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Clinical Medicine (London, England) Dec 2017Physicians reading this will have a broad range of in-depth knowledge about their own subspecialty. However, in daily medical practice there are topics of which all... (Review)
Review
Physicians reading this will have a broad range of in-depth knowledge about their own subspecialty. However, in daily medical practice there are topics of which all physicians should have some knowledge. Those who deal with young people should have some knowledge of the needs of the hearing-impaired population within this group of patients. This article is intended to provide an overview of young people with hearing impairment (HIYP), the challenges they face and what we can do to help them. In this paper, we assume that data published regarding hearing-impaired children apply to HIYP from 13 years (the age at which the transition process begins) to 25 years of age (the age at which 'youth' according to the World health Organization and the Education Health Care Plan ends).
Topics: Adolescent; Adult; Branchio-Oto-Renal Syndrome; Cochlear Implantation; Cochlear Implants; Communication; Correction of Hearing Impairment; Deafness; Education of Hearing Disabled; Educational Status; Goiter, Nodular; Hearing Loss; Hearing Loss, Sensorineural; Humans; Lipreading; Mainstreaming, Education; Nephritis, Hereditary; Patient Preference; Persons With Hearing Impairments; Physician-Patient Relations; Postural Balance; Sign Language; Tinnitus; Transition to Adult Care; Usher Syndromes; Young Adult
PubMed: 29196352
DOI: 10.7861/clinmedicine.17-6-521 -
Developmental Biology Nov 2020The Six1 transcription factor plays a major role in craniofacial development. Mutations in SIX1 and its co-factor, EYA1, are causative for about 50% of...
The Six1 transcription factor plays a major role in craniofacial development. Mutations in SIX1 and its co-factor, EYA1, are causative for about 50% of Branchio-otic/Branchio-oto-renal syndrome (BOR) patients, who are characterized by variable craniofacial, otic and renal malformations. We previously screened for other proteins that might interact with Six1 to identify additional genes that may play a role in BOR, and herein characterize the developmental role of one of them, Microspherule protein 1 (Mcrs1). We found that in cultured cells, Mcrs1 bound to Six1 and in both cultured cells and embryonic ectoderm reduced Six1-Eya1 transcriptional activation. Knock-down of Mcrs1 in embryos caused an expansion of the domains of neural plate genes and two genes expressed in both the neural plate and neural crest (zic1, zic2). In contrast, two other genes expressed in pre-migratory neural crest (foxd3, sox9) were primarily reduced. Cranial placode genes showed a mixture of expanded and diminished expression domains. At larval stages, loss of Mcrs1 resulted in a significant reduction of otic vesicle gene expression concomitant with a smaller otic vesicle volume. Experimentally increasing Mcrs1 above endogenous levels favored the expansion of neural border and neural crest gene domains over cranial placode genes; it also reduced otic vesicle gene expression but not otic vesicle volume. Co-expression of Mcrs1 and Six1 as well as double knock-down and rescue experiments establish a functional interaction between Mcrs1 and Six1 in the embryo, and demonstrate that this interaction has an important role in the development of craniofacial tissues including the otic vesicle.
Topics: Animals; Ectoderm; Embryo, Nonmammalian; Gene Expression Regulation, Developmental; Homeodomain Proteins; Neural Crest; RNA-Binding Proteins; Skull; Xenopus Proteins; Xenopus laevis
PubMed: 32891623
DOI: 10.1016/j.ydbio.2020.08.013 -
Science Immunology Feb 2020We investigated the molecular and cellular basis of severe combined immunodeficiency (SCID) in six patients with otofaciocervical syndrome type 2 who failed to attain T...
