Otitis Media in a New Mouse Model for CHARGE Syndrome with a Deletion in the Chd7 Gene

Tian, Cong; Yu, He; Yang, Bin; Han, Fengchan; Zheng, Yuxin; Bartels, Cynthia F.; Schelling, Deborah K.; Arnold, James E.; Scacheri, Peter C.; Zheng, Qing Yin

doi:10.1371/journal.pone.0034944

Cited by 26 publications

(29 citation statements)

References 49 publications

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“…However the specific anomalies described vary somewhat between the models. With respect to the eyes for example, our zebrafish models show an underdeveloped lens, the previously described zebrafish models show retinal disorganization, the frog models develop colobomas, and the mouse models present with keratoconjunctivitis sicca (7, 13, 24, 39). The underlying basis for these differences is not known, but interestingly, this phenotypic variability is highly reminiscent of that seen among human patients with CHARGE syndrome and warrants further study.…”

Section: Discussionmentioning

confidence: 80%

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Knockdown of fbxl10/kdm2bb rescues chd7 morphant phenotype in a zebrafish model of CHARGE syndrome

Balow¹,

Pierce²,

Zentner

et al. 2013

Developmental Biology

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CHARGE syndrome is a sporadic autosomal-dominant genetic disorder characterized by a complex array of birth defects so named for its cardinal features of ocular coloboma, heart defects, choanal atresia, growth retardation, genital abnormalities, and ear abnormalities. Approximately two-thirds of individuals clinically diagnosed with CHARGE syndrome have heterozygous loss-of-function mutations in the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7), an ATP-dependent chromatin remodeler. To examine the role of Chd7 in development, a zebrafish model was generated through morpholino (MO)-mediated targeting of the zebrafish chd7 transcript. High doses of chd7 MO induce lethality early in embryonic development. However, low dose-injected embryos are viable, and by 4 days post-fertilization, morphant fish display multiple defects in organ systems analogous to those affected in humans with CHARGE syndrome. The chd7 morphants show elevated expression of several potent cell-cycle inhibitors including ink4ab (p16/p15), p21 and p27, accompanied by reduced cell proliferation. We also show that Chd7 is required for proper organization of neural crest-derived craniofacial cartilage structures. Strikingly, MO-mediated knockdown of the jumonji domain-containing histone demethylase fbxl10/kdm2bb, a repressor of ribosomal RNA (rRNA) genes, rescues cell proliferation and cartilage defects in chd7 morphant embryos and can lead to complete rescue of the CHARGE syndrome phenotype. These results indicate that CHARGE-like phenotypes in zebrafish can be mitigated through modulation of fbxl10 levels and implicate FBXL10 as a possible therapeutic target in CHARGE syndrome.

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Section: Discussionmentioning

confidence: 80%

“…To date, zebrafish, frogs, and mice have been used to study the role of CHD7 in development (7, 8, 13, 23, 24, 38, 39). The overall phenotype and the organ systems affected in the chd7 morphants reported here are consistent with those previously observed in the other models (Supplemental Table 1).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of fbxl10/kdm2bb rescues chd7 morphant phenotype in a zebrafish model of CHARGE syndrome

Balow¹,

Pierce²,

Zentner

et al. 2013

Developmental Biology

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“…Cilia dysfunctions have been implicated in a number of conditions, including neonatal respiratory distress, chronic nasal congestion, bronchiectasis and sinusitis, and chronic otitis media with effusion67810111263646566. Despite the significant association and likely contributory role of cilia in OM671112636667, the most common childhood disease, only a sparse number of studies examined ciliation in the epithelium that lines the middle ear cavity and thus have provided only a partial understanding of ciliation in the middle ear13141617686970. Moreover, the orientation of the cilia, which is the structural feature of cilia critical to their motility output and clearance function, has not even been studied.…”

Section: Discussionmentioning

confidence: 99%

Cilia distribution and polarity in the epithelial lining of the mouse middle ear cavity

