scholarly journals A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 411
Author(s):  
María Lachgar ◽  
Matías Morín ◽  
Manuela Villamar ◽  
Ignacio del Castillo ◽  
Miguel Ángel Moreno-Pelayo
Keyword(s):  
Hearing Loss ◽  
Stop Codon ◽  
Coiled Coil ◽  
Premature Stop Codon ◽  
Scaffolding Protein ◽  
Common Mechanism ◽  
Chinese Family ◽  
Truncating Mutation ◽  
Spanish Family ◽  
Sensory Defect

Nonsyndromic hereditary hearing loss is a common sensory defect in humans that is clinically and genetically highly heterogeneous. So far, 122 genes have been associated with this disorder and 50 of them have been linked to autosomal dominant (DFNA) forms like DFNA68, a rare subtype of hearing impairment caused by disruption of a stereociliary scaffolding protein (HOMER2) that is essential for normal hearing in humans and mice. In this study, we report a novel HOMER2 variant (c.832_836delCCTCA) identified in a Spanish family by using a custom NGS targeted gene panel (OTO-NGS-v2). This frameshift mutation produces a premature stop codon that may lead in the absence of NMD to a shorter variant (p.Pro278Alafs*10) that truncates HOMER2 at the CDC42 binding domain (CBD) of the coiled-coil structure, a region that is essential for protein multimerization and HOMER2-CDC42 interaction. c.832_836delCCTCA mutation is placed close to the previously identified c.840_840dup mutation found in a Chinese family that truncates the protein (p.Met281Hisfs*9) at the CBD. Functional assessment of the Chinese mutant revealed decreased protein stability, reduced ability to multimerize, and altered distribution pattern in transfected cells when compared with wild-type HOMER2. Interestingly, the Spanish and Chinese frameshift mutations might exert a similar effect at the protein level, leading to truncated mutants with the same Ct aberrant protein tail, thus suggesting that they can share a common mechanism of pathogenesis. Indeed, age-matched patients in both families display quite similar hearing loss phenotypes consisting of early-onset, moderate-to-profound progressive hearing loss. In summary, we have identified the third variant in HOMER2, which is the first one identified in the Spanish population, thus contributing to expanding the mutational spectrum of this gene in other populations, and also to clarifying the genotype–phenotype correlations of DFNA68 hearing loss.

scholarly journals A Novel Frameshift Mutation of SCNN1G Causing Liddle Syndrome with Normokalemia

2019 ◽  
Vol 32 (8) ◽  
pp. 752-758
Author(s):  
Peng Fan ◽  
Yu-Mo Zhao ◽  
Di Zhang ◽  
Ying Liao ◽  
Kun-Qi Yang ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Frameshift Mutation ◽  
Stop Codon ◽  
Single Gene ◽  
Family Members ◽  
Premature Stop Codon ◽  
Chinese Family ◽  
Autosomal Dominant Disorder ◽  
Liddle Syndrome ◽  
Genetic Sequencing

Abstract BACKGROUND Liddle syndrome (LS) is an autosomal dominant disorder caused by single-gene mutations of the epithelial sodium channel (ENaC). It is characterized by early-onset hypertension, spontaneous hypokalemia and low plasma renin and aldosterone concentrations. In this study, we reported an LS pedigree with normokalemia resulting from a novel SCNN1G frameshift mutation. METHODS Peripheral blood samples were collected from the proband and eight family members for DNA extraction. Next-generation sequencing and Sanger sequencing were performed to identify the SCNN1G mutation. Clinical examinations were used to comprehensively evaluate the phenotypes of two patients. RESULTS Genetic analysis identified a novel SCNN1G frameshift mutation, p.Arg586Valfs*598, in the proband with LS. This heterozygous frameshift mutation generated a premature stop codon and deleted the vital PY motif of ENaC. The same mutation was present in his elder brother with LS, and his mother without any LS symptoms. Biochemical examination showed normokalemia in the three mutation carriers. The mutation identified was not found in any other family members, 100 hypertensives, or 100 healthy controls. CONCLUSIONS Our study identified a novel SCNN1G frameshift mutation in a Chinese family with LS, expanding the genetic spectrum of SCNN1G. Genetic testing helped us identify LS with a pathogenic mutation when the genotypes and phenotype were not completely consistent because of the hypokalemia. This case emphasizes that once a proband is diagnosed with LS by genetic testing, family genetic sequencing is necessary for early diagnosis and intervention for other family members, to protect against severe cardiovascular complications.