We investigated the molecular and cellular basis of severe combined immunodeficiency (SCID) in six patients with otofaciocervical syndrome type 2 who failed to attain T cell reconstitution after allogeneic hematopoietic stem cell transplantation, despite successful engraftment in three of them. We identified rare biallelic rare variants in all patients. We demonstrated that these mutant PAX1 proteins have an altered conformation and flexibility of the paired box domain and reduced transcriptional activity. We generated patient-derived induced pluripotent stem cells and differentiated them into thymic epithelial progenitor cells and found that they have an altered transcriptional profile, including for genes involved in the development of the thymus and other tissues derived from pharyngeal pouches. These results identify biallelic, loss-of-function mutations as the cause of a syndromic form of SCID due to altered thymus development.
Topics: Branchio-Oto-Renal Syndrome; Epithelial Cells; Humans; Infant; Male; Paired Box Transcription Factors; Severe Combined Immunodeficiency; Thymus Gland
PubMed: 32111619
DOI: 10.1126/sciimmunol.aax1036 -
Disease Models & Mechanisms Feb 2024The association between ear and kidney anomalies has long been recognized. However, little is known about the underlying mechanisms. In the last two decades, embryonic...
The association between ear and kidney anomalies has long been recognized. However, little is known about the underlying mechanisms. In the last two decades, embryonic development of the inner ear and kidney has been studied extensively. Here, we describe the developmental pathways shared between both organs with particular emphasis on the genes that regulate signalling cross talk and the specification of progenitor cells and specialised cell types. We relate this to the clinical features of oto-renal syndromes and explore links to developmental mechanisms.
Topics: Humans; Branchio-Oto-Renal Syndrome; Kidney; Kidney Diseases; Organogenesis; Embryonic Development
PubMed: 38353121
DOI: 10.1242/dmm.050447 -
Frontiers in Cell and Developmental... 2022The vertebrate Six1 and Six2 arose by gene duplication from the and have since diverged in their developmental expression patterns. Both genes are expressed in nephron...
The vertebrate Six1 and Six2 arose by gene duplication from the and have since diverged in their developmental expression patterns. Both genes are expressed in nephron progenitors of human fetal kidneys, and mutations in SIX1 or SIX2 cause branchio-oto-renal syndrome or renal hypodysplasia respectively. Since ∼80% of SIX1 target sites are shared by SIX2, it is speculated that SIX1 and SIX2 may be functionally interchangeable by targeting common downstream genes. In contrast, in mouse kidneys, Six1 expression in the metanephric mesenchyme lineage overlaps with Six2 only transiently, while Six2 expression is maintained in the nephron progenitors throughout development. This non-overlapping expression between Six1 and Six2 in mouse nephron progenitors promoted us to examine if Six1 can replace Six2. Surprisingly, forced expression of Six1 failed to rescue Six2-deficient kidney phenotype. We found that Six1 mediated Eya1 nuclear translocation and inhibited premature epithelialization of the progenitors but failed to rescue the proliferation defects and cell death caused by Six2-knockout. Genome-wide binding analyses showed that Six1 selectively occupied a small subset of Six2 target sites, but many Six2-bound loci crucial to the renewal and differentiation of nephron progenitors lacked Six1 occupancy. Altogether, these data indicate that Six1 cannot substitute Six2 to drive nephrogenesis in mouse kidneys, thus demonstrating that the difference in physiological roles of Six1 and Six2 in kidney development stems from both transcriptional regulations of the genes and divergent biochemical properties of the proteins.
PubMed: 35178390
DOI: 10.3389/fcell.2022.815249 -
Frontiers in Genetics 2022High incidence of chronic otitis media is associated with human craniofacial syndromes, suggesting that defects in the formation of the middle ear and associated...
