Laminopathies in Russian families

Abstract

Mutations in LMNA gene produce a wide spectrum of disorders called laminopathies. In this article, the first cases of laminopathies from Russia are reported. In 10 unrelated families, 9 different mutations were identified: Asp47His, Gly232Arg, c.[781_783delAAG, 781insGTGGAGCAGTATAAGAAA], Arg249Gln (in two families), Arg377His, Arg541His, Ala350Pro, Leu52Pro, and Gly635Asp. Mutations Arg249Gln, Arg377His, and Arg541His were reported previously, others are novel. Four cases present de novo mutations, among them two cases with Arg249Gln are found. Because this mutation occurred de novo also in other reported cases, a mutational 'hot spot' was supposed. Three phenotypes were observed: autosomal dominant (AD) Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle MD type 1B, and AD dilated cardiomyopathy with conduction defect type 1A (DCM1A). Atypical clinical presentations were a very severe EDMD and an infantile DCM1A.

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

“…9696 c.746G>A 4 p.R249Q Missense Coil 2a (Benedetti, et al, 2007;Ki, et al, 2002;Muchir, et al, 2004;Raffaele Di Barletta, et al, 2000;Rudenskaya, et al, 2008;Vytopil, et al, 2003) (Onishi, et al, 2002) 2570 c.1072G>A 6 p.E358K Missense Coil 2b (Benedetti, et al, 2007;Mercuri, et al, 2004;Quijano-Roy, et al, 2008) (Benedetti, et al, 2007;Bonne, et al, 1999;Brette, et al, 2004;Colomer, et al, 2002;Fidzianska and Glinka, 2006;Golzio, et al, 2007;Muchir, et al, 2004;Raffaele Di Barletta, et al, 2000;Vytopil, et al, 2003) (Arbustini, et al, 2005) 7288 c.1580G>C 9 p.R527P Missense Tail (Ig-fold) (Benedetti, et al, 2007;Bonne, et al, 1999;Raffaele Di Barletta, et al, 2000;van der Kooi, et al, 2002) 1527 c.1583C>A 9 p.T528K Missense Tail (Ig-fold) (Benedetti, et al, 2007;Fokkema, et al, 2005;Raffaele Di Barletta, et al, 2000) 1200 c.1583C>G 9 p.T528R Missense Tail (Ig-fold) (Fokkema, et al, 2005;Vytopil, et al, 2003) (Bakay, et al, 2006;Young, et al, 2005) 51 c.1930C>T 11 p.R644C Missense Tail (Lamin A specific) (Csoka, et al, 2004;Genschel, et al, 2001;Mercuri, et al, 2005;Muntoni, et al, 2006;Pasotti, et al, 2008;…”

Lamin A/C mutations in dilated cardiomyopathy

“…Sumo pathway regulates a wide range of cellular processes through the attachment of small ubiquitin-related modifier (sumo) to various substrates. Sumo1 was found to be mislocalized in the presence of lamin A and C mutants both in vitro (C2C12 and Cos7 cells) and in vivo (primary myoblasts and myopathic muscle tissue from the Lmna H222P/H222P mice) [18,40]. In cell models, trapping of sumo1 correlated with an increased steady-state level of sumoylation.…”

“…A DCM patient encompassing exons 3-12 deletion showed diminished lamin A and C staining in the endomyocardial biopsy with discontinuous nuclear envelopes and invasion of mitochondria into the nuclear space [17]. Another DCM patient carrying a LMNA mutation displayed dramatic morphological alterations in approximately 30% of the cardiomyocyte's nuclei including a complete loss of the nuclear envelope [18]. However, other mutation carriers did not present with such dramatic abnormalities [17,18].…”

“…Another DCM patient carrying a LMNA mutation displayed dramatic morphological alterations in approximately 30% of the cardiomyocyte's nuclei including a complete loss of the nuclear envelope [18]. However, other mutation carriers did not present with such dramatic abnormalities [17,18]. Nevertheless, cardiomyocytes from DCM patients with LMNA mutations usually display reduced lamin A and C in the nuclei with nuclear membrane damage such as focal disruptions, blebs and nuclear pore clustering [19,20].…”

“…However, wild type lamin A transfected alone has consistently shown to localize to the inner nuclear lamina with some nucleoplasmic localization. Conversely, lamin C has been shown to localize as intranuclear aggregate [18,[32][33][34][35][36]. Intranuclear lamin C has shown to be more mobile than intranuclear lamin A [36,37].…”