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1.
Gene ; 761: 144996, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32738421

RESUMO

Sensorineural deafness in mammals is most commonly caused by damage to inner ear sensory epithelia, or hair cells, and can be attributed to genetic and environmental causes. After undergoing trauma, many non-mammalian organisms, including reptiles, birds, and zebrafish, are capable of regenerating damaged hair cells. Mammals, however, are not capable of regenerating damaged inner ear sensory epithelia, so that hair cell damage is permanent and can lead to hearing loss. The field of epigenetics, which is the study of various phenotypic changes caused by modification of genetic expression rather than alteration of DNA sequence, has seen numerous developments in uncovering biological mechanisms of gene expression and creating various medical treatments. However, there is a lack of information on the precise contribution of epigenetic modifications in the auditory system, specifically regarding their correlation with development of inner ear (cochlea) and consequent hearing impairment. Current studies have suggested that epigenetic modifications influence differentiation, development, and protection of auditory hair cells in cochlea, and can lead to hair cell degeneration. The objective of this article is to review the existing literature and discuss the advancements made in understanding epigenetic modifications of inner ear sensory epithelial cells. The analysis of the emerging epigenetic mechanisms related to inner ear sensory epithelial cells development, differentiation, protection, and regeneration will pave the way to develop novel therapeutic strategies for hearing loss.


Assuntos
Células Ciliadas Auditivas/citologia , Células Ciliadas Auditivas/fisiologia , Perda Auditiva Neurossensorial/genética , Animais , Diferenciação Celular/genética , Surdez/genética , Orelha Interna/crescimento & desenvolvimento , Epigênese Genética , Células Ciliadas Auditivas Internas/citologia , Células Ciliadas Auditivas Internas/fisiologia , Perda Auditiva/genética , Humanos , Regeneração/genética
2.
Artigo em Chinês | MEDLINE | ID: mdl-32842192

RESUMO

To study the clinical features and causes of congenital Usher hearing loss in one child. Clinical examination, audiological tests, visual acuity examination were conducted in the proband and its family members, and second-generation sequencing technology for deafness gene detection was employed. The proband exhibited profound sensorineural deafness(hearing threshold>90 dB nHL). There was no visual loss after follow-up. Other family members had no history of hearing loss. The gene test indicated that the proband had a frameshift mutation for the thymine(T) deletion at the 1527 site of the Usher1C gene. The mutation was a homozygous mutation, and was from the father and the mother, respectively, which caused the truncation of the encoded protein. Normal function, Usher syndrome or non-syndromic deafness DFNB18 can occur. This is the first case in China demonstrating congenital deafness due to homozygous mutation of Usher1C gene c. 1527delT. This study enriches the gene spectrum of deafness in China.


Assuntos
Surdez/genética , Perda Auditiva Neurossensorial/genética , Síndromes de Usher , Criança , China , Testes Genéticos , Humanos , Mutação , Linhagem
3.
Nat Commun ; 11(1): 3548, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32669541

RESUMO

Congenital CMV infection (cCMVi) affects 0.5-1% of all live births worldwide, making it the leading cause of sensorineural hearing loss (SNHL) in childhood. The majority of infants with cCMVi have normal hearing at birth, but are at risk of developing late-onset SNHL. Currently, we lack reliable biomarkers to predict the development of SNHL in these infants. Here, we evaluate blood transcriptional profiles in 80 infants with cCMVi (49 symptomatic, 31 asymptomatic), enrolled in the first 3 weeks of life, and followed for 3 years to assess emergence of late-onset SNHL. The biosignatures of symptomatic and asymptomatic cCMVi are indistinguishable, suggesting that immune responses of infants with asymptomatic and symptomatic cCMVi are not different. Random forest analyses of initial samples in infants with cCMVi, irrespective of their clinical classification, identify a 16-gene classifier signature associated with the development of SNHL with 92% accuracy, suggesting its potential value as a biomarker.