High incidence of chronic otitis media is associated with human craniofacial syndromes, suggesting that defects in the formation of the middle ear and associated structures can have a knock-on effect on the susceptibility to middle ear inflammation. Patients with branchio-oto-renal (BOR) syndrome have several defects in the ear leading to both sensorineural and conductive hearing loss, including otitis media. 40% of BOR syndrome cases are due to haploinsufficiency, with mouse models affecting , mimicking many of the defects found in patients. Here, we characterize the onset, consequences, and underlying causes of chronic otitis media in heterozygous mice. Cavitation defects were evident in these mice from postnatal day (P)11 onwards, with mesenchyme around the promontory and attic regions of the middle ear space. This mesenchyme was still prominent in adult heterozygous mice, while the wild-type littermates had fully aerated ears from P14 onwards. MicroCT analysis highlighted a significantly smaller bulla, confirming the link between bulla size defects and the ability of the mesenchyme to retract successfully. Otitis media was observed from P14, often presenting unilaterally, resulting in hyperplasia of the middle ear mucosa, expansion of secretory cells, defects in the motile cilia, and changes in basal epithelial cell markers. A high incidence of otitis media was identified in older mice but only associated with ears with retained mesenchyme. To understand the impact of the environment, the mouse line was rederived onto a super-clean environment. Cavitation defects were still evident at early stages, but these generally resolved over time, and importantly, no signs of otitis media were observed at 6 weeks. In conclusion, we show that a small bulla size is closely linked to defects in cavitation and the presence of retained mesenchyme. A delay in retraction of the mesenchyme predates the onset of otitis media, making the ears susceptible to its development. Early exposure to OM appears to exacerbate the cavitation defect, with mesenchyme evident in the middle ear throughout the animal's life. This highlights that permanent damage to the middle ear can arise as a consequence of the early onset of OM.
PubMed: 36299576
DOI: 10.3389/fgene.2022.933416 -
Children (Basel, Switzerland) Dec 2022Branchiootorenal (BOR) syndrome is a rare autosomal dominant inherited disease with a prevalence of approximately 1 in 40,000 newborns. This disease is characterized by...
Branchiootorenal (BOR) syndrome is a rare autosomal dominant inherited disease with a prevalence of approximately 1 in 40,000 newborns. This disease is characterized by hearing loss, preauricular pits, branchial fistulas or cysts, and renal dysplasia. We discovered a case of BOR syndrome in a premature 2-week-old female infant with a gestational age of 32 weeks and two days. She and her family had major symptoms and a family history of BOR. BOR syndrome was confirmed by whole-genome sequencing and structural variant calling, which revealed an exon 5-6 deletion. The infant had recurrent sleep and feeding cyanosis with second branchial anomalies. Via videofluoroscopic swallowing study and a modified barium swallow test, penetration into the vocal cords was observed before and during swallowing when bottle feeding. This is the first report of a preterm infant early diagnosed with BOR syndrome in which deletion margin was accurately identified by whole-genome sequencing and structural variant calling in Republic of Korea.
PubMed: 36670626
DOI: 10.3390/children10010076 -
Genesis (New York, N.Y. : 2000) Dec 2021The vertebrate Six (Sine oculis homeobox) family of homeodomain transcription factors plays critical roles in the development of several organs. Six1 plays a central...
The vertebrate Six (Sine oculis homeobox) family of homeodomain transcription factors plays critical roles in the development of several organs. Six1 plays a central role in cranial placode development, including the precursor tissues of the inner ear, as well as other cranial sensory organs and the kidney. In humans, mutations in SIX1 underlie some cases of Branchio-oto-renal (BOR) syndrome, which is characterized by moderate-to-severe hearing loss. We utilized CRISPR/Cas9 technology to establish a six1 mutant line in Xenopus tropicalis that is available to the research community. We demonstrate that at larval stages, the six1-null animals show severe disruptions in gene expression of putative Six1 target genes in the otic vesicle, cranial ganglia, branchial arch, and neural tube. At tadpole stages, six1-null animals display dysmorphic Meckel's, ceratohyal, and otic capsule cartilage morphology. This mutant line will be of value for the study of the development of several organs as well as congenital syndromes that involve these tissues.
Topics: Animals; Branchial Region; Branchio-Oto-Renal Syndrome; CRISPR-Cas Systems; Congenital Abnormalities; Embryonic Development; Ganglia, Parasympathetic; Gene Expression; Gene Expression Regulation, Developmental; Hearing Loss; Homeodomain Proteins; Humans; Neural Tube; Skull; Transcription Factors; Xenopus; Xenopus Proteins
PubMed: 34664392
DOI: 10.1002/dvg.23453 -
Molecular Genetics & Genomic Medicine Feb 2019Branchio-oto-renal (BOR) syndrome is one of the most common autosomal dominant hearing loss syndromes and features clinical and genetic heterogeneity. When there is no...
