The yeast nuclear geneMRF1encodes a mitochondrial peptide chain release factor and cures several mitochondrial RNA splicing defects

Abstract The βIVS-2-654 C→T mutation accounts for approximately 20% of β thalassemia mutations in southern China; it causes aberrant RNA splicing and leads to β0 thalassemia. To provide an animal model for testing therapies for correcting splicing defects, we have used the “plug and socket” method of gene targeting in murine embryonic stem cells to replace the two (cis) murine adult β globin genes with a single copy of the human βIVS-2-654 gene. No homozygous mice survive postnatally. Heterozygous mice carrying this mutant gene produce reduced amounts of the mouse β globin chains and no human β globin, and have a moderate form of β thalassemia. The heterozygotes show the same aberrant splicing as their human counterparts and provide an animal model for testing therapies to correct splicing defects at either the RNA or DNA level.

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Analysis of RNA splicing defects in PITX2 mutants supports a gene dosage model of Axenfeld-Rieger syndrome

BMC Medical Genetics ◽

10.1186/1471-2350-7-59 ◽

2006 ◽

Vol 7 (1) ◽

Cited By ~ 12

Author(s):

Nicole L Maciolek ◽

Wallace LM Alward ◽

Jeffrey C Murray ◽

Elena V Semina ◽

Mark T McNally

Keyword(s):

Rna Splicing ◽

Gene Dosage ◽

Rieger Syndrome ◽

Splicing Defects

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Specific transcription and RNA splicing defects in five cloned β-thalassaemia genes

Nature ◽

10.1038/302591a0 ◽

1983 ◽

Vol 302 (5909) ◽

pp. 591-596 ◽

Cited By ~ 350

Author(s):

Richard Treisman ◽

Stuart H. Orkin ◽

Tom Maniatis

Keyword(s):

Rna Splicing ◽

Splicing Defects

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RNA Splicing Defects in Hypertrophic Cardiomyopathy: Implications for Diagnosis and Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms21041329 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1329

Author(s):

Marta Ribeiro ◽

Marta Furtado ◽

Sandra Martins ◽

Teresa Carvalho ◽

Maria Carmo-Fonseca

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Rna Splicing ◽

Clinical Utility ◽

Clinical Diagnostics ◽

Rna Analysis ◽

Uncertain Significance ◽

Associated Proteins ◽

High Throughput Dna Sequencing ◽

Splicing Defects ◽

Diagnostic Outcomes

Hypertrophic cardiomyopathy (HCM), the most common inherited heart disease, is predominantly caused by mutations in genes that encode sarcomere-associated proteins. Effective gene-based diagnosis is critical for the accurate clinical management of patients and their family members. However, the introduction of high-throughput DNA sequencing approaches for clinical diagnostics has vastly expanded the number of variants of uncertain significance, leading to many inconclusive results that limit the clinical utility of genetic testing. More recently, developments in RNA analysis have been improving diagnostic outcomes by identifying new variants that interfere with splicing. This review summarizes recent discoveries of RNA mis-splicing in HCM and provides an overview of research that aims to apply the concept of RNA therapeutics to HCM.

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