Assuntos
Infecções por Citomegalovirus/sangue , Citomegalovirus/imunologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/imunologia , Perda Auditiva Neurossensorial/epidemiologia , Infecções Assintomáticas , Biomarcadores/sangue , Estudos de Casos e Controles , Pré-Escolar , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/congênito , Infecções por Citomegalovirus/virologia , Feminino , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/imunologia , Perda Auditiva Neurossensorial/virologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Estudos Prospectivos , Medição de Risco/métodos , Transcriptoma/genética
5.
Proc Natl Acad Sci U S A ; 117(26): 15137-15147, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32554502

RESUMO

RNA modifications play a fundamental role in cellular function. Pseudouridylation, the most abundant RNA modification, is catalyzed by the H/ACA small ribonucleoprotein (snoRNP) complex that shares four core proteins, dyskerin (DKC1), NOP10, NHP2, and GAR1. Mutations in DKC1, NOP10, or NHP2 cause dyskeratosis congenita (DC), a disorder characterized by telomere attrition. Here, we report a phenotype comprising nephrotic syndrome, cataracts, sensorineural deafness, enterocolitis, and early lethality in two pedigrees: males with DKC1 p.Glu206Lys and two children with homozygous NOP10 p.Thr16Met. Females with heterozygous DKC1 p.Glu206Lys developed cataracts and sensorineural deafness, but nephrotic syndrome in only one case of skewed X-inactivation. We found telomere attrition in both pedigrees, but no mucocutaneous abnormalities suggestive of DC. Both mutations fall at the dyskerin-NOP10 binding interface in a region distinct from those implicated in DC, impair the dyskerin-NOP10 interaction, and disrupt the catalytic pseudouridylation site. Accordingly, we found reduced pseudouridine levels in the ribosomal RNA (rRNA) of the patients. Zebrafish dkc1 mutants recapitulate the human phenotype and show reduced 18S pseudouridylation, ribosomal dysregulation, and a cell-cycle defect in the absence of telomere attrition. We therefore propose that this human disorder is the consequence of defective snoRNP pseudouridylation and ribosomal dysfunction.


Assuntos
Catarata/genética , Proteínas de Ciclo Celular/genética , Enterocolite/genética , Perda Auditiva Neurossensorial/genética , Síndrome Nefrótica/genética , Proteínas Nucleares/genética , Ribonucleoproteínas Nucleolares Pequenas/genética , Animais , Criança , Feminino , Predisposição Genética para Doença , Humanos , Longevidade , Masculino , Modelos Moleculares , Simulação de Dinâmica Molecular , Mutação , Linhagem , Conformação Proteica , RNA Ribossômico/genética , Peixe-Zebra
6.
Hum Genet ; 139(10): 1325-1343, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32399598

RESUMO

Perrault syndrome is a rare heterogeneous condition characterised by sensorineural hearing loss and premature ovarian insufficiency. Additional neuromuscular pathology is observed in some patients. There are six genes in which variants are known to cause Perrault syndrome; however, these explain only a minority of cases. We investigated the genetic cause of Perrault syndrome in seven affected individuals from five different families, successfully identifying the cause in four patients. This included previously reported and novel causative variants in known Perrault syndrome genes, CLPP and LARS2, involved in mitochondrial proteolysis and mitochondrial translation, respectively. For the first time, we show that pathogenic variants in PEX6 can present clinically as Perrault syndrome. PEX6 encodes a peroxisomal biogenesis factor, and we demonstrate evidence of peroxisomal dysfunction in patient serum. This study consolidates the clinical overlap between Perrault syndrome and peroxisomal disorders, and highlights the need to consider ovarian function in individuals with atypical/mild peroxisomal disorders. The remaining patients had variants in candidate genes such as TFAM, involved in mtDNA transcription, replication, and packaging, and GGPS1 involved in mevalonate/coenzyme Q10 biosynthesis and whose enzymatic product is required for mouse folliculogenesis. This genomic study highlights the diverse molecular landscape of this poorly understood syndrome.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/genética , Aminoacil-tRNA Sintetases/genética , Proteínas de Ligação a DNA/genética , Dimetilaliltranstransferase/genética , Endopeptidase Clp/genética , Farnesiltranstransferase/genética , Predisposição Genética para Doença , Geraniltranstransferase/genética , Disgenesia Gonadal 46 XX/genética , Perda Auditiva Neurossensorial/genética , Proteínas Mitocondriais/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Sequência de Bases , Criança , DNA Mitocondrial/genética , Feminino , Expressão Gênica , Disgenesia Gonadal 46 XX/diagnóstico , Disgenesia Gonadal 46 XX/patologia , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Ovário/metabolismo , Ovário/patologia , Linhagem , Peroxissomos/metabolismo , Peroxissomos/patologia
7.
Hum Genet ; 139(10): 1315-1323, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32382995

