Clinical and molecular characterization of a novel LMX1A frameshift mutation near the C-terminus lead to familial non-syndromic sensorineural hearing loss
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ABSTRACT:
PROVIDER: PRJNA825501 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18713659_1.fastq.gz | Fastqsanger.gz | |||
| SRR18713659_2.fastq.gz | Fastqsanger.gz | |||
| SRR18713660_1.fastq.gz | Fastqsanger.gz | |||
| SRR18713660_2.fastq.gz | Fastqsanger.gz | |||
| SRR18713661_1.fastq.gz | Fastqsanger.gz |
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Project description:Next Generation Sequencing Facilitates Quantitative Analysis of HEI-OC1 cells transduced with vector control, LMX1A WT or c.915dup variant.
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Project description:Background The genetic diversity of loci and mutations underlying hereditary hearing loss is an active area of investigation. To identify loci associated with predominantly non-syndromic sensorineural hearing loss, we performed exome sequencing of families and of single probands, as well as copy number variation (CNV) mapping in a case-control cohort. Results Analysis of three distinct families revealed several candidate loci in two families and a single strong candidate gene, MYH7B, for hearing loss in one family. MYH7B encodes a Type II myosin, consistent with a role for cytoskeletal proteins in hearing. High-resolution genome-wide CNV analysis of 150 cases and 157 controls revealed deletions in genes known to be involved in hearing (e.g. GJB6, OTOA, and STRC, encoding connexin 30, otoancorin, and stereocilin, respectively), supporting CNV contributions to hearing loss phenotypes. Additionally, a novel region on chromosome 16 containing part of the PDXDC1 gene was found to be frequently deleted in hearing loss patients (OR = 3.91, 95% CI: 1.62-9.40, p = 1.45 x 10-7). Conclusions We conclude that many known as well as novel loci and distinct types of mutations not typically tested in clinical settings can contribute to the etiology of hearing loss. Our study also demonstrates the challenges of exome sequencing and genome-wide CNV mapping for direct clinical application, and illustrates the need for functional and clinical follow-up as well as curated open-access databases. Single replicates of 151 non-syndromic hereditary hearing loss cases and 157 controls with normal hearing were analyzed.
2014-12-19 | E-GEOD-64088 | biostudies-arrayexpress
Project description:Rahman syndrome (RMNS) is a rare genetic disorder characterized by mild to severe intellectual disability, hypotonia, anxiety, autism spectrum disorder, vision problems, bone abnormalities, and dysmorphic facies. De novo heterozygous mutations in H1-4 encoding the linker histone H1.4 are found in individuals with RMNS; however, the underlying mechanisms causing significantly impaired neurodevelopment are not understood. So far, all neurodevelopmental associated mutations in H1-4 are small insertions or deletions that create a shared frameshift, resulting in a H1.4 protein that is both truncated and possessing an abnormal C-terminus frameshifted tail (H1.4 CFT). To expand understanding of mutations and phenotypes associated with mutant H1-4, we identified additional and new DNA variants at both the C- and N-terminus of H1.4. The clinical features of mutations identified at the C-terminus are consistent with other reports that strengthen the support of pathogenicity of H1.4 CFT. However, the pathogenicity of disrupting variants at the N-terminus could not be determined. To understand how H1.4 CFT may disrupt brain function, we exogenously expressed wildtype or H1.4 CFT protein in primary rat hippocampal neurons and assessed neuronal structure and function. Genome-wide transcriptome analysis revealed ~400 genes altered specifically in the presence of H1.4 CFT. Neuronal genes downregulated by H1.4 CFT were enriched for functional categories involved in synaptic communication and neuropeptide signaling. Neurons expressing H1.4 CFT showed reduced activity on extracellular electrode arrays, indicating that these transcriptional changes were sufficient to disrupt physiological neuronal function. These data are the first to characterize the consequence of H1.4 CFT in neurons. Our data provide initial insights into causes of neurodevelopmental impairments associated with these frameshift mutations in the C-terminus of H1.4 and highlight the need for future studies on the function of normal histone H1.4 in neurons.
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Project description:Conventionally the etiology of congenital Non-Syndromic Hearing Loss has been attributed to mutations in the genes involved in ion homeostasis or the structural compartments of the inner ear. However, this contributes to only a part of the problem, as still the determinants for a large majority of the Non-Syndromic Hearing loss seems to be an enigma. Evidences indicate that pathogens like Rubella, Cytomegalovirus, and many other infections can also result in congenital hearing loss. Additionally, there are variety of factors other than the viral mediators, that can act as stressors to trigger an altered immune response, during the gestational period of the mother. It is also known that non-specific stimulation of the immune system can mimic an infection status. This indicates a strong role for environmental factors toward their contribution to the pathology, possibly by influencing the host immune response. These varieties of known or unknown environmental factors interact with the susceptible variants in immune response genes in defining the threshold for protection or infection in an individual. Considering this background we propose to present this perspective that threshold of the host immune response during the prenatal conditions, in response to environmental stimulus, might be determined by the susceptible variants in immune response genes. This in turn can directly or indirectly influence the genes involved in maintaining the structural components or ion homeostasis, resulting in hearing loss. The threshold of immune response alterations may be heavily dependent on the immunogenetic profile of the mother or the fetus.
