Abnormal respiratory cilia in non-syndromic Leber congenital amaurosis with CEP290 mutations

Papon, Jean‐François; Perrault, Isabelle; Coste, A.; Louis, Bruno; Gérard, Xavier; Hanein, Sylvain; Fares-Taie, Lucas; Gerber, Sylvie; Defoort‐Dhellemmes, Sabine; Vojtek, Anne Marie; Kaplan, Josseline; Rozet, Jean–Michel; Escudier, Estelle

doi:10.1136/jmg.2010.077883

Cited by 48 publications

(41 citation statements)

References 36 publications

(28 reference statements)

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“…We note CD in the respiratory epithelia also has been reported in patients with Leber congenital amaurosis (LCA), 32 a ciliopathy involving cone-rod dystrophy due to defects in the connecting cilium required for photoreceptor biogenesis. Patients exhibit “rarefaction of ciliated cells,” which also was observed in many of our heterotaxy patients with CD.…”

Section: Discussionsupporting

confidence: 53%

High Prevalence of Respiratory Ciliary Dysfunction in Congenital Heart Disease Patients With Heterotaxy

et al. 2012

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Background Patients with congenital heart disease (CHD) and heterotaxy show high postsurgical morbidity/mortality, with some developing respiratory complications. Although this finding is often attributed to the CHD, airway clearance and left-right patterning both require motile cilia function. Thus, airway ciliary dysfunction (CD) similar to that of primary ciliary dyskinesia (PCD) may contribute to increased respiratory complications in heterotaxy patients. Methods and Results We assessed 43 CHD patients with heterotaxy for airway CD. Videomicrocopy was used to examine ciliary motion in nasal tissue, and nasal nitric oxide (nNO) was measured; nNO level is typically low with PCD. Eighteen patients exhibited CD characterized by abnormal ciliary motion and nNO levels below or near the PCD cutoff values. Patients with CD aged >6 years show increased respiratory symptoms similar to those seen in PCD. Sequencing of all 14 known PCD genes in 13 heterotaxy patients with CD, 12 without CD, 10 PCD disease controls, and 13 healthy controls yielded 0.769, 0.417, 1.0, and 0.077 novel variants per patient, respectively. One heterotaxy patient with CD had the PCD causing DNAI1 founder mutation. Another with hyperkinetic ciliary beat had 2 mutations in DNAH11, the only PCD gene known to cause hyperkinetic beat. Among PCD patients, 2 had known PCD causing CCDC39 and CCDC40 mutations. Conclusions Our studies show that CHD patients with heterotaxy have substantial risk for CD and increased respiratory disease. Heterotaxy patients with CD were enriched for mutations in PCD genes. Future studies are needed to assess the potential benefit of prescreening and prophylactically treating heterotaxy patients for CD.

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Section: Discussionsupporting

confidence: 53%

High Prevalence of Respiratory Ciliary Dysfunction in Congenital Heart Disease Patients With Heterotaxy

et al. 2012

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“…Application of this model to all of the CEP290 patients described in the literature (table S2) (14–19) again showed that predicted protein levels were robustly associated with disease severity ( P < 0.0001, Fisher’s exact test) (Fig. 2C).…”

Section: Resultsmentioning

confidence: 70%

Basal exon skipping and genetic pleiotropy: A predictive model of disease pathogenesis

et al. 2015

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Genetic pleiotropy, the phenomenon by which mutations in the same gene result in markedly different disease phenotypes, has proven difficult to explain with traditional models of disease pathogenesis. We have developed a model of pleiotropic disease that explains, through the process of basal exon skipping, how different mutations in the same gene can differentially affect protein production, with the total amount of protein produced correlating with disease severity. Mutations in the centrosomal protein of 290 kDa (CEP290) gene are associated with a spectrum of phenotypically distinct human diseases (the ciliopathies). Molecular biologic examination of CEP290 transcript and protein expression in cells from patients carrying CEP290 mutations, measured by quantitative polymerase chain reaction and Western blotting, correlated with disease severity and corroborated our model. We show that basal exon skipping may be the mechanism underlying the disease pleiotropy caused by CEP290 mutations. Applying our model to a different disease gene, CC2D2A (coiled-coil and C2 domains–containing protein 2A), we found that the same correlations held true. Our model explains the phenotypic diversity of two different inherited ciliopathies and may establish a new model for the pathogenesis of other pleiotropic human diseases.

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“…None of the patients had optic atrophy or retinal coloboma, and none had any known nonocular medical conditions suggestive of a CEP290-associated multisystem ciliopathy syndrome (Joubert syndrome, Senior-Løken syndrome, Meckel-Gruber syndrome, or Bardet-Biedl syndrome). 2 Although subtle nonocular findings, such as abnormalities of respiratory cilia, have been associated with LCA-CEP290, 16,17 here we refer to LCA-CEP290 in our six patients as ''nonsyndromic'' to differentiate it from the four syndromes listed above.…”

Section: Methodsmentioning

confidence: 99%

Full-Field Pupillary Light Responses, Luminance Thresholds, and Light Discomfort Thresholds inCEP290Leber Congenital Amaurosis Patients

Collison¹,

Park

Fishman

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To investigate visual function in patients with CEP290 Leber congenital amaurosis (LCA-CEP290), using three full-field tests that can be performed by patients with poor fixation. METHODS.Six patients (age range, 9-39 years) with LCA-CEP290 participated in the study. Stimuli for all three tests (full-field stimulus test [FST], pupillometry, and light discomfort threshold [LDT] testing) were generated by the Diagnosys ColorDome ganzfeld, by using achromatic stimuli as well as long-and short-wavelength stimuli to target rod and cone photoreceptors with all three tests and, in the latter two tests, melanopsin photoreceptors.RESULTS. Dark-adapted FST thresholds in LCA-CEP290 patients were cone mediated and elevated between 4.8 and 6.2 log units above the normal achromatic threshold. The FST threshold was not measurable in one patient. The rod-mediated transient pupillary light reflex (PLR) was absent in all but the youngest patient, where unreliable responses precluded PLR quantification. Cone-mediated transient PLRs were subnormal in five patients, and absent in another. Sustained melanopsin-mediated PLRs were measurable in all patients. Full-field LDT thresholds were elevated compared to normal controls, and were lower for short-wavelengh than for long-wavelength stimuli.CONCLUSIONS. The FST thresholds and transient PLRs were cone mediated in our cohort LCA-CEP290 patients. Rod-mediated PLRs were undetectable, whereas melanopsin-mediated sustained responses were detected in all patients, suggesting a relative preservation of innerretina function. The LDT elevations for the patients are somewhat paradoxical, given their subjective perception of photoaversion. Relative aversion to short-wavelength light suggests influence from melanopsin on LDTs in these patients.

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Abnormal respiratory cilia in non-syndromic Leber congenital amaurosis with CEP290 mutations

Cited by 48 publications

References 36 publications

High Prevalence of Respiratory Ciliary Dysfunction in Congenital Heart Disease Patients With Heterotaxy

High Prevalence of Respiratory Ciliary Dysfunction in Congenital Heart Disease Patients With Heterotaxy

Basal exon skipping and genetic pleiotropy: A predictive model of disease pathogenesis

Full-Field Pupillary Light Responses, Luminance Thresholds, and Light Discomfort Thresholds inCEP290Leber Congenital Amaurosis Patients

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