scholarly journals Protection against Fatal Sindbis Virus Encephalitis by Beclin, a Novel Bcl-2-Interacting Protein

1998 ◽  
Vol 72 (11) ◽  
pp. 8586-8596 ◽  
Author(s):  
Xiao Huan Liang ◽  
Linda K. Kleeman ◽  
Hui Hui Jiang ◽  
Gerald Gordon ◽  
James E. Goldman ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Sindbis Virus ◽  
Stop Codon ◽  
Coiled Coil ◽  
Resonance Energy Transfer ◽  
Premature Stop Codon ◽  
Resonance Energy ◽  
Cellular Protein ◽  
Interacting Protein ◽  
Induced Apoptosis

ABSTRACT bcl-2, the prototypic cellular antiapoptotic gene, decreases Sindbis virus replication and Sindbis virus-induced apoptosis in mouse brains, resulting in protection against lethal encephalitis. To investigate potential mechanisms by which Bcl-2 protects against central nervous system Sindbis virus infection, we performed a yeast two-hybrid screen to identify Bcl-2-interacting gene products in an adult mouse brain library. We identified a novel 60-kDa coiled-coil protein, Beclin, which we confirmed interacts with Bcl-2 in mammalian cells, using fluorescence resonance energy transfer microscopy. To examine the role of Beclin in Sindbis virus pathogenesis, we constructed recombinant Sindbis virus chimeras that express full-length human Beclin (SIN/beclin), Beclin lacking the putative Bcl-2-binding domain (SIN/beclinΔBcl-2BD), or Beclin containing a premature stop codon near the 5′ terminus (SIN/beclinstop). The survival of mice infected with SIN/beclin was significantly higher (71%) than the survival of mice infected with SIN/beclinΔBcl-2BD (9%) or SIN/beclinstop (7%) (P < 0.001). The brains of mice infected with SIN/beclin had fewer Sindbis virus RNA-positive cells, fewer apoptotic cells, and lower viral titers than the brains of mice infected with SIN/beclinΔBcl-2BD or SIN/beclinstop. These findings demonstrate that Beclin is a novel Bcl-2-interacting cellular protein that may play a role in antiviral host defense.

scholarly journals Truncating Mutation in FOXC2 Gene in Familial Hemorrhoids and Varicose Veins

2020 ◽  
Vol 14 ◽  
Keyword(s):  
Frameshift Mutation ◽  
Stop Codon ◽  
Varicose Veins ◽  
Premature Stop Codon ◽  
Genetic Mutations ◽  
Physiological Factors ◽  
Vascular Integrity ◽  
Truncating Mutation ◽  
Two Samples

Hemorrhoids and varicose veins are conditions resulting from loss of vascular integrity and, despite being worldwide health concerns, their pathogenesis has not been clearly defined. Many risk factors have been linked to the development of these complications including diet, defecating habits, alcohol consumption and other physiological factors. There are limited studies involving the possible role of genetic mutations in the development of hemorrhoids and varicose veins. FoxC2 is an important transcription factor that plays many roles in a variety of embryonic developmental processes, including angiogenesis. In the current study, we aimed to investigate the role of the FOXC2 gene variations in the development of familial hemorrhoids and varicose veins in the Jordanian population. Thirty-two samples were collected from eight families manifested hemorrhoids and/or varicose veins conditions. DNA sequencing was performed to screen variation in the FOXC2 gene. Two individuals with severe and early onset of hemorrhoids and varicose veins from the same family showed a frameshift mutation (881'inT) in the coding exon of the FOXC2 gene resulting in a premature stop codon at position +1386 (294 residues truncated peptide). In conclusion, our results support a possible role of genetic predisposition in the development of hemorrhoids and varicose veins with a frequency of 6% in the selected population

scholarly journals Identification of Main Genetic Causes Responsible for Non-Syndromic Hearing Loss in a Peruvian Population

Genes ◽  
2019 ◽  
Vol 10 (8) ◽  
pp. 581 ◽  
Author(s):  
Figueroa-Ildefonso ◽  
Bademci ◽  
Rajabli ◽  
Cornejo-Olivas ◽  
Villanueva ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Genetic Factors ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Gjb2 Gene ◽  
Pathogenic Variants ◽  
Novel Variants ◽  
Syndromic Hearing Loss ◽  
Different Populations ◽  
Global Population