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Project description:Background The genetic diversity of loci and mutations underlying hereditary hearing loss is an active area of investigation. To identify loci associated with predominantly non-syndromic sensorineural hearing loss, we performed exome sequencing of families and of single probands, as well as copy number variation (CNV) mapping in a case-control cohort. Results Analysis of three distinct families revealed several candidate loci in two families and a single strong candidate gene, MYH7B, for hearing loss in one family. MYH7B encodes a Type II myosin, consistent with a role for cytoskeletal proteins in hearing. High-resolution genome-wide CNV analysis of 150 cases and 157 controls revealed deletions in genes known to be involved in hearing (e.g. GJB6, OTOA, and STRC, encoding connexin 30, otoancorin, and stereocilin, respectively), supporting CNV contributions to hearing loss phenotypes. Additionally, a novel region on chromosome 16 containing part of the PDXDC1 gene was found to be frequently deleted in hearing loss patients (OR = 3.91, 95% CI: 1.62-9.40, p = 1.45 x 10-7). Conclusions We conclude that many known as well as novel loci and distinct types of mutations not typically tested in clinical settings can contribute to the etiology of hearing loss. Our study also demonstrates the challenges of exome sequencing and genome-wide CNV mapping for direct clinical application, and illustrates the need for functional and clinical follow-up as well as curated open-access databases.
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Project description:Tremendous progress has been made in our understanding of the molecular basis of hearing and hearing loss. Through recent advances, we have begun to understand the fascinating biology of the auditory system and unveiled new molecular mechanisms of hearing impairment. Changes in the diagnostic impact of genetic testing have occurred, as well as exciting developments in therapeutic options. Molecular diagnosis, which is already a reality for several hearing-associated genes, will doubtlessly continue to increase in the near future, both in terms of the number of mutations tested and the spectrum of genes. Genetic analysis for hearing loss is mostly used for diagnosis and treatment, and relatively rarely for reproductive decisions, in contrast to other inherited disorders. Inherited hearing loss, however, is characterized by impressive genetic heterogeneity. An abundance of genes carry a large number of mutations, but specific mutations in a single gene may lead to syndromic or non-syndromic hearing loss. Some mutations predominate in individual ethnic groups. For clinical and laboratory diagnosticians, it is challenging to keep abreast of the unfolding discoveries. This review aims to provide the framework pertinent to diagnosticians and a practical approach to mutation analysis in the hearing impaired.
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Project description:The Wiskott-Aldrich Syndrome Protein (WASP) family is known for its participation in cytoskeleton reorganization (Marchand et al., 2001 and Jia et al., 2010). In 2007, the human subtelomeric MGC52000 genes were renamed as Wiskott-Aldrich Syndrome Protein and SCAR Homolog (WASH). Human WASH proteins are part of the WASP protein family and colocalize with actin in cells and promote Arp2/3-dependent actin polymerization in vitro (Linardopoulou et al., 2007). WASH multiprotein complex consists of seven subunits: notable to mention Strumpelin and Was Protein Family Homolog (WASH)-interacting protein (SWIP), which is encoded by KIAA1033/WASHC4 gene, FAM21 and Arp2/3. The Arp2/3 dependent actin polymerization from G-actin to F-actin is an important step in regulation of the cytoskeleton, enabling multiple endosomal transport processes (Kelleher et al., 1995 and Derivery et al., 2010). Linardopoulou and colleagues have also shown in an animal model (Drosophila), that the single WASH ortholog is essential for viability (Linardopoulou et al., 2007), strengthening the concept, that WASHC4 plays a crucial role in muscle cell integrity and function. A link between autosomal recessive intellectual disability (ARID) and mutations in the KIAA1033/WASHC4 gene was first recognized in 2011 by Ropers and colleagues. Very recently, Assoum and colleagues reported three additional patients (from two unrelated families) with syndromic ID. Two of them being sisters (8 and 6 years), both presenting with learning disabilities, macrocephaly, dysmorphic features, skeletal anomalies and subependymal heterotopic nodules due to a compound heterozygous mutation of the KIAA1033/WASHC4 gene (p.[Gln442*] and p.[Asp1048Gly]). In this study, we precisely describe the clinical phenotype of the two siblings and provide additional information (histological and proteomic data) derived from the muscle biopsy of the elder sibling to confirm the pathogenicity of the reported variant and establish the function of WASHC4 as relevant for muscle homeostasis. Which, as far as the authors know, has not yet been described in literature.
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Project description:This paper aims to present a third world case of Non-Syndromic sensorineural hearing loss (NSHL) due to a novel missense variant in COL11A1 gene, defined as DFNA37 non-syndromic hearing loss. The clinical features of a 6-year-old boy affected by a bilateral moderate to severe down-sloping sensorineural hearing loss are presented, as well as the genetic analysis, the latter identifying a heterozygous missense variation in the COL11A1 gene. In addition, in families with autosomal dominant transmission, COL11A1 gene should be considered in the genetic workup of the NSHL with prelingual onset.
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