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• W2073111593 abstract "Emery-Dreifuss muscular dystrophy (EMD) is a condition characterized by the clinical triad of early-onset contractures, progressive weakness in humeroperoneal muscles, and cardiomyopathy with conduction block. The disease was described for the first time as an X-linked muscular dystrophy, but autosomal dominant and autosomal recessive forms were reported. The genes for X-linked EMD and autosomal dominant EMD (AD-EMD) were identified. We report here that heterozygote mutations in LMNA, the gene for AD-EMD, may cause diverse phenotypes ranging from typical EMD to no phenotypic effect. Our results show that LMNA mutations are also responsible for the recessive form of the disease. Our results give further support to the notion that different genetic forms of EMD have a common pathophysiological background. The distribution of the mutations in AD-EMD patients (in the tail and in the 2A rod domain) suggests that unique interactions between lamin A/C and other nuclear components exist that have an important role in cardiac and skeletal muscle function. Emery-Dreifuss muscular dystrophy (EMD) is a condition characterized by the clinical triad of early-onset contractures, progressive weakness in humeroperoneal muscles, and cardiomyopathy with conduction block. The disease was described for the first time as an X-linked muscular dystrophy, but autosomal dominant and autosomal recessive forms were reported. The genes for X-linked EMD and autosomal dominant EMD (AD-EMD) were identified. We report here that heterozygote mutations in LMNA, the gene for AD-EMD, may cause diverse phenotypes ranging from typical EMD to no phenotypic effect. Our results show that LMNA mutations are also responsible for the recessive form of the disease. Our results give further support to the notion that different genetic forms of EMD have a common pathophysiological background. The distribution of the mutations in AD-EMD patients (in the tail and in the 2A rod domain) suggests that unique interactions between lamin A/C and other nuclear components exist that have an important role in cardiac and skeletal muscle function. Emery-Dreifuss muscular dystrophy (EMD) (MIM 310300and 310200) is a condition characterized by the clinical triad of early-onset contractures, progressive weakness in humeroperoneal muscles, and cardiomyopathy with conduction block (Emery Emery, 1989Emery AEH Emery-Dreifuss syndrome.J Med Genet. 1989; 26: 637-641Crossref PubMed Scopus (168) Google Scholar; Toniolo et al. Toniolo et al., 1998Toniolo D Bione S Arahata K Emery-Dreifuss muscular dystrophy.in: Emery AEH Neuromuscular disorders: clinical and molecular genetics. Wiley, London1998: 87-103Google Scholar). It is important to recognize EMD as separate disorder, because the disease is associated with life-threatening cardiomyopathy that can be managed by insertion of cardiac pacemakers. The disease was described for the first time as an X-linked disorder (Emery and Dreifuss Emery and Dreifuss, 1966Emery AEH Dreifuss FE Unusual type of benign X-linked muscular dystrophy.J Neurol Neurosurg Psychiatry. 1966; 29: 338-342Crossref PubMed Scopus (288) Google Scholar), and members of many families who showed X-linked recessive inheritance were later described. Autosomal dominant (Fenichel et al. Fenichel et al., 1982Fenichel GM Sul YC Kilroy AW Blouin R An autosomal-dominant dystrophy with humeroperopelvic distribution and cardiomyopathy.Neurology. 1982; 32: 1399-1401Crossref PubMed Google Scholar; Miller et al. Miller et al., 1985Miller RG Layzer RB Mellenthin MA Golabi M Francoz RA Mall JC Emery-Dreifuss muscular dystrophy with autosomal dominant transmission.Neurology. 1985; 35: 1230-1233Crossref PubMed Google Scholar; Yates Yates, 1997Yates JR 43rd ENMC International Workshop on Emery-Dreifuss muscular dystrophy.Neuromuscul Disord. 1997; 7: 67-69Abstract Full Text PDF PubMed Scopus (23) Google Scholar) and autosomal recessive forms (Takamoto et al. Takamoto et al., 1984Takamoto K Hirose K Uono M Nokana I A genetic variant of Emery-Dreifuss disease.Arch Neurol. 1984; 41: 1292-1293Crossref PubMed Scopus (22) Google Scholar; Taylor et al. Taylor et al., 1998Taylor J Sewry CA Dubowitz V Muntoni F Early onset autosomal recessive muscular dystrophy with Emery-Dreifuss phenotype and normal emerin expression.Neurology. 