RESUMO

We present detailed comparative analyses to assess population-level differences in patterns of genetic deafness between European/American and Japanese cohorts with non-syndromic hearing loss. One thousand eighty-three audiometric test results (921 European/American and 162 Japanese) from members of 168 families (48 European/American and 120 Japanese) with non-syndromic hearing loss secondary to pathogenic variants in one of three genes (KCNQ4, TECTA, WFS1) were studied. Audioprofile characteristics, specific mutation types, and protein domains were considered in the comparative analyses. Our findings support differences in audioprofiles driven by both mutation type (non-truncating vs. truncating) and ethnic background. The former finding confirms data that ascribe a phenotypic consequence to different mutation types in KCNQ4; the latter finding suggests that there are ethnic-specific effects (genetic and/or environmental) that impact gene-specific audioprofiles for TECTA and WFS1. Identifying the drivers of ethnic differences will refine our understanding of phenotype-genotype relationships and the biology of hearing and deafness.


Assuntos
Proteínas da Matriz Extracelular/genética , Genótipo , Perda Auditiva Neurossensorial/genética , Canais de Potássio KCNQ/genética , Proteínas de Membrana/genética , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Audiometria , Estudos de Casos e Controles , Criança , Pré-Escolar , Grupo com Ancestrais do Continente Europeu , Feminino , Proteínas Ligadas por GPI/genética , Expressão Gênica , Estudos de Associação Genética , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/etnologia , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Lactente , Recém-Nascido , Japão , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Estados Unidos
8.
Medicine (Baltimore) ; 99(19): e19763, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32384426

RESUMO

INTRODUCTION: Pendred syndrome (PDS)/DFNB 4 is a disorder with fluctuating and progressive hearing loss, vertigo, and thyroid goiter. We identified pathophysiology of a neurodegenerative disorder in PDS patient derived cochlear cells that were induced via induced pluripotent stem cells and found sirolimus, an mTOR inhibitor, as an inhibitor of cell death with the minimum effective concentration less than 1/10 of the approved dose for other diseases. Given that there is no rational standard therapy for PDS, we planned a study to examine effects of low dose oral administration of sirolimus for the fluctuating and progressive hearing loss, and the balance disorder of PDS by daily monitor of their audio-vestibular symptoms. METHODS AND ANALYSIS: This is a phase I/IIa double blind parallel-group single institute trial in patient with PDS/DFNB4. Sixteen of outpatients with fluctuating hearing diagnosed as PDS in SLC26A4 genetic testing aged in between 7 and 50 years old at the time of consent are given either placebo or sirolimus tablet (NPC-12T). In NPC-12T placebo arm, placebo will be given for 36 weeks; in active substance arm, placebo will be given for 12 weeks and the NPC-12T for 24 weeks. Primary endpoints are safety and tolerability. The number of occurrences and types of adverse events and of side effects will be sorted by clinical symptoms and by abnormal change of clinical test results. A 2-sided 95% confidence interval of the incidence rate by respective dosing arms will be calculated using the Clopper-Pearson method. Clinical effects on audio-vestibular tests performed daily and precise physiological test at each visit will also be examined as secondary and expiratory endpoints. TRIAL REGISTRATION NUMBER: JMA-IIA00361; Pre-results.


Assuntos
Bócio Nodular/tratamento farmacológico , Perda Auditiva Neurossensorial/tratamento farmacológico , Sirolimo/administração & dosagem , Aqueduto Vestibular/anormalidades , Adolescente , Adulto , Audiometria , Criança , Método Duplo-Cego , Feminino , Bócio Nodular/genética , Perda Auditiva Neurossensorial/genética , Humanos , Masculino , Pessoa de Meia-Idade , Transportadores de Sulfato/genética , Resultado do Tratamento , Testes de Função Vestibular , Adulto Jovem
9.
PLoS Genet ; 16(5): e1008826, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32453729

