A synonymous codon change in the LMNA gene alters mRNA splicing and causes limb girdle muscular dystrophy type 1B

Тодорова, Албена; Halliger-Keller, B.; Mc, Walter; Mc, Dabauvalle; Lochmüller, H.; Cr, Müller

doi:10.1136/jmg.40.10.e115

Cited by 25 publications

(11 citation statements)

References 15 publications

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“…Such mutation-types are very rare mutational events and only one other such mutation has been described so far in the LMNA gene. It is located on the last nucleotide of exon 2 (c.513G>A; p.K171K) and was found in four patients diagnosed with LGMD1B (Todorova, et al, 2003). mRNA analysis on these patients showed that this results in a partial skipping of the canonical 5' splice site in intron 2 and the alternative use of a cryptic GT donor site within intron 2 leading to an insertion of 15 additional amino acids between exon 2 and 3 (Todorova, et al, 2003).…”

Section: Discussionmentioning

confidence: 98%

Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations

Scharner

Brown²,

Bower

et al. 2011

Hum. Mutat.

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Section: Discussionmentioning

confidence: 98%

Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations

Scharner

Brown²,

Bower

et al. 2011

Hum. Mutat.

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“…Hegele et al (123) Mandibuloacral dysplasia Usually autosomal recessive LMNA R527H most common; K542N, A529V, and heterozygous R527C/R471C (1 case) also reported; 2 cases with compound heterozygous mutations in ZMPSTE24 (116) et al described a dramatic loss of vascular smooth muscle cells (VSMCs) in the medial layer of the descending aorta, other great vessels, smaller arteries, and arterioles. 3 Intimal thickening was present, although the intima was acellular as well.…”

Section: Diseasementioning

confidence: 99%

“…112 A mouse model with one of the common EDMD LMNA mutations (H222P) develops locomotory difficulties and develops cardiac chamber dilation and hypokinesia with conduction defects. 113 Two other highly overlapping conditions caused by LMNA mutations that are similar to EDMD and prone to sudden death from cardiac arrhythmias 114 are limb girdle muscular dystrophy type 1B (LGMD-1B) 115,116 and dilated cardiomyopathy type 1A (DCM-1A) (Table). Although families carrying LMNA mutations tend to present quite similarly, the overlapping nature of the laminopathies and the inability to predict phenotypes based on the location or type of mutations is clear when considering the case of 3 members of the same family with the same LMNA mutation yet with different clinical phenotypes.…”

Section: Other Related Laminopathiesmentioning

confidence: 99%

Mechanisms of Cardiovascular Disease in Accelerated Aging Syndromes

Capell

Collins

Nabel

2007

Circulation Research

122

101

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Abstract-In the past several years, remarkable progress has been made in the understanding of the mechanisms of premature aging. These rare, genetic conditions offer valuable insights into the normal aging process and the complex biology of cardiovascular disease. Many of these advances have been made in the most dramatic of these disorders, Hutchinson-Gilford progeria syndrome. Although characterized by features of normal aging such as alopecia, skin wrinkling, and osteoporosis, patients with Hutchinson-Gilford progeria syndrome are affected by accelerated, premature arteriosclerotic disease that leads to heart attacks and strokes at a mean age of 13 years. In this review, we highlight recent advances in the biology of premature aging uncovered in Hutchinson-Gilford progeria syndrome and other accelerated aging syndromes, advances that provide insight into the mechanisms of cardiovascular diseases ranging from atherosclerosis to arrhythmias. (Circ Res. 2007;101:13-26.)Key Words: premature aging Ⅲ progeria Ⅲ Werner syndrome Ⅲ genome instability P remature aging syndromes, such as Hutchinson-Gilford progeria syndrome (HGPS), result in fatal cardiovascular disease. 1 Cardiovascular features of HGPS share striking similarities and dissimilarities with atherosclerosis. In this review, we present recent discoveries in this burgeoning scientific field, focus on cardiovascular aspects, and describe how developments may lead not only to new treatments and therapies for these rare conditions but also to new mechanistic insights into the biology of cardiovascular diseases, such as atherosclerosis and arrhythmias.

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“…To date, at least seven LGMD1B-related mutations disrupting LMNA normal splicing have been identified, but only mutations confirmed to alter splicing outcomes are discussed here. A synonymous mutation in the last nucleotide of exon 2 (c.513G>A) causes partial retention of 45 bases of intron 2 through the activation of a downstream cryptic splice site 68. A transversion near the 5′ splice site of intron 9 (c.1608+5G>C) promotes partial retention of intron 9 and therefore introduces an extra 105 bases until it encounters a stop codon in intron 9,69 whereas a mutation near the 3′ splice site of intron 9 (c.1609-3C>G) leads to in-frame exon 10 skipping (r.1609_1698del) 70.…”

Section: Aberrant Splicing Caused By Mutations In Lmnamentioning

confidence: 99%

Normal and aberrant splicing ofLMNA

2014

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The LMNA gene gives rise to at least three isoforms (lamin A, C, lamin AΔ10) as a result of normal alternative splicing, regulated by cis- and trans-acting regulatory factors, as well as the 5' and 3' untranslated regions of the gene. The two main isoforms, lamin A and C, are constitutive components of the fibrous nuclear lamina and have diverse physiological roles, ranging from mechanical nuclear membrane maintenance to gene regulation. The clinical spectrum of diseases (called 'laminopathies') caused by LMNA mutations is broad, including at least eight well-characterised phenotypes, some of which are confined to the skeletal muscles or skin, while others are multisystemic. This review discusses the different alternatively spliced isoforms of LMNA and the regulation of LMNA splicing, as well as the subgroup of mutations that affect splicing of LMNA pre-mRNA, and also seeks to bridge the mis-splicing of LMNA at transcript level and the resulting clinical phenotypes. Finally, we discuss the manipulation of LMNA splicing by splice-switching antisense oligonucleotides and its therapeutic potential for the treatment of some laminopathies.

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A synonymous codon change in the LMNA gene alters mRNA splicing and causes limb girdle muscular dystrophy type 1B

Cited by 25 publications

References 15 publications

Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations

Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations

Mechanisms of Cardiovascular Disease in Accelerated Aging Syndromes

Normal and aberrant splicing ofLMNA

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