1998; 51: 1116-1120Crossref PubMed Scopus (18) Google Scholar) of EMD were also reported. As the clinical symptoms are very similar, it has been suggested that the different genetic forms may have a common pathophysiological background. The genes for X-linked (X-EMD) and autosomal-dominant EMD (AD-EMD) have been identified (Bione et al. Bione et al., 1994Bione S Maestrini M Rivella S Mancini M Regis S Romeo G Toniolo D Identification of a novel X-linked gene responsible for Emery Dreifuss muscular dystrophy.Nat Genet. 1994; 8: 323-327Crossref PubMed Scopus (730) Google Scholar; Bonne et al. Bonne et al., 1999Bonne G Raffaele di Barletta M Varnous S Becane HM Hammouda EH Merlini L Muntoni F et al.Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy.Nat Genet. 1999; 21: 285-288Crossref PubMed Scopus (1039) Google Scholar). The X-EMD gene encodes emerin, a ubiquitous protein localized, in most cell types, to the inner nuclear membrane (Nagano et al. Nagano et al., 1996Nagano A Koga R Ogawa M Kurano Y Kawada J Okada R Hayashi YK et al.Emerin deficiency at the nuclear membrane in patients with Emery-Dreifuss muscular dystrophy.Nat Genet. 1996; 12: 254-259Crossref PubMed Scopus (280) Google Scholar; Cartegni et al. Cartegni et al., 1997Cartegni L Raffaele di Barletta M Barresi R Squarzoni S Sabatelli P Maraldi N Mora M et al.Heart-specific localization of emerin: new insights into Emery-Dreifuss muscular dystrophy.Hum Mol Genet. 1997; 6: 2257-2264Crossref PubMed Scopus (119) Google Scholar; Manilal et al. Manilal et al., 1998Manilal S Recan D Sewry CA Hoeltzenbein M Llense S Leturcq F Deburgrave N et al.Mutations in Emery-Dreifuss muscular dystrophy and their effects on emerin protein expression.Hum Mol Genet. 1998; 7: 855-864Crossref PubMed Scopus (89) Google Scholar; Morris and Manilal Morris and Manilal, 1999Morris GE Manilal S Heart to heart: from nuclear proteins to Emery-Dreifuss muscular dystrophy.Hum Mol Genet. 1999; 8: 1847-1851Crossref PubMed Scopus (83) Google Scholar). Emerin most likely interacts with the nuclear lamina, a mesh of intermediate filaments (the lamins) that constitute the nuclear cytoskeleton (Stuurman et al. Stuurman et al., 1998Stuurman N Heins S Aebi U Nuclear lamins: their structure, assembly and interactions.J Struct Biol. 1998; 122: 42-66Crossref PubMed Scopus (567) Google Scholar). AD-EMD is caused by mutations in the gene LMNA, which encodes two lamins, A and C, by differential maturation of the 3′ end of the mRNA (Lin and Worman Lin and Worman, 1993Lin F Worman HJ Structural organization of the human gene encoding nuclear Lamin A and nuclear Lamin C.J Biol Chem. 1993; 268: 16321-16326Abstract Full Text PDF PubMed Google Scholar). The finding that lamin A/C and emerin mutations are responsible for clinically similar disorders shows that in skeletal muscle and heart, interactions between nuclear membrane components are critical for skeletal and cardiac muscle function, and loss of integrity of the nuclear envelope is an underlying cause of muscular dystrophy. From the study of mutations in the LMNA gene in selected AD-EMD pedigrees, it was apparent that the clinical manifestations in individuals affected by AD-EMD could be quite different from those with the typical EMD phenotype (Bonne et al. Bonne et al., 1999Bonne G Raffaele di Barletta M Varnous S Becane HM Hammouda EH Merlini L Muntoni F et al.Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy.Nat Genet. 1999; 21: 285-288Crossref PubMed Scopus (1039) Google Scholar). We have, therefore, investigated additional cases of AD-EMD, to extend the number of known mutations and to look for phenotype-genotype correlations. Most of the patients we studied were males who had been referred for diagnosis of X-EMD. Few were familial cases; the majority were sporadic (table 1). Only some of the patients had a classical EMD phenotype (patients TB, FG, AH, and CE-30); others were diagnosed as atypical EMD (DPC and PD) or as affected by congenital muscular dystrophy, limb girdle muscular dystrophy, or rigid-spine syndrome. The cardiac involvement was also heterogeneous. Both bradyarrhythmias (which frequently required pacemaker implantation) and tachyarrhythmias were observed in patients (table 1). In some patients, dilated cardiomyopathy (DCM) or restrictive cardiomyopathy (RCM) were reported (table 1). Patient Rb was diagnosed at age 31 years after severe heart block. Echocardiography showed mild DCM. Patient II-1 is a member of a family that will be described in detail elsewhere (Brodsky et al. Brodsky et al., 2000Brodsky GL Muntoni F Miocic S Sinagra G Sewry C Mestroni L Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement.Circulation. 