GJB1

SUMMARY:
This result expands the spectrum of mutations in GJB1 known to be associated with CMTX and contributes to the diagnosis of CMT and clinical genetic counseling.

TITLE:
A novel splicing mutation in 5’UTR of GJB1 causes X-linked Charcot-Marie-tooth disease

DESCRIPTION:
CONCLUSION: Our study provides theoretical guidance for prenatal diagnosis and subsequent fertility of this family. This result expands the spectrum of mutations in GJB1 known to be associated with CMTX and contributes to the diagnosis of CMT and clinical genetic counseling.

CONTENT:
Mol Genet Genomic Med. 2022 Nov 17:e2108. doi: 10.1002/mgg3.2108. Online ahead of print.

ABSTRACT

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is the most frequent hereditary motor sensory neurological disease. GJB1 gene is the second most frequent cause of CMT, accounting for approximately 10% of CMT cases worldwide. We identified a large Han family with X-linked CMT disease.

METHODS: In this study, the probands and his mother underwent electrophysiological examinations and other family members were assessed retrospectively. Whole-exome sequencing, Sanger sequencing, and SNP array linkage analysis were performed to find and confirm the variant. The functional effect of the identified variant was further investigated in HEK293 cells and MCF-7 cells by minigene splicing assay.

RESULTS: The affected individuals had some clinical symptoms including symmetric atrophy and progressive weakness of the distal muscles in their twenties. Electrophysiological examinations result in peripheral nerve injury of the upper and lower limbs. Whole-exome sequencing identified a novel hemizygous deletion mutation (NM_000166: c.-16-8_-14del) in the GJB1 gene. SNP array linkage analysis and co-segregation analysis confirmed this mutation. Minigene splicing assay verified that this mutation leads to the activation of cryptic splicing sites in exon 2 which results in the deletion of exon 2.

CONCLUSION: Our study provides theoretical guidance for prenatal diagnosis and subsequent fertility of this family. This result expands the spectrum of mutations in GJB1 known to be associated with CMTX and contributes to the diagnosis of CMT and clinical genetic counseling.

PMID:36394156 | DOI:10.1002/mgg3.2108

SOURCE:
Molecular genetics & genomic medicine

TAGS:
GJB1

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-11-17T11:09:38Z

DATE – DOI: 2022-11-17T11:09:38Z
DATE – PUBMED: 2022 Nov 17
DATE OUTPUT MATCHED: True

DATE – ADDED:
Thu, 17 Nov 2022 06:00:00 -0500

DATE – RETRIEVED:
11/17/22 07:03PM
2022-11-17T19:03:55-05:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36394156,doi:10.1002/mgg3.2108

PUBMED ID:
pubmed:36394156

DOI:
10.1002/mgg3.2108

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36394156/

LINK – DOI:
https://doi.org/10.1002/mgg3.2108

LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1002/mgg3.2108

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-11-17T19:03:55-05:00, https://www.cmttreatmentreport.com.

SUMMARY:
GJB1 variants-induced cell stress and dysfunction.

TITLE:
Novel mutations in GJB1 trigger intracellular aggregation and stress granule formation in X-linked Charcot-Marie-Tooth Disease

DESCRIPTION:
X-linked Charcot-Marie-Tooth Disease type 1(CMT1X) is the second most common form of inherited peripheral neuropathy that is caused by mutations in the gap junction beta-1 (GJB1) gene. Using targeted exome-sequencing, we investigated four CMT families from central-southern China and identified two novel missense variants (p.F31S and p.W44G) and two previously reported variants (p.R220Pfs^(*)23 and p.R164Q) of GJB1. All four probands presented typical early-onset peripheral neuropathy, of which…

CONTENT:
Front Neurosci. 2022 Sep 26;16:972288. doi: 10.3389/fnins.2022.972288. eCollection 2022.

ABSTRACT

X-linked Charcot-Marie-Tooth Disease type 1(CMT1X) is the second most common form of inherited peripheral neuropathy that is caused by mutations in the gap junction beta-1 (GJB1) gene. Using targeted exome-sequencing, we investigated four CMT families from central-southern China and identified two novel missense variants (p.F31S and p.W44G) and two previously reported variants (p.R220Pfs* 23 and p.R164Q) of GJB1. All four probands presented typical early-onset peripheral neuropathy, of which the R220Pfs* 23 carrier also had neurologic manifestations in the central nervous system. We then constructed GJB1 expression vectors and performed cell biological analysis in vitro . Expression of FLAG-tagged GJB1 at various time points after transfection revealed evident protein aggregation with both wild-type and mutant forms, indicated with immunostaining and immunoblotting. Detergent-based sequential fractionation confirmed that all mutants were higher expressed and more prone to aggregate than the wild-type, whereas the R220Pfs* 23 mutant showed the greatest amount of SDS-soluble multimers and monomers among groups. Moreover, intracellular aggregation probably occurs in the endoplasmic reticulum compartment rather than the Golgi apparatus. Gap junction plaques were present in all groups and were only compromised in frameshift mutant. Further evidence reveals significant intracellular stress granule formation induced by mutated GJB1 and impaired cell viability indicative of cytotoxicity of self-aggregates. Together, our findings demonstrate novel GJB1 variants-induced cell stress and dysfunction and provide insights into understanding the pathomechanisms of GJB1-CMTX1 and other related disorders.

PMID:36225735 | PMC:PMC9548587 | DOI:10.3389/fnins.2022.972288

SOURCE:
Frontiers in neuroscience

TAGS:
GJB1

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-09-26T05:23:21Z

DATE – DOI: 2022-09-26T05:23:21Z
DATE – PUBMED: 2022 Sep 26
DATE OUTPUT MATCHED: True

DATE – ADDED:
Thu, 13 Oct 2022 06:00:00 -0400

DATE – RETRIEVED:
10/13/22 07:00AM
2022-10-13T07:00:49-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36225735,pmc:PMC9548587,doi:10.3389/fnins.2022.972288

PUBMED ID:
pubmed:36225735

DOI:
10.3389/fnins.2022.972288

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36225735/

LINK – DOI:
https://doi.org/10.3389/fnins.2022.972288

LINK – PUBLISHER:
https://www.frontiersin.org/articles/10.3389/fnins.2022.972288/full

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-10-13T07:00:49-04:00, https://www.cmttreatmentreport.com.