Aberrant Splicing in GJB1 and the Relevance of 5′ UTR in CMTX1 Pathogenesis

Boso, Federica; Taioli, Federica; Cabrini, Ilaria; Cavallaro, Tiziana; Fabrizi, Gian Maria

doi:10.3390/brainsci11010024

Cited by 10 publications

(9 citation statements)

References 34 publications

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“…This results in a decrease in the mRNA and, consequently, protein expression level. This mechanism was detected for 5′‐UTR splice‐site variants of various genes 12–14 . Recently, it was shown that splice‐site variant in the POMC 5′‐UTR (c.‐71 + 1G > A) leads to a decrease in both mRNA and protein expression level.…”

Section: Discussionmentioning

confidence: 93%

Splice‐site variant in the RPS7 5′‐UTR leads to a decrease in the mRNA level and development of Diamond‐Blackfan anemia

et al. 2022

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Diamond‐Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by erythroid aplasia. Pathogenic variants in ribosomal protein (RP) genes, GATA1, TSR2, and EPO, are considered to be the etiology of DBA. Variants in 5′‐untranslated regions (UTRs) of these genes are poorly studied and can complicate the variant interpretation. We investigated the functional consequences NM_001011.4:c.‐19 + 1G > T variant in the donor splice‐site of the RPS7 5′‐UTR. This variant was found in a family where two sons with DBA were carriers. Father, who also had this variant, developed myelodysplastic syndrome, which caused his death. Search for candidate causal variants and copy number variations in DBA‐associated genes left RPS7 variant as the best candidate. Trio whole exome sequencing analysis revealed no pathogenic variants in other genes. Functional analysis using luciferase expression system revealed that this variant leads to disruption of splicing. Also, a decrease in the levels of mRNA and protein expression was detected. In conclusion, the established consequences of 5′‐UTR splice‐site variant c.‐19 + 1G > T in the RPS7 gene provide evidence that it is likely pathogenic.

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Section: Discussionmentioning

confidence: 93%

Splice‐site variant in the RPS7 5′‐UTR leads to a decrease in the mRNA level and development of Diamond‐Blackfan anemia

et al. 2022

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“…Likewise, Benedetti et al proved that a c.‐16‐3C>G substitution activated a cryptic splice site which resulted in the deletion of the first 278 nucleotides of exon 2, which consisted of part of our result (Benedetti et al, 2010). However, it was previously reported that the change of the canonical splice site sequence (c.‐17+1G>T) causes the retention of the whole intron 1 into the mRNA and demonstrated a 70% reduction of the transcript level of GJB1 expression (Boso et al, 2020). When compared to this report, our patients also had fairly typical clinical, neurophysiological and pathological features, bearing a phenotype that co‐segregated with the variant.…”

Section: Discussionmentioning

confidence: 99%

“…Promoter P2 positions in intron 1 of transcript NM_001097642 and is responsible for the expression of the transcript NM_000166.6 in the peripheral nervous system. Though these two different transcripts include different 5′UTR, they provide mRNAs with identical coding regions (Boso et al, 2020). To date, most of the known variants are in the coding region, with the majority being missense mutations and rarer cases with frameshift and premature stop codon mutations or ample deletions.…”

Section: Introductionmentioning

confidence: 99%

“…To date, most of the known variants are in the coding region, with the majority being missense mutations and rarer cases with frameshift and premature stop codon mutations or ample deletions. Thanks to the broader availability of genetic screening, recent research reported that the noncoding region of GJB1 is the key regulator of protein expression and mutations in this region are the major cause of X‐linked CMT, accounting for 10% of patients with GJB1 mutations (Boso et al, 2020; Tomaselli et al, 2017). Recent research reported that variations of the UTR may become pathogenic by disrupting the sequences that regulate transcription or by impairing mRNA translation and stability, thus influencing protein expression.…”

Section: Introductionmentioning

confidence: 99%

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A novel splicing mutation in 5'UTR of GJB1 causes X‐linked Charcot—Marie–tooth disease

Yin

et al. 2022

Molec Gen & Gen Med

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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.

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“…Most mutations are missense variants and are believed to cause predominantly loss of function phenotypes [249]. Interestingly, several variants in the non-coding regions of GJB1 have been demonstrated to cause CMT1X [250][251][252], at least in some cases due to abnormal splicing of GJB1 [253]. Furthermore, copy number variations in GJB1 have also been identified in patients with CMT1X [254,255].…”

Section: Connexin 32-associated Neuropathy: Epidemiology and Clinical...mentioning

confidence: 99%

Mechanisms and Treatments in Demyelinating CMT

Fridman

Saporta

2021

Neurotherapeutics

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Demyelinating forms of Charcot-Marie-Tooth disease (CMT) are genetically and phenotypically heterogeneous and result from highly diverse biological mechanisms including gain of function (including dominant negative effects) and loss of function. While no definitive treatment is currently available, rapid advances in defining the pathomechanisms of demyelinating CMT have led to promising pre-clinical studies, as well as emerging clinical trials. Especially promising are the recently completed pre-clinical genetic therapy studies in PMP-22, GJB1, and SH3TC2-associated neuropathies, particularly given the success of similar approaches in humans with spinal muscular atrophy and transthyretin familial polyneuropathy. This article focuses on neuropathies related to mutations in PMP-22, MPZ, and GJB1, which together comprise the most common forms of demyelinating CMT, as well as on select rarer forms for which promising treatment targets have been identified. Clinical characteristics and pathomechanisms are reviewed in detail, with emphasis on therapeutically targetable biological pathways. Also discussed are the challenges facing the CMT research community in its efforts to advance the rapidly evolving biological insights to effective clinical trials. These considerations include the limitations of currently available animal models, the need for personalized medicine approaches/allele-specific interventions for select forms of demyelinating CMT, and the increasing demand for optimal clinical outcome assessments and objective biomarkers.

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Aberrant Splicing in GJB1 and the Relevance of 5′ UTR in CMTX1 Pathogenesis

Cited by 10 publications

References 34 publications

Splice‐site variant in the RPS7 5′‐UTR leads to a decrease in the mRNA level and development of Diamond‐Blackfan anemia

Splice‐site variant in the RPS7 5′‐UTR leads to a decrease in the mRNA level and development of Diamond‐Blackfan anemia

A novel splicing mutation in 5'UTR of GJB1 causes X‐linked Charcot—Marie–tooth disease

Mechanisms and Treatments in Demyelinating CMT

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