Desmin splice variants causing cardiac and skeletal myopathy

Desmin myopathy is a hereditary or sporadic cardiac and skeletal myopathy characterised by intracytoplasmic accumulation of desmin reactive deposits in muscle cells. We have characterised novel splice site mutations in the gene desminresulting in deletion of the entire exon 3 during the pre-mRNA spl...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medical genetics 2000-11, Vol.37 (11), p.851-857
Main Authors: Park, Kye-Yoon, Dalakas, Marinos C, Goebel, Hans H, Ferrans, Victor J, Semino-Mora, Christina, Litvak, Svetlana, Takeda, Kazuyo, Goldfarb, Lev G
Format: Article
Language:English
Subjects:
Adult
Amino acids
Base Sequence
Biological and medical sciences
Biopsy
cardiac and skeletal myopathy
Cardiology. Vascular system
Cardiomyopathy
Cloning
Desmin - genetics
desmin splice site mutations
DNA - chemistry
DNA - genetics
DNA Mutational Analysis
DNA, Complementary - chemistry
DNA, Complementary - genetics
expression study
Family Health
Female
genotype-phenotype correlation
Haplotypes
Heart
Humans
Male
Medical sciences
Middle Aged
Molecular Sequence Data
Muscle, Skeletal - pathology
Muscular Diseases - genetics
Muscular Diseases - pathology
Mutation
Myocarditis. Cardiomyopathies
Myocardium - pathology
Original
Patients
Pedigree
Polymorphism, Single Nucleotide
RNA Splicing - genetics
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Desmin myopathy is a hereditary or sporadic cardiac and skeletal myopathy characterised by intracytoplasmic accumulation of desmin reactive deposits in muscle cells. We have characterised novel splice site mutations in the gene desminresulting in deletion of the entire exon 3 during the pre-mRNA splicing. Sequencing of cDNA and genomic DNA identified a heterozygous de novo A to G change at the +3 position of the splice donor site of intron 3 (IVS3+3A→G) in a patient with sporadic skeletal and cardiac myopathy. A G to A transition at the highly conserved –1 nucleotide position of intron 2 affecting the splice acceptor site (IVS2-1G→A) was found in an unrelated patient with a similar phenotype. Expression of genomic DNA fragments carrying the IVS3+3A→G and IVS2-1G→A mutations confirmed that these mutations cause exon 3 deletion. Aberrant splicing leads to an in frame deletion of 32 complete codons and is predicted to result in mutant desmin lacking 32 amino acids from the 1B segment of the alpha helical rod. Functional analysis of the mutant desmin in SW13 (vim-) cells showed aggregation of abnormal coarse clumps of desmin positive material dispersed throughout the cytoplasm. This is the first report on the pathogenic potentials of splice site mutations in the desmingene.
ISSN:0022-2593
1468-6244
1468-6244
DOI:10.1136/jmg.37.11.851