RESUMO

Hearing loss (HL) is one of the most common sensory impairments and etiologically and genetically heterogeneous disorders in humans. Muscular dystrophies (MDs) are neuromuscular disorders characterized by progressive degeneration of skeletal muscle accompanied by non-muscular symptoms. Aberrant glycosylation of α-dystroglycan causes at least eighteen subtypes of MD, now categorized as MD-dystroglycanopathy (MD-DG), with a wide spectrum of non-muscular symptoms. Despite a growing number of MD-DG subtypes and increasing evidence regarding their molecular pathogeneses, no comprehensive study has investigated sensorineural HL (SNHL) in MD-DG. Here, we found that two mouse models of MD-DG, Largemyd/myd and POMGnT1-KO mice, exhibited congenital, non-progressive, and mild-to-moderate SNHL in auditory brainstem response (ABR) accompanied by extended latency of wave I. Profoundly abnormal myelination was found at the peripheral segment of the cochlear nerve, which is rich in the glycosylated α-dystroglycan-laminin complex and demarcated by "the glial dome." In addition, patients with Fukuyama congenital MD, a type of MD-DG, also had latent SNHL with extended latency of wave I in ABR. Collectively, these findings indicate that hearing impairment associated with impaired Schwann cell-mediated myelination at the peripheral segment of the cochlear nerve is a notable symptom of MD-DG.


Assuntos
Nervo Coclear/metabolismo , Distroglicanas/genética , Perda Auditiva Neurossensorial/metabolismo , Proteína Básica da Mielina/metabolismo , N-Acetilglucosaminiltransferases/genética , Síndrome de Walker-Warburg/fisiopatologia , Adolescente , Animais , Criança , Pré-Escolar , Modelos Animais de Doenças , Feminino , Técnicas de Inativação de Genes , Glicosilação , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva Neurossensorial/genética , Humanos , Lactente , Masculino , Camundongos , Síndrome de Walker-Warburg/complicações , Síndrome de Walker-Warburg/genética , Adulto Jovem
10.
Gene ; 747: 144677, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32304785

RESUMO

The progressive, late-onset, nonsyndromic, sensorineural hearing loss (PNSHL) is the most common cause of sensory impairment globally, with presbycusis affecting greater than a third of individuals over the age of 65. The etiology underlying PNSHL include presbycusis, noise-induced hearing loss, drug ototoxicity, and delayed-onset autosomal dominant hearing loss (AD PNSHL). The objective of this article is to discuss the potential diagnostic and therapeutic applications of genomic medicine in PNSHL. Genomic factors contribute greatly to PNSHL. The heritability of presbycusis ranges from 25 to 75%. Current therapies for PNSHL range from sound amplification to cochlear implantation (CI). PNSHL is an excellent candidate for genomic medicine approaches as it is common, has well-described pathophysiology, has a wide time window for treatment, and is amenable to local gene therapy by currently utilized procedural approaches. AD PNSHL is especially suited to genomic medicine approaches that can disrupt the expression of an aberrant protein product. Gene therapy is emerging as a potential therapeutic strategy for the treatment of PNSHL. Viral gene delivery approaches have demonstrated promising results in human clinical trials for two inherited causes of blindness and are being used for PNSHL in animal models and a human trial. Non-viral gene therapy approaches are useful in situations where a transient biologic effect is needed or for delivery of genome editing reagents (such as CRISPR/Cas9) into the inner ear. Many gene therapy modalities that have proven efficacious in animal trials have potential to delay or prevent PNSHL in humans. The development of new treatment modalities for PNSHL will lead to improved quality of life of many affected individuals and their families.


Assuntos
Terapia Genética , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/terapia , Análise Custo-Benefício , Epigênese Genética , Técnicas de Transferência de Genes , Terapia Genética/economia , Perda Auditiva Neurossensorial/genética , Humanos
11.
BMC Med Genet ; 21(1): 68, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32234020

RESUMO

BACKGROUND: The TWNK gene encodes the twinkle protein, which is a mitochondrial helicase for DNA replication. The dominant TWNK variants cause progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, while the recessive variants cause mitochondrial DNA depletion syndrome 7 and Perrault syndrome 5. Perrault syndrome is characterized by sensorineural hearing loss in both males and females and gonadal dysfunction in females. Patients with Perrault syndrome may present early-onset cerebellar ataxia, whereas middle-age-onset cerebellar ataxia caused by TWNK variants is rare. CASE PRESENTATION: A Japanese female born to consanguineous parents presented hearing loss at age 48, a staggering gait at age 53, and numbness in her distal extremities at age 57. Neurological examination revealed sensorineural hearing loss, cerebellar ataxia, decreased deep tendon reflexes, and sensory disturbance in the distal extremities. Laboratory tests showed no abnormal findings other than a moderate elevation of pyruvate concentration levels. Brain magnetic resonance imaging revealed mild cerebellar atrophy. Using exome sequencing, we identified a homozygous TWNK variant (NM_021830: c.1358G>A, p.R453Q). CONCLUSIONS: TWNK variants could cause middle-age-onset cerebellar ataxia. Screening for TWNK variants should be considered in cases of cerebellar ataxia associated with deafness and/or peripheral neuropathy, even if the onset is not early.