: Hearing loss (HL) is a common sensory disorder affecting over 5% of the global population. The etiology underlying HL includes congenital and acquired causes; genetic factors are the main cause in over 50% of congenital cases. Pathogenic variants in the GJB2 gene are a major cause of congenital non-syndromic hearing loss (NSHL), while their distribution is highly heterogeneous in different populations. To the best of our knowledge, there is no data regarding the genetic etiologies of HL in Peru. In this study, we screened 133 Peruvian families with NSHL living in Lima. We sequenced both exons of the GJB2 gene for all probands. Seven probands with familial NSHL that remained negative for GJB2 variants underwent whole genome sequencing (WGS). We identified biallelic pathogenic variants in GJB2 in 43 probands; seven were heterozygous for only one allele. The c.427C>T variant was the most common pathogenic variant followed by the c.35delG variant. WGS revealed three novel variants in MYO15A in two probands, one of them was predicted to affect splicing and the others produce a premature stop codon. The Peruvian population showed a complex profile for genetic variants in the GJB2 gene, this particular profile might be a consequence of the admixture history in Peru.

scholarly journals A Novel Nonsense Mutation ofPOU4F3Gene Causes Autosomal Dominant Hearing Loss

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Chi Zhang ◽  
Mingming Wang ◽  
Yun Xiao ◽  
Fengguo Zhang ◽  
Yicui Zhou ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Nonsense Mutation ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Stop Codon ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Chinese Family ◽  
Nonsyndromic Hearing Loss ◽  
Truncated Protein

POU4F3gene encodes a transcription factor which plays an essential role in the maturation and maintenance of hair cells in cochlea and vestibular system. Several mutations ofPOU4F3have been reported to cause autosomal dominant nonsyndromic hearing loss in recent years. In this study, we describe a pathogenic nonsense mutation located inPOU4F3in a four-generation Chinese family. Target region capture sequencing was performed to search for the candidate mutations from 81 genes related to nonsyndromic hearing loss in this family. A novel nonsense mutation ofPOU4F3, c.337C>T (p.Gln113⁎), was identified in a Chinese family characterized by late-onset progressive nonsyndromic hearing loss. The novel mutation cosegregated with hearing loss in this family and was absent in 200 ethnicity-matched controls. The mutation led to a stop codon and thus a truncated protein with no functional domains remained. Transient transfection and immunofluorescence assay revealed that the subcellular localization of the truncated protein differed markedly from normal protein, which could be the underlying reason for complete loss of its normal function. Here, we report the first nonsense mutation ofPOU4F3associated with progressive hearing loss and explored the possible underlying mechanism. Routine examination ofPOU4F3is necessary for the genetic diagnosis of hereditary hearing loss in the future.

A Novel IRF6 Frameshift Mutation in a Large Chinese Pedigree With Van der Woude syndrome

2021 ◽  
pp. 105566562110109
Author(s):  
Qi Peng ◽  
Wenyan Qin ◽  
Siping Li ◽  
Meihua Huang ◽  
Chunbao Rao ◽  
...  
Keyword(s):  
Stop Codon ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Premature Stop Codon ◽  
Chinese Family ◽  
The Novel ◽  
Protein Alignment ◽  
Van Der Woude Syndrome ◽  
Psychological Burden ◽  
Irf6 Gene

Aims: Van der Woude syndrome (VWS) is one of the most common craniofacial anomalies, causing significant functional and psychological burden to the patients. This study aimed to identify the genetic cause of VWS in a Chinese family. Methods: Whole genome sequencing (WGS) was performed to screen for pathogenic mutations. Various Bioinformatics tools were used to assess the pathogenicity of the variants. Cosegregation analysis of the candidate variant was carried out. Interpretation of variants was performed according to the American College of Medical Genetics and Genomics guidelines. Results: A novel frameshift duplication c.373_374dupAA (p.Asn125Lys fs*43) was identified in exon 4 of the interferon regulatory factor 6 (IRF6) gene in all 3 affected members, which were not found in unaffected family members. The novel mutation leads to a frameshift and a premature stop codon which caused putative truncated protein. Protein alignment indicated high evolutionary conservation of the p.N125 residue, and this mutation was predicted by online tools to be damaging and deleterious. Conclusions: This study demonstrates that the novel mutation c.373_374dupAA (p.Asn125Lysfs*43) in the IRF6 gene corresponds to the VWS in this family. The discovery of this pathogenic variant enriches the genotypic spectrum of IRF6 gene and contributes to genetic diagnosis and counseling of families with VWS.

