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1.
Hum Mol Genet ; 29(9): 1520-1536, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32337552

RESUMO

Here we define a ~200 Kb genomic duplication in 2p14 as the genetic signature that segregates with postlingual progressive sensorineural autosomal dominant hearing loss (HL) in 20 affected individuals from the DFNA58 family, first reported in 2009. The duplication includes two entire genes, PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), in addition to four uncharacterized long non-coding (lnc) RNA genes and part of a novel protein-coding gene. Quantitative analysis of mRNA expression in blood samples revealed selective overexpression of CNRIP1 and of two lncRNA genes (LOC107985892 and LOC102724389) in all affected members tested, but not in unaffected ones. Qualitative analysis of mRNA expression identified also fusion transcripts involving parts of PPP3R1, CNRIP1 and an intergenic region between PLEK and CNRIP1, in the blood of all carriers of the duplication, but were heterogeneous in nature. By in situ hybridization and immunofluorescence, we showed that Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea including the spiral ganglion neurons, suggesting changes in expression levels of these genes in the hearing organ could underlie the DFNA58 form of deafness. Our study highlights the value of studying rare genomic events leading to HL, such as copy number variations. Further studies will be required to determine which of these genes, either coding proteins or non-coding RNAs, is or are responsible for DFNA58 HL.


Assuntos
Proteínas Sanguíneas/genética , Calcineurina/genética , Perda Auditiva Neurossensorial/genética , Proteínas de Membrana/genética , Fosfoproteínas/genética , Adolescente , Adulto , Animais , Calcineurina/sangue , Criança , Duplicação Cromossômica/genética , Cromossomos Humanos Par 2/genética , Variações do Número de Cópias de DNA/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença , Genoma Humano/genética , Perda Auditiva Neurossensorial/sangue , Perda Auditiva Neurossensorial/patologia , Heterozigoto , Humanos , Masculino , Proteínas de Membrana/sangue , Camundongos , Pessoa de Meia-Idade , Neurônios/metabolismo , Neurônios/patologia , Fosfoproteínas/sangue , RNA Mensageiro/sangue , Gânglio Espiral da Cóclea/metabolismo , Gânglio Espiral da Cóclea/patologia , Adulto Jovem
2.
Int J Mol Sci ; 19(9)2018 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-30150563

RESUMO

GJB2 mutations are the leading cause of non-syndromic inherited hearing loss. GJB2 encodes connexin-26 (CX26), which is a connexin (CX) family protein expressed in cochlea, skin, liver, and brain, displaying short cytoplasmic N-termini and C-termini. We searched for CX26 C-terminus binding partners by affinity capture and identified 12 unique proteins associated with cell junctions or cytoskeleton (CGN, DAAM1, FLNB, GAPDH, HOMER2, MAP7, MAPRE2 (EB2), JUP, PTK2B, RAI14, TJP1, and VCL) by using mass spectrometry. We show that, similar to other CX family members, CX26 co-fractionates with TJP1, VCL, and EB2 (EB1 paralogue) as well as the membrane-associated protein ASS1. The adaptor protein CGN (cingulin) co-immuno-precipitates with CX26, ASS1, and TJP1. In addition, CGN co-immunoprecipitation with CX30, CX31, and CX43 indicates that CX association is independent on the CX C-terminus length or sequence. CX26, CGN, FLNB, and DAMM1 were shown to distribute to the organ of Corti and hepatocyte plasma membrane. In the mouse liver, CX26 and TJP1 co-localized at the plasma membrane. In conclusion, CX26 associates with components of other membrane junctions that integrate with the cytoskeleton.


Assuntos
Conexina 26/metabolismo , Conexinas/metabolismo , Junções Intercelulares/metabolismo , Sequência de Aminoácidos , Animais , Argininossuccinato Sintase/genética , Argininossuccinato Sintase/metabolismo , Conexina 26/genética , Conexinas/genética , Citoesqueleto/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Órgão Espiral/metabolismo , Ligação Proteica , Mapas de Interação de Proteínas , Homologia de Sequência de Aminoácidos , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismo
3.
Stem Cell Res ; 71: 103181, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37595341

RESUMO

The DFNA58 locus contains a genomic duplication involving three protein-coding genes (CNRIP1, PLEK, and PPP3R1's exon 1) and other uncharacterized lncRNA genes (LOC101927723, LOC107985892 and LOC102724389). To clarify the role of these genes in hearing and precisely determine their role in hearing loss, four iPSC lines were generated from two carriers and two noncarriers of the duplication.