Assuntos
Ataxia Cerebelar/genética , DNA Helicases/genética , Proteínas Mitocondriais/genética , Ataxia Cerebelar/complicações , Ataxia Cerebelar/diagnóstico , Consanguinidade , Feminino , Marcha Atáxica/complicações , Marcha Atáxica/diagnóstico , Marcha Atáxica/genética , Disgenesia Gonadal 46 XX/diagnóstico , Disgenesia Gonadal 46 XX/genética , Perda Auditiva/complicações , Perda Auditiva/diagnóstico , Perda Auditiva/genética , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Homozigoto , Humanos , Japão , Transtornos de Início Tardio/diagnóstico , Transtornos de Início Tardio/genética , Pessoa de Meia-Idade , Mutação , Linhagem
12.
BMC Med Genet ; 21(1): 79, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32295532

RESUMO

BACKGROUND: Congenital chloride diarrhea (CLD; OMIM 214700) is a rare autosomal recessive disorder caused by pathogenic variations in the solute carrier family 26 member A3 (SLC26A3) gene. Without salt substitution, this chronic diarrheal disorder causes severe dehydration and electrolyte disturbances. Homozygous variants in the nearby gene SLC26A4 disrupt anion exchange in the inner ear and the thyroid, causing Pendred syndrome (PDS; OMIM 274600), which is the most frequent form of syndromic deafness. CASE PRESENTATION: We report an unusual co-occurrence of two rare homozygous mutations in both the SLC26A3 and SLC26A4 genes, causing a rare combination of both CLD and PDS in two siblings. Although the clinical pictures were typical, the combined loss of these anion transporters might modulate the risk of renal injury associated with CLD. CONCLUSIONS: Familial presentation of two rare autosomal recessive disorders with loss of function of different SLC26 anion transporters is described. Independent homozygous variants in the SLC26A3 and SLC26A4 genes cause CLD and PDS in siblings, shedding light on co-occurrence of rare recessive traits in the progeny of consanguineous couples.


Assuntos
Antiportadores de Cloreto-Bicarbonato/genética , Diarreia/congênito , Bócio Nodular/genética , Perda Auditiva Neurossensorial/genética , Erros Inatos do Metabolismo/genética , Transportadores de Sulfato/genética , Diarreia/diagnóstico , Diarreia/genética , Diarreia/patologia , Feminino , Genes Recessivos/genética , Testes Genéticos , Bócio Nodular/diagnóstico , Bócio Nodular/patologia , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Humanos , Lactente , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/patologia , Mutação , Linhagem , Gravidez , Doenças Raras/diagnóstico , Doenças Raras/genética , Doenças Raras/patologia , Irmãos
13.
PLoS Genet ; 16(4): e1008643, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32294086

RESUMO

Hereditary hearing loss is challenging to diagnose because of the heterogeneity of the causative genes. Further, some genes involved in hereditary hearing loss have yet to be identified. Using whole-exome analysis of three families with congenital, severe-to-profound hearing loss, we identified a missense variant of SLC12A2 in five affected members of one family showing a dominant inheritance mode, along with de novo splice-site and missense variants of SLC12A2 in two sporadic cases, as promising candidates associated with hearing loss. Furthermore, we detected another de novo missense variant of SLC12A2 in a sporadic case. SLC12A2 encodes Na+, K+, 2Cl- cotransporter (NKCC) 1 and plays critical roles in the homeostasis of K+-enriched endolymph. Slc12a2-deficient mice have congenital, profound deafness; however, no human variant of SLC12A2 has been reported as associated with hearing loss. All identified SLC12A2 variants mapped to exon 21 or its 3'-splice site. In vitro analysis indicated that the splice-site variant generates an exon 21-skipped SLC12A2 mRNA transcript expressed at much lower levels than the exon 21-included transcript in the cochlea, suggesting a tissue-specific role for the exon 21-encoded region in the carboy-terminal domain. In vitro functional analysis demonstrated that Cl- influx was significantly decreased in all SLC12A2 variants studied. Immunohistochemistry revealed that SLC12A2 is located on the plasma membrane of several types of cells in the cochlea, including the strial marginal cells, which are critical for endolymph homeostasis. Overall, this study suggests that variants affecting exon 21 of the SLC12A2 transcript are responsible for hereditary hearing loss in humans.