2000; 101: 473-476Crossref PubMed Scopus (278) Google Scholar); the patient presented with severe DCM and variable skeletal muscle involvement. Patient DPC, in whom a pacemaker had been implanted when he was 41 years old, died of sudden cardiac arrest at age 49 years. Finally, some patients (for example, MG, at age 40 years) did not show evidence of cardiac involvement.Table 1Patients AnalyzedPatientAge (years)SexInheritanceDiagnosisCardiac InvolvementMutationExonEffect of MutationReferenceMG40MSporadicX-EMD or CMDNoneC644T4H222Y…FG17MSporadicX-EMDPacemaker at age 16 yearsG746A4R249Q…CE-3033aAge at death.MSporadicX-EMDAV blockG746A4R249Q…Rb31MSporadicX-EMDPacemaker at 31 years + DCMG746A4R249Q…II-1…MFamilialLGMD1A + EMDDCM960delT6FS from R321Brodsky et al. (Brodsky et al., 2000Brodsky GL Muntoni F Miocic S Sinagra G Sewry C Mestroni L Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement.Circulation. 2000; 101: 473-476Crossref PubMed Scopus (278) Google Scholar)PD16MSporadicEMDNoneG1007A6R336Q…DPC49aAge at death.MSporadicEMDPacemaker at 41 years + RCMC1357T7R453W…MS39MSporadicX-EMD or RSSPacemaker at 31 yearsC1357T7R453WVoit et al. (Voit et al., 1988Voit T Krogman O Lenard HG Neuen-Jacob E Wechsler W Goebel HH Rahlf G et al.EMD: disease spectrum and differential diagnosis.Neuropediatrics. 1988; 19: 62-71Crossref PubMed Scopus (68) Google Scholar)LC42MSporadicX-EMD or RSSTachyarrhythmia and AV blockC1357T7R453W…21a-III/521MSporadicX-EMDNoneC1357T7R453W…AH31FFamilialAD-EMDPacemaker at age 28 yearsT1406C8I469TOrstavik et al. (Orstavik et al., 1990Orstavik KH Kloster R Lippestad C Rode L Hovig T Fuglseth KN Emery-Dreifuss syndrome in three generations of females, including identical twins.Clin Genet. 1990; 38: 447-451Crossref PubMed Scopus (14) Google Scholar)TB58MSporadicX-EMDPacemaker at age 43 yearsG1580C9R527P…GC23MSporadicX-EMD or RSSTachyarrhythmia and AV blockC1583A9T528K…Note.—CMD = congenital muscular dystrophy; AV = atrioventricular; DCM = dilated cardiomyopathy; F = female; M = male; RSS = rigid spine syndrome; RCM = restrictive cardiomyopathy.a Age at death. Open table in a new tab Note.—CMD = congenital muscular dystrophy; AV = atrioventricular; DCM = dilated cardiomyopathy; F = female; M = male; RSS = rigid spine syndrome; RCM = restrictive cardiomyopathy. In all patients, mutations in the X-linked emerin gene were excluded by sequence analysis (Bione et al. Bione et al., 1995Bione S Small K Aksmanovic VMA D'Urso M Ciccodicola A Merlini L Morandi L et al.Identification of new mutations in the Emery-Dreifuss muscular dystrophy gene and evidence for genetic heterogeneity of the disease.Hum Mol Genet. 1995; 4: 1859-1863Crossref PubMed Scopus (77) Google Scholar). A set of 27 primers was used to PCR-amplify all exons and exon-intron junctions of the LMNA gene, as described elsewhere (Bonne et al. Bonne et al., 1999Bonne G Raffaele di Barletta M Varnous S Becane HM Hammouda EH Merlini L Muntoni F et al.Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy.Nat Genet. 1999; 21: 285-288Crossref PubMed Scopus (1039) Google Scholar). Because we found recurrent mutations, the strategy for mutation detection was to use direct sequencing of PCR products for exons 6–9 and to analyze the rest of the gene by single strand conformation polymorphism (SSCP). PCR products of exons showing band shifts were sequenced. Mutations in the LMNA gene were found in 13 patients of the 25 we analyzed (table 1). Only one patient, II-1, had a 1-bp deletion (960delT); all other mutations were nonconservative modifications of highly conserved amino acid residues (data not shown). In most instances, the mutations also caused a change in the amino acid charge that could disrupt the highly organized structure of the lamins (Stuurman et al. Stuurman et al., 1998Stuurman N Heins S Aebi U Nuclear lamins: their structure, assembly and interactions.J Struct Biol. 1998; 122: 42-66Crossref PubMed Scopus (567) Google Scholar). Absence of the mutations among 100 chromosomes of individuals not presenting the phenotype was determined by restriction-enzyme digestion or by denaturing high-performance liquid chromatography (DHPLC) (Oefner and Underhill Oefner and Underhill, 1995Oefner PJ Underhill PA Comparative DNA sequence by denaturing high performance liquid chromatography (DHPLC).Am J Hum Genet. 