Assuntos
Perda Auditiva , Células-Tronco Pluripotentes Induzidas , Humanos , Leucócitos Mononucleares , Perda Auditiva/genética , Audição , Éxons
4.
Eur J Hum Genet ; 16(1): 89-96, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17851452

RESUMO

Nonsyndromic autosomal recessive deafness accounts for 80% of hereditary deafness. To date, 52 loci responsible for autosomal recessive deafness have been mapped and 24 genes identified. Here, we report a large inbred Brazilian pedigree with 26 subjects affected by prelingual deafness. Given the extensive consanguinity found in this pedigree, the most probable pattern of inheritance is autosomal recessive. However, our linkage and mutational analysis revealed, instead of an expected homozygous mutation in a single gene, two different mutant alleles and a possible third undetected mutant allele in the MYO15A gene (DFNB3 locus), as well as evidence for other causes for deafness in the same pedigree. Among the 26 affected subjects, 15 were homozygous for the novel c.10573delA mutation in the MYO15A gene, 5 were compound heterozygous for the mutation c.10573delA and the novel deletion c.9957_9960delTGAC and one inherited only a single c.10573delA mutant allele, while the other one could not be identified. Given the extensive consanguinity of the pedigree, there might be at least one more deafness locus segregating to explain the condition in some of the subjects whose deafness is not clearly associated with MYO15A mutations, although overlooked environmental causes could not be ruled out. Our findings illustrate a high level of etiological heterogeneity for deafness in the family and highlight some of the pitfalls of genetic analysis of large genes in extended pedigrees, when homozygosity for a single mutant allele is expected.


Assuntos
Surdez/genética , Miosinas/genética , Alelos , Audiometria , Sequência de Bases , Brasil , Mapeamento Cromossômico , Consanguinidade , Análise Mutacional de DNA , Primers do DNA/genética , Surdez/fisiopatologia , Feminino , Genes Recessivos , Haplótipos , Heterozigoto , Homozigoto , Humanos , Masculino , Mutação , Linhagem , Deleção de Sequência
5.
Gene ; 511(2): 280-4, 2012 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-22995349

RESUMO

We ascertained a Brazilian family with nine individuals affected by autosomal dominant nonsyndromic sensorineural hearing loss. The bilateral hearing loss affected mainly mid-high frequencies, was apparently stable with an early onset. Microsatellites close to the DFNA8/DFNA12 locus, which harbors the TECTA gene, showed significant multipoint lod scores (3.2) close to marker D11S4107. Sequencing of the exons and exon-intron boundaries of the TECTA gene in one affected subject revealed the deletion c.5383+5delGTGA in the 5' end of intron 16, that includes the last two bases of the donor splice site consensus sequence. This mutation segregates with deafness within the family. To date, 33 different TECTA mutations associated with autossomal dominant hearing loss have been described. Among them is the mutation reported herein, first described by Hildebrand et al. (2011) in a UK family. The audioprofiles from the UK and Brazilian families were similar. In order to investigate the transcripts produced by the mutated allele, we performed cDNA analysis of a lymphoblastoid cell line from an affected heterozygote with the c.5383+5delGTGA and a noncarrier from the same family. The analysis allowed us to identify an aberrant transcript with skipping of exon 16, without affecting the reading frame. One of the dominant TECTA mutations already described, a synonymous substitution in exon 16 (c.5331G

Assuntos
Surdez/genética , Proteínas da Matriz Extracelular/genética , Genes Dominantes , RNA Mensageiro/genética , Sequência de Bases , Brasil , Primers do DNA , Feminino , Proteínas Ligadas por GPI/genética , Ligação Genética , Humanos , Masculino , Linhagem
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