Assuntos
Perda Auditiva Neurossensorial/congênito , Perda Auditiva Neurossensorial/genética , Mutação , Domínios Proteicos/genética , Membro 2 da Família 12 de Carreador de Soluto/química , Membro 2 da Família 12 de Carreador de Soluto/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Cloretos/metabolismo , Cóclea/metabolismo , Cóclea/patologia , Surdez/congênito , Surdez/genética , Éxons/genética , Feminino , Expressão Gênica , Células HEK293 , Humanos , Lactente , Macaca fascicularis , Masculino , Linhagem , Processamento de RNA , RNA Mensageiro/análise , RNA Mensageiro/genética , Membro 2 da Família 12 de Carreador de Soluto/metabolismo
16.
J Neurosci ; 40(15): 2976-2992, 2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32152201

RESUMO

Hepatocyte growth factor (HGF) is a multifunctional protein that signals through the MET receptor. HGF stimulates cell proliferation, cell dispersion, neuronal survival, and wound healing. In the inner ear, levels of HGF must be fine-tuned for normal hearing. In mice, a deficiency of HGF expression limited to the auditory system, or an overexpression of HGF, causes neurosensory deafness. In humans, noncoding variants in HGF are associated with nonsyndromic deafness DFNB39 However, the mechanism by which these noncoding variants causes deafness was unknown. Here, we reveal the cause of this deafness using a mouse model engineered with a noncoding intronic 10 bp deletion (del10) in Hgf Male and female mice homozygous for del10 exhibit moderate-to-profound hearing loss at 4 weeks of age as measured by tone burst auditory brainstem responses. The wild type (WT) 80 mV endocochlear potential was significantly reduced in homozygous del10 mice compared with WT littermates. In normal cochlea, endocochlear potentials are dependent on ion homeostasis mediated by the stria vascularis (SV). Previous studies showed that developmental incorporation of neural crest cells into the SV depends on signaling from HGF/MET. We show by immunohistochemistry that, in del10 homozygotes, neural crest cells fail to infiltrate the developing SV intermediate layer. Phenotyping and RNAseq analyses reveal no other significant abnormalities in other tissues. We conclude that, in the inner ear, the noncoding del10 mutation in Hgf leads to developmental defects of the SV and consequently dysfunctional ion homeostasis and a reduction in the EP, recapitulating human DFNB39 nonsyndromic deafness.SIGNIFICANCE STATEMENT Hereditary deafness is a common, clinically and genetically heterogeneous neurosensory disorder. Previously, we reported that human deafness DFNB39 is associated with noncoding variants in the 3'UTR of a short isoform of HGF encoding hepatocyte growth factor. For normal hearing, HGF levels must be fine-tuned as an excess or deficiency of HGF cause deafness in mouse. Using a Hgf mutant mouse with a small 10 bp deletion recapitulating a human DFNB39 noncoding variant, we demonstrate that neural crest cells fail to migrate into the stria vascularis intermediate layer, resulting in a significantly reduced endocochlear potential, the driving force for sound transduction by inner ear hair cells. HGF-associated deafness is a neurocristopathy but, unlike many other neurocristopathies, it is not syndromic.


Assuntos
Cóclea/fisiopatologia , Potenciais Evocados Auditivos do Tronco Encefálico/genética , Perda Auditiva Neurossensorial/genética , Fator de Crescimento de Hepatócito/genética , Crista Neural/crescimento & desenvolvimento , Estria Vascular/patologia , Animais , Contagem de Células , Orelha Interna/anormalidades , Feminino , Células Ciliadas Auditivas , Perda Auditiva Neurossensorial/patologia , Homeostase , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Crista Neural/patologia , Sondas RNA
17.
J Comput Assist Tomogr ; 44(3): 386-388, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32168082

