Pathogenic NPHP5 mutations impair protein interaction with Cep290, a prerequisite for ciliogenesis

Barbelanne, Marine; Song, Jia; Ahmadzai, Mustafa; Tsang, William Y.W.

doi:10.1093/hmg/ddt100

Cited by 60 publications

(87 citation statements)

References 37 publications

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“…By contrast, as previously reported (25,26), much of the A small number of CEP290 null cells formed primary cilia positive for the ciliary markers poly-glutamylated tubulin and ARL13B (Supplemental Figure 1E). However, cilia in the mutant cells exhibited a significant decrease in Smo-EGFP fluorescence intensity when compared with cilia from CEP290 WT cells (Figure 2, A and B).…”

Section: This Suggests That Although Eupatilin Can Promote Ciliogenessupporting

confidence: 74%

Eupatilin rescues ciliary transition zone defects to ameliorate ciliopathy-related phenotypes

Kim¹,

Kim²,

Jung³

et al. 2018

Journal of Clinical Investigation

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Section: This Suggests That Although Eupatilin Can Promote Ciliogenessupporting

confidence: 74%

Eupatilin rescues ciliary transition zone defects to ameliorate ciliopathy-related phenotypes

Kim¹,

Kim²,

Jung³

et al. 2018

Journal of Clinical Investigation

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“…¼ not significant. mislocalization, and were ineffective in binding of CEP290; both abnormalities impair cilia assembly (13).…”

Section: Photoreceptor Sensory Ciliummentioning

confidence: 97%

“…This analysis, however, was only partial as most antibodies tested and used to define the ciliary axoneme were not specific in dog retina; these included antibodies against RPGR, RPGRIP1, RP1 (Supplementary Material, Table S3). As well, antibodies, both commercially available (n ¼ 3) and custom-made (2), against NPHP5 did not label (13). Cognizant of these limitations, we examined by confocal microscopy three antibodies that in dogs labeled components of the photoreceptor sensory cilium: acetylated a tubulin, rootletin (30) and MAP9 (Downs et al, unpublished information).…”

Section: Photoreceptor Sensory Cilium Is Present In Mutant Retinasmentioning

confidence: 99%

“…Although the mutation in dogs (20) truncates the C-terminal 268 amino acids and eliminates the second of two BBS binding domains, and the CEP290 binding domain (18), the truncated protein appears to be sufficient to drive differentiation and cilia formation. The canine mutation, presumably, also would delete the second calmodulin-binding (CaM), domain and 5 of the 29 amino acid of the first domain (20); in cultured cells, mutations in this domain do not impair cilia formation (13,39). Regardless, it is surprising that ciliogenesis is not fully impaired given the extent of the canine NPHP5 mutation.…”

Section: Photoreceptor Sensory Ciliummentioning

confidence: 99%

“…NPHP5 patients show early and rapid rod degeneration with unexpected preservation of central cones that function poorly or not at all (11,12). The gene product localizes to renal cilia and to the photoreceptor connecting cilium/transitional zone (9), and is required for early cilia assembly and ciliogenesis (13,14). Additionally, NPHP5 interacts with several proteins responsible for X-linked retinitis pigmentosa (RPGR) (15), LCA, SLSN or Joubert syndrome (CEP290) (10,16,17) and the BBSome subunits that have been implicated in Bardet Biedl Syndrome (18,19).…”

Section: Introductionmentioning

confidence: 99%

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Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

et al. 2016

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Ciliary defects can result in severe disorders called ciliopathies. Mutations in NPHP5 cause a ciliopathy characterized by severe childhood onset retinal blindness, Leber congenital amaurosis (LCA), and renal disease. Using the canine NPHP5-LCA model we compared human and canine retinal phenotypes, and examined the early stages of photoreceptor development and degeneration, the kinetics of photoreceptor loss, the progression of degeneration and the expression profiles of selected genes. NPHP5-mutant dogs recapitulate the human phenotype of very early loss of rods, and relative retention of the central retinal cone photoreceptors that lack function. In mutant dogs, rod and cone photoreceptors have a sensory cilium, but develop and function abnormally and then rapidly degenerate; L/M cones are more severely affected than S-cones. The lack of outer segments in mutant cones indicates a ciliary dysfunction. Genes expressed in mutant rod or both rod and cone photoreceptors show significant downregulation, while those expressed only in cones are unchanged. Many genes in celldeath and -survival pathways also are downregulated. The canine disease is a non-syndromic LCA-ciliopathy, with normal renal structures and no CNS abnormalities. Our results identify the critical time points in the pathogenesis of the photoreceptor disease, and bring us closer to defining a potential time window for testing novel therapies for translation to patients. †

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Clinical and molecular findings in a cohort of 152 Brazilian severe early onset inherited retinal dystrophy patients

Sallum

Motta

Arno

et al. 2020

American J of Med Genetics Pt C

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Leber congenital amaurosis (LCA) and early-onset retinal dystrophy (EORD) are severe inherited retinal dystrophy that can cause deep blindness childhood. They represent 5% of all retinal dystrophies in the world population and about 10% in Brazil. Clinical findings and molecular basis of syndromic and nonsyndromic LCA/EORD in a Brazilian sample (152 patients/137 families) were studied. In this population, 15 genes were found to be related to the phenotype, 38 new variants were detected and four new complex alleles were discovered. Among 123 variants found, the most common were CEP290: c.2991+1655A>G, CRB1: p.Cys948Tyr, and RPGRIP1: exon10-18 deletion. K E Y W O R D S causal genes, childhood blindness, early-onset retinal dystrophy (EORD), genotypephenotype, Leber congenital amaurosis (LCA), pathogenic variants 1 | INTRODUCTION Leber congenital amaurosis (LCA) is the most severe and earliest onset inherited retinal dystrophy. Affected individuals usually present, in the first year of life with severe visual impairment, nystagmus and occasionally a systemic manifestation (Francis, 2006). Phenotypic variability in fundus abnormality, refractive errors, photophobia or lightseeking behavior, nyctalopia, nystagmus, low visual acuity, and Franceschetti's oculo-digital sign, are also commonly observed in these patients (Chung & Traboulsi, 2009; den Hollander, Roepman, Koenekoop, & Cremers, 2008). Early-onset retinal dystrophy (EORD) can be considered as belonging to the same LCA spectrum but a milder form, where signs and symptoms appear after the first year of life up to 5-7 years-old (Weleber, Francis, Trzupek, & Beattie, 2004), but still a disease that severely compromises vision. Clinically, LCA and EORD are similar and may represent a continuum; the distinction between them is an extinguished or markedly diminished ERG response before the first year of life for individuals with

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Pathogenic NPHP5 mutations impair protein interaction with Cep290, a prerequisite for ciliogenesis

Cited by 60 publications

References 37 publications

Eupatilin rescues ciliary transition zone defects to ameliorate ciliopathy-related phenotypes

Eupatilin rescues ciliary transition zone defects to ameliorate ciliopathy-related phenotypes

Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

Clinical and molecular findings in a cohort of 152 Brazilian severe early onset inherited retinal dystrophy patients

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