Luo

Taylor

et al. 2017

Sci Rep

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The middle ear conducts sound to the cochlea for hearing. Otitis media (OM) is the most common illness in childhood. Moreover, chronic OM with effusion (COME) is the leading cause of conductive hearing loss. Clinically, COME is highly associated with Primary Ciliary Dyskinesia, implicating significant contributions of cilia dysfunction to COME. The understanding of middle ear cilia properties that are critical to OM susceptibility, however, is limited. Here, we confirmed the presence of a ciliated region near the Eustachian tube orifice at the ventral region of the middle ear cavity, consisting mostly of a lumen layer of multi-ciliated and a layer of Keratin-5-positive basal cells. We also found that the motile cilia are polarized coordinately and display a planar cell polarity. Surprisingly, we also found a region of multi-ciliated cells that line the posterior dorsal pole of the middle ear cavity which was previously thought to contain only non-ciliated cells. Our study provided a more complete understanding of cilia distribution and revealed for the first time coordinated polarity of cilia in the epithelium of the mammalian middle ear, thus illustrating novel structural features that are likely critical for middle ear functions and related to OM susceptibility.

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“…Heritability studies have shown that genetic factors can play an important role in otitis media susceptibility, but few contributing genes have been identified in human populations [1]. In contrast to human studies, a growing number of mouse mutations have been identified that manifest a high incidence of otitis media, including Eya4 , Tlr4 , p73 , MyD88 , Fas , E2f4 , Plg , Fbxo11 , Evi1 [1,2], Sh3pxd2b [3], Rpl38 [4], Isl1 [5], Chd7 [6], Lmna1 [7], Phex [8], Oxgr1 [9], Tgif1 [10], and Mcph1 [11]. The wide diversity of these genes and their mutant pathologies, including craniofacial abnormalities with Eustachian tube malformations and innate immune response defects, underscores the complex nature of otitis media.…”

Section: Introductionmentioning

confidence: 99%

Ectopic Mineralization and Conductive Hearing Loss in Enpp1asj Mutant Mice, a New Model for Otitis Media and Tympanosclerosis

2016

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Otitis media (OM), inflammation of the middle ear, is a common cause of hearing loss in children and in patients with many different syndromic diseases. Studies of the human population and mouse models have revealed that OM is a multifactorial disease with many environmental and genetic contributing factors. Here, we report on otitis media-related hearing loss in asj (ages with stiffened joints) mutant mice, which bear a point mutation in the Enpp1 gene. Auditory-evoked brainstem response (ABR) measurements revealed that around 90% of the mutant mice (Enpp1asj/asj) tested had moderate to severe hearing impairment in at least one ear. The ABR thresholds were variable and generally elevated with age. We found otitis media with effusion (OME) in all of the hearing-impaired Enpp1asj/asj mice by anatomic and histological examinations. The volume and inflammatory cell content of the effusion varied among the asj mutant mice, but all mutants exhibited a thickened middle ear epithelium with fibrous polyps and more mucin-secreting goblet cells than controls. Other abnormalities observed in the Enpp1 mutant mice include over-ossification at the round window ridge, thickened and over-calcified stapedial artery, fusion of malleus and incus, and white patches on the inside of tympanic membrane, some of which are typical symptoms of tympanosclerosis. An excessive yellow discharge was detected in the outer ear canal of older asj mutant mice, with 100% penetrance by 5 months of age, and contributes to the progressive nature of the hearing loss. This is the first report of hearing loss and ear pathology associated with an Enpp1 mutation in mice. The Enpp1asj mutant mouse provides a new animal model for studying tympanosclerotic otitis and otitis media with effusion, and also provides a specific model for the hearing loss recently reported to be associated with human ENPP1 mutations causing generalized arterial calcification of infancy and hypophosphatemic rickets.

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Otitis Media in a New Mouse Model for CHARGE Syndrome with a Deletion in the Chd7 Gene

Cited by 26 publications

References 49 publications

Knockdown of fbxl10/kdm2bb rescues chd7 morphant phenotype in a zebrafish model of CHARGE syndrome

Knockdown of fbxl10/kdm2bb rescues chd7 morphant phenotype in a zebrafish model of CHARGE syndrome

Cilia distribution and polarity in the epithelial lining of the mouse middle ear cavity

Ectopic Mineralization and Conductive Hearing Loss in Enpp1asj Mutant Mice, a New Model for Otitis Media and Tympanosclerosis

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