RESUMO

PURPOSE: Incomplete partition III (IP-III) characterized by congenital mixed or sensorineural hearing loss is a rare genetic disease transmitted through X-linked inheritance. Incomplete partition III can be easily achieved based on pathognomonic computed tomography findings. The aims of this study were to investigate the otic capsule abnormalities in IP-III and to report irregular contour of membranous labyrinth and hypomineralized areas at otic capsule, which have not previously been described. MATERIALS AND METHODS: The otic capsule features of 10 subjects (8 affected patients, 1 of whom is a female; 2 carrier mothers), who were diagnosed on clinical and typical radiologic findings, were analyzed. RESULTS: All patients had typical IP-III as described in the literature. Seven of 10 patients had irregular contour. Seven of 10 patients demonstrated hypomineralized areas, which were very hypodense to normally develop otic capsule areas. One affected patients and 2 carrier mothers had a normal-looking membranous labyrinth contour and normal mineralization at otic capsule. CONCLUSIONS: We report for the first time the irregular contour of inner ear structures and hypodense otic capsule areas in patients with IP-III. We think that though speculative, abnormal development of the inner endosteal layer results in irregular contour of inner ear structures. Hypomineralized areas at otic capsule could be explained by abnormal development of middle enchondral layer due to reduced or absent vascular supply from middle ear mucosa during fetal life. These findings may be accepted as additional criteria of IP-III.


Assuntos
Orelha Interna , Perda Auditiva Neurossensorial , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Idoso , Desmineralização Patológica Óssea/diagnóstico por imagem , Desmineralização Patológica Óssea/patologia , Criança , Pré-Escolar , Orelha Interna/anormalidades , Orelha Interna/diagnóstico por imagem , Feminino , Perda Auditiva Neurossensorial/diagnóstico por imagem , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Masculino , Adulto Jovem
18.
Nat Commun ; 11(1): 1343, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32165640

RESUMO

Enlarged vestibular aqueduct (EVA) is one of the most commonly identified inner ear malformations in hearing loss patients including Pendred syndrome. While biallelic mutations of the SLC26A4 gene, encoding pendrin, causes non-syndromic hearing loss with EVA or Pendred syndrome, a considerable number of patients appear to carry mono-allelic mutation. This suggests faulty pendrin regulatory machinery results in hearing loss. Here we identify EPHA2 as another causative gene of Pendred syndrome with SLC26A4. EphA2 forms a protein complex with pendrin controlling pendrin localization, which is disrupted in some pathogenic forms of pendrin. Moreover, point mutations leading to amino acid substitution in the EPHA2 gene are identified from patients bearing mono-allelic mutation of SLC26A4. Ephrin-B2 binds to EphA2 triggering internalization with pendrin inducing EphA2 autophosphorylation weakly. The identified EphA2 mutants attenuate ephrin-B2- but not ephrin-A1-induced EphA2 internalization with pendrin. Our results uncover an unexpected role of the Eph/ephrin system in epithelial function.


Assuntos
Efrina-A2/genética , Bócio Nodular/genética , Perda Auditiva Neurossensorial/genética , Transportadores de Sulfato/genética , Sequência de Aminoácidos , Animais , Efrina-A1/genética , Efrina-A1/metabolismo , Efrina-A2/química , Efrina-A2/metabolismo , Efrina-B2/genética , Efrina-B2/metabolismo , Bócio Nodular/metabolismo , Perda Auditiva Neurossensorial/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação Puntual , Ligação Proteica , Transportadores de Sulfato/química , Transportadores de Sulfato/metabolismo
19.
Mol Immunol ; 121: 28-37, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32151906