BACKGROUND
Branchio-oto-renal (BOR) syndrome is one of the most common autosomal dominant hearing loss syndromes and features clinical and genetic heterogeneity. When there is no renal deformity, this disease can also be called branchio-otic (BO) syndrome. Though many genes have been reported, there are still many BO syndrome-related genes to be identified. To identify a hitherto unknown candidate gene causing BO syndrome in a three-generation Chinese family, clinical, genetic, and functional analyses were employed.
METHODS
Whole-exome sequencing (WES) was conducted in three affected family members and two unaffected family members. PCR-Sanger sequencing was performed in all of the family members for segregation analysis and verification of the candidate variants. PCR-Sanger sequencing was also employed in 150 healthy people to examine the variants. In silico analysis was used to predict possible changes in the protein structure that may affect the phenotype.
RESULTS
We identified a heterozygous missense variant in ANLN: NM_018685.4: c.G1105A; NP_061155.2: p.G369R that segregated in the pedigree with an autosomal dominant pattern. No variant was found in the 150 controls and normal family members at this site. The variant c.G1105A was located in a highly conserved F-actin binding site. The amino acid residue at position 369 in the ANLN protein was highly conserved across different species.
CONCLUSION
In this study, we identified, for the first time, a heterozygous missense variant in ANLN (NM_018685.4: c.G1105A; NP_061155.2: p.G369R) that is likely to be a candidate causative gene of BO syndrome in a specific Chinese family.
Topics: Adult; Branchio-Oto-Renal Syndrome; Child; Female; Heterozygote; Humans; Male; Microfilament Proteins; Middle Aged; Mutation, Missense; Pedigree
PubMed: 30548429
DOI: 10.1002/mgg3.525 -
Developmental Dynamics : An Official... Jan 2018In vertebrates, cranial sensory placodes give rise to neurosensory and endocrine structures, such as the olfactory epithelium, inner ear, and anterior pituitary. We...
BACKGROUND
In vertebrates, cranial sensory placodes give rise to neurosensory and endocrine structures, such as the olfactory epithelium, inner ear, and anterior pituitary. We report here the establishment of a transgenic mouse line that expresses Cre recombinase under the control of Six1-21, a major placodal enhancer of the homeobox gene Six1.
RESULTS
In the new Cre-expressing line, mSix1-21-NLSCre, the earliest Cre-mediated recombination was induced at embryonic day 8.5 in the region overlapping with the otic-epibranchial progenitor domain (OEPD), a transient, common precursor domain for the otic and epibranchial placodes. Recombination was later observed in the OEPD-derived structures (the entire inner ear and the VIIth-Xth cranial sensory ganglia), olfactory epithelium, anterior pituitary, pharyngeal ectoderm and pouches. Other Six1-positive structures, such as salivary/lacrimal glands and limb buds, were also positive for recombination. Moreover, comparison with another mouse line expressing Cre under the control of the sensory neuron enhancer, Six1-8, indicated that the continuous and complex expression pattern of Six1 during sensory organ formation is pieced together by separate enhancers.
CONCLUSIONS
mSix1-21-NLSCre has several unique characteristics to make it suitable for analysis of cell lineage and gene function in sensory placodes as well as nonplacodal Six1-positive structures. Developmental Dynamics 247:250-261, 2018. © 2017 Wiley Periodicals, Inc.
Topics: Animals; Gene Expression Regulation, Developmental; Homeodomain Proteins; Mice; Mice, Transgenic; Neural Plate; Olfactory Bulb; Olfactory Receptor Neurons; Sensory Receptor Cells
PubMed: 29106072
DOI: 10.1002/dvdy.24603