Novel Identification of a Four-base-pair Deletion Mutation in PITX2 in a Rieger Syndrome Family

2003 ◽  
Vol 82 (12) ◽  
pp. 1008-1012 ◽  
Author(s):  
Y. Wang ◽  
H. Zhao ◽  
X. Zhang ◽  
H. Feng
Keyword(s):  
Base Pair ◽  
Stop Codon ◽  
Critical Role ◽  
Premature Stop Codon ◽  
Chinese Family ◽  
Loss Of Function ◽  
Rieger Syndrome ◽  
Mutational Screening ◽  
Base Pair Deletion ◽  
Pitx2 Gene

Rieger syndrome is one of the most serious causes of tooth agenesis. Mutations in the PITX2, FOXC1, and PAX6 genes have been associated with Rieger syndrome. We have studied a three-generation Chinese family affected with Rieger syndrome and showing prominent dental abnormalities. Mutational screening and sequence analysis of the PITX2 gene revealed a previously unidentified four-base-pair deletion of nucleotides 717-720 in exon 5 in all affected members. The mutation causes a frame shift after Thr44, the 7th amino acid of the homeo-domain, and introduces a premature stop codon in the gene sequence. This deletion is the first unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that the oligodontia and other phenotypes of Rieger syndrome observed in this family are due to this PITX2 mutation, and these data further support the critical role of PIXT2 in tooth morphogenesis.

scholarly journals Mutation detection and prenatal diagnosis of XLHED pedigree

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e3691 ◽  
Author(s):  
Yao Lin ◽  
Wei Yin ◽  
Zhuan Bian
Keyword(s):  
Prenatal Diagnosis ◽  
Structural Changes ◽  
Frameshift Mutation ◽  
Stop Codon ◽  
Direct Sequencing ◽  
Premature Stop Codon ◽  
Deciduous Teeth ◽  
Chinese Family ◽  
Female Carrier ◽  
Causative Gene

Background The phenotypic characters of X -linked Hypohidrotic Ectodermal Dysplasia (XLHED) are the dysplasia of epithelial- and mesenchymal-derived organs. Ectodysplasin (EDA) is the causative gene of XLHED. Methods The current study reported a large Chinese XLHED pedigree. The genomic DNA of adult and fetus was extracted from peripheral blood and shed chorion cell respectively. The nucleotide variation in EDA gene was screened through direct sequencing the coding sequence. The methylation state of EDA gene’s promoter was evaluated by pyrosequencing. Results This Chinese XLHED family had two male patients and three carriers. All of them were with a novel EDA frameshift mutation. The mutation, c.172-173insGG, which leads to an immediate premature stop codon in exon one caused severe structural changes of EDA. Prenatal diagnosis suggested that the fetus was a female carrier. The follow-up observation of this child indicated that she had mild hypodontia of deciduous teeth at age six. The methylation level of EDA gene’s promoter was not related to carriers’ phenotype changes in this family. Discussion We reported a new frameshift mutation of EDA gene in a Chinese family. Prenatal diagnosis can help to predict the disease status of the fetus.

scholarly journals Molecular characterization of pathogenic OTOA gene conversions in hearing loss patients

2021 ◽  
Author(s):  
Sacha Laurent ◽  
Corinne Gehrig ◽  
Thierry Nouspikel ◽  
Sami S Amr ◽  
Andrea Oza ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Allelic Loss ◽  
Loss Of Function ◽  
Chain Reactions ◽  
Polymerase Chain Reactions ◽  
Long Read ◽  
Gene Conversions

Bi-allelic loss-of-function variants of OTOA are a well-known cause of moderate-to-severe hearing loss. Whereas non-allelic homologous recombination-mediated deletions of the gene are well known, gene conversions to pseudogene OTOAP1 have been reported in the literature but never fully described nor their pathogenicity assessed. Here, we report two unrelated patients with moderate hearing-loss, who were compound heterozygotes for a converted allele and a deletion of OTOA. The conversions were initially detected through sequencing depths anomalies at the OTOA locus after exome sequencing, then confirmed with long range polymerase chain reactions. Both conversions lead to loss-of-function by introducing a premature stop codon in exon 22 (p.Glu787*). Using genomic alignments and long read nanopore sequencing, we found that the two probands carry stretches of converted DNA of widely different lengths (at least 9 kbp and around 900 bp, respectively).

Sign in / Sign up

Export Citation Format

Share Document