RESUMO

INTRODUCTION: H Syndrome is an autosomal recessive (AR) disease caused by defects in SLCA29A3 gene. This gene encodes the equilibrative nucleoside transporter, the protein which is highly expressed in spleen, lymph node and bone marrow. Autoinflammation and autoimmunity accompanies H Syndrome (HS). AIM: The aim was to further elucidate the mechanisms of disease by molecular studies in a patient with SLC29A3 gene defect. PATIENT AND METHODS: Mitochondrial dysfunction, lysosomal integrity, cytokine response in response to stimulation with different pattern recognition receptor ligands, and circulating cell-free mitochondrial-DNA(ccf-mtDNA) level in plasma were analyzed compared to controls to understand the cellular triggers of autoinflammation. RNA sequencing (RS) analyses were also performed in monocytes before/after culture with lipopolysaccharide. RESULTS: Patient had progressive destructive arthropathy in addition to clinical findings due to combined immunodeficiency. Pure red cell aplasia (PRCA), vitiligo, diabetes, multiple autoantibody positivity, lymphopenia, increased acute phase reactants were present. Recent thymic emigrants (RTE), naïve T cells were decreased, effector memory CD4 + T cells, nonclassical inflammatory monocytes were increased. Patient's peripheral blood mononuclear cells secreted more IL-1ß and IL-6, showed lysosomal disruption and significant mitochondrial dysfunction compared to healthy controls. Plasma ccf-mtDNA level was significantly elevated compared to age-matched controls (p < 0.05). RNA sequencing studies revealed decreased expression of NLR Family Caspase Recrument-Domain Containing 4(NLRC4), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4(PFKFB4), serine dehydratase(SDS), heparan sulfate(Glucosamine) 3-O-sulfotransferase 1(HS3ST1), neutral cholesterol ester hydrolase 1 (NCEH1), and interleukin-8 (IL-8) in patient's monocytes compared to controls. Longstanding PRCA, which is possibly autoimmune, resolved after initiating monthly intravenous immunoglobulins (IVIG) and low dose steroids to the patient. CONCLUSION: Although autoinflammation and autoimmunity are reported in HS, by functional analyses we here show in the present patient that over-active inflammasome pathway in HS might be related with mitochondrial and lysosomal dysfunction. Increased plasma ccf-mtDNA may be used as a biomarker of inflammasomopathy in HS. HS should be included in the classification of primary immunodeficiency diseases.


Assuntos
Autoimunidade/genética , Contratura/genética , Perda Auditiva Neurossensorial/genética , Histiocitose/genética , Síndromes de Imunodeficiência/genética , Proteínas de Transporte de Nucleosídeos/genética , Adolescente , Contratura/tratamento farmacológico , Contratura/imunologia , Contratura/patologia , Glucocorticoides/uso terapêutico , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Neurossensorial/imunologia , Perda Auditiva Neurossensorial/patologia , Histiocitose/tratamento farmacológico , Histiocitose/imunologia , Histiocitose/patologia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Inflamassomos/imunologia , Lisossomos/imunologia , Lisossomos/patologia , Masculino , Mitocôndrias/imunologia , Mitocôndrias/patologia , Resultado do Tratamento
20.
BMC Med Genet ; 21(1): 27, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32039712

RESUMO

BACKGROUND: Stickler syndrome is the most common genetic cause of rhegmatogenous retinal detachment (RRD) in children, and has a high risk of blindness. Type I (STL1) is the most common subtype, caused by COL2A1 mutations. This study aims to analyze the mutation spectrum of COL2A1 and further elucidate the genotype-phenotype relationships in the East Asian populations with STL1, which is poorly studied at present. METHODS: By searching MEDLINE, Web of Science, CNKI, Wanfang Data, HGMD and Clinvar, all publications associated with STL1 were collected. Then, they were carefully screened to obtain all reported STL1-related variants in COL2A1 and clinical features in East Asian patients with STL1. RESULTS: There were 274 COL2A1 variants identified in 999 patients with STL1 from 466 unrelated families, and more than half of them were truncation mutations. Of the 107 STL1 patients reported in the East Asian population, it was found that patients with truncation mutations had milder systemic phenotypes, whereas patients with splicing mutations had severer phenotypes. In addition, several recurrent variants (c.3106C > T, c.1833 + 1G > A, c.2710C > T and c.1693C > T) were found. CONCLUSIONS: Genotype-phenotype correlations should certainly be studied carefully, contributed to making personalized follow-up plans and predicting prognosis of this disorder. Genome editing holds great potential for treating inherited diseases caused by pathogenic mutations. In this study, several recurrent variants were found, providing potential candidate targets for genetic manipulation in the future.


Assuntos
Artrite/genética , Doenças do Tecido Conjuntivo/genética , Análise Mutacional de DNA , Perda Auditiva Neurossensorial/genética , Mutação/genética , Descolamento Retiniano/genética , Artrite/epidemiologia , Artrite/patologia , Doenças do Tecido Conjuntivo/epidemiologia , Doenças do Tecido Conjuntivo/patologia , Oftalmopatias Hereditárias , Estudos de Associação Genética , Perda Auditiva Neurossensorial/epidemiologia , Perda Auditiva Neurossensorial/patologia , Humanos , Fenótipo , Descolamento Retiniano/epidemiologia , Descolamento Retiniano/patologia
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