick; Moraine, Claude; Parent, Philippe; Marcorelles, Pascale; Dauge, Marie-Christine; Roume, J.; Merrer, Martine Le; Meiner, Vardiella; Meir, Karen; Ménez, F.; Beaufrère, Anne-Marie; Francannet, Christine; Tantau, Julia; Sinico, M; Dumez, Yves; Macdonald, Fiona; Münnich, Arnold; Lyonnet, Stanislas; Gubler, Marie–Claire; Génin, Emmanuelle; Johnson, Colin A.; Vekemans, Michel; Encha‐Razavi, Férechté; Attié‐Bitach, Tania

doi:10.1086/519494

Cited by 244 publications

(224 citation statements)

References 25 publications

(38 reference statements)

Supporting

Mentioning

212

Contrasting

Unclassified

Order By: Relevance

“…Despite two patients displaying an occipital encephalocele, no ARL13B variants have been found in Meckel syndrome fetuses (Cantagrel et al 9 and personal data), although Meckel syndrome has been shown to be the extreme lethal phenotype of JS for other genes. [29][30][31][32][33] In conclusion, we have identified a novel homozygous missense variant in ARL13B/JBTS8 in a JS patient with retinal involvement and obesity. We have shown that this variant is hypomorphic, as it is unable to rescue efficiently either the arl13b sco zebrafish phenotype or the deficiencies in Arl13b hnn MEFs.…”

Section: Discussionmentioning

confidence: 66%

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

et al. 2014

Self Cite

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

Section: Discussionmentioning

confidence: 66%

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

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Despite these differences, it is apparent that sensory cells are much more susceptible to mutations in CEP290 than other ciliary systems. Nonsense mutations of CEP290 result in Joubert syndrome, characterized by retinal degeneration, cerebellar vermis aplasia, and nephronophthisis, and Meckel syndrome, an autosomal recessive lethal condition characterized by CNS, kidney, and liver malformations (15,21,22,25). Missense mutations (such as those detected in LCA and the rd16 mice), however, appear to only affect sensory systems, resulting in retinal degeneration and olfactory dysfunction in both humans and mice, with no overt kidney or cerebellar defects.…”

Section: Discussionmentioning

confidence: 99%

“…Genetic mutations in ciliary, basal body, and centrosomal proteins lead to pleiotropic human diseases, including polycystic kidney disease, Bardet-Biedl syndrome, Senior-Loken syndrome, Meckel syndrome, and retinitis pigmentosa (RP) (2,7,(13)(14)(15). Nephrocystins are a family of ciliary proteins that are likely involved in cargo sorting during transport from the basal body to the ciliary axoneme (16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons

McEwen¹,

Koenekoop

Khanna

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

146

156

View full text Add to dashboard Cite

Cilia regulate diverse functions such as motility, fluid balance, and sensory perception. The cilia of olfactory sensory neurons (OSNs) compartmentalize the signaling proteins necessary for odor detection; however, little is known regarding the mechanisms of protein sorting/entry into olfactory cilia. Nephrocystins are a family of ciliary proteins likely involved in cargo sorting during transport from the basal body to the ciliary axoneme. In humans, loss-offunction of the cilia-centrosomal protein CEP290/NPHP6 is associated with Joubert and Meckel syndromes, whereas hypomorphic mutations result in Leber congenital amaurosis (LCA), a form of early-onset retinal dystrophy. Here, we report that CEP290 -LCA patients exhibit severely abnormal olfactory function. In a mouse model with hypomorphic mutations in CEP290 [retinal dystrophy-16 mice (rd16)], electro-olfactogram recordings revealed an anosmic phenotype analogous to that of CEP290 -LCA patients. Despite the loss of olfactory function, cilia of OSNs remained intact in the rd16 mice. As in wild type, CEP290 localized to dendritic knobs of rd16 OSNs, where it was in complex with ciliary transport proteins and the olfactory G proteins G olf and G␥13. Interestingly, we observed defective ciliary localization of G olf and G␥13 but not of G protein-coupled odorant receptors or other components of the odorant signaling pathway in the rd16 OSNs. Our data implicate distinct mechanisms for ciliary transport of olfactory signaling proteins, with CEP290 being a key mediator involved in G protein trafficking. The assessment of olfactory function can, therefore, serve as a useful diagnostic tool for genetic screening of certain syndromic ciliary diseases.nephrocystin ͉ olfaction

show abstract

“…These include Ableson-helper integration-1 (AHI1), Nephrocystin-1 (NPHP1), Centrosomal protein-290 (CEP290), Transmembrane protein 67 (TMEM67) and Retinitis pigmentosa GTPase regulator-interacting protein-like (RPGRIP1L). Each of the genes encodes a modular scaffolding protein without clear enzymatic domains, but sharing several protein-interaction domains of unknown function, suggesting that they may be part of a signaling complex [28][29][30][31][32][33][34][35][36] The Joubert syndrome connection with cilia Although the function of JSRD proteins remains largely unknown, recent evidence suggests roles in either mediating the assembly/stability of cilia or mediating cargo transport within cilia. When tested directly, at least three of the encoded proteins, NPHP1, CEP290 and RPGRIP1L have demonstrated localization to the basal body or cilium [32,[35][36][37], further suggesting a role at the cilium or basal body.…”

Section: Joubert Syndrome and Related Disordersmentioning

confidence: 99%

Cerebellar development and disease

Millen¹,

Gleeson²

2008

Current Opinion in Neurobiology

170

141

View full text Add to dashboard Cite

The molecular control of cell type specification within the developing cerebellum as well as the genetic causes of the most common human developmental cerebellar disorders have long remained mysterious. Recent genetic lineage and loss-of-function data from mice have revealed unique and non-overlapping anatomical origins for GABAergic neurons from ventricular zone precursors and glutamatergic cell from rhombic lip precursors, mirroring distinct origins for these neurotransmitterspecific cell types in the cerebral cortex. Mouse studies elucidating the role of Ptf1a as a cerebellar ventricular zone GABerigic fate switch were actually preceded by the recognition that PTF1A mutations in humans cause cerebellar agenesis, a birth defect of the human cerebellum. Indeed, several genes for congenital human cerebellar malformations have recently been identified, including genes causing Joubert syndrome, Dandy-Walker malformation and Ponto-cerebellar hypoplasia. These studies have pointed to surprisingly complex roles for transcriptional regulation, mitochondrial function and neuronal cilia in patterning, homeostasis and cell proliferation during cerebellar development. Together mouse and human studies are synergistically advancing our understanding of the developmental mechanisms that generate the uniquely complex mature cerebellum.

show abstract

Pleiotropic Effects of CEP290 (NPHP6) Mutations Extend to Meckel Syndrome

Cited by 244 publications

References 25 publications

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

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

Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons

Cerebellar development and disease

Contact Info

Product

Resources

About