1995; : 266Google Scholar,Oefner and Underhill, 1998Oefner PJ Underhill PA Comparative DNA mutation detection using denaturing high performance liquid chromatography (DHPLC).in: Dracopoli NC Haines JL Korf BR Moir DT Morton CC Seidman CE Seidman JG Current protocols in human genetics. Wiley, New York1998: 7.10.1-7.10.12Google Scholar). Our analysis showed that, in addition to AD-EMD, the LMNA gene is responsible for AR-EMD and for a semidominant form of the disorder. Both SSCP and sequence analysis (fig. 1a) demonstrated that patient MG (table 1) was a homozygote for the mutation C664T, causing the amino acid change H222Y in a histidine conserved from human to chicken and in lamin B1 (data not shown). Sequence analysis of the rest of the LMNA gene in the patient demonstrated that C664T was the only mutation. His parents, who were first cousins, were heterozygotes. The mutation was not found among 200 chromosomes of individuals unaffected by EMD that we analyzed by DHPLC. Patient MG presented with a very severe form of muscular dystrophy that had been diagnosed either as an atypical EMD or as congenital muscular dystrophy. The patient experienced difficulties when he started walking at age 14 mo; at age 5 years, he could not stand because of contractures. At age 40 years, he presented severe and diffuse muscle wasting and was confined to a wheelchair. His intelligence was normal; careful cardiological examination showed that he did not have cardiac problems. His parents were unaffected. They had had recent clinical and cardiological examinations, including electrocardiograms, echocardiographs, and Holter electrocardiograms. None of them presented skeletal muscle or cardiac alterations. DNA from family members of sporadic patients was analyzed (when it was available) to determine whether some of the relatives, especially the very young ones, might be carriers of the mutation or might be mildly or not yet affected. Patient PD carried a R366Q amino acid change (table 1). Analysis of the patient's family members showed that the mutation was present in the proband's grandmother and mother and in one of the sisters (fig. 1b). After we found the mutation, we carefully examined these family members for the presence of clinical symptoms. At the time of the study, the proband's grandmother was 80 years old and healthy, as was the proband's mother at age 40 years. The proband's sister had slightly elevated creatine kinase levels and no other symptoms at age 12 years. All the exons of patient PD were examined by direct sequencing, but no other mutation was found. To exclude the possibility that the mutation was a polymorphism, 200 chromosomes of unaffected individuals were analyzed by DHPLC. We did not find the mutation in the unaffected population. Patient PD had a very mild disorder: he showed early Achilles-tendon contractures and very mild, nonprogressive pelvic-girdle muscle weakness. Lumbar spine rigidity and retraction of the elbows started at age 13 years. At age 17 years, neurological examination showed moderate rigid spine, bilateral elbow retraction and equinism, and mild pelvic-girdle weakness. Cardiologic examination indicated that the proband's heart was normal. The appearance of a mild phenotype in the third generation, in the absence of a second mutation in LMNA, suggested the existence of a modifier gene or genes that may have been responsible for the heterogeneity of the phenotype (Toniolo et al. Toniolo et al., 1998Toniolo D Bione S Arahata K Emery-Dreifuss muscular dystrophy.in: Emery AEH Neuromuscular disorders: clinical and molecular genetics. Wiley, London1998: 87-103Google Scholar; Bonne et al. Bonne et al., 1999Bonne G Raffaele di Barletta M Varnous S Becane HM Hammouda EH Merlini L Muntoni F et al.Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy.Nat Genet. 1999; 21: 285-288Crossref PubMed Scopus (1039) Google Scholar). In summary, the mutation analysis of the LMNA gene in patients affected with EMD showed that mutations in LMNA caused a range of diverse phenotypes and a larger clinical variability than that observed for X-EMD. We definitively demonstrated the existence of AR-EMD, and we showed that, in the same pedigree, a mutation may have different penetrance and behave either as dominant or as recessive. Our results indicate that the LMNA gene should be studied, in the absence of a typical EMD phenotype, in all patients presenting early contractures of humeroperoneal muscle, a rigid spine, or both. Differences caused by penetrance of the mutations may complicate the diagnosis and must be taken into account. We analyzed a small group of patients referred for diagnosis of X-EMD. Mutations in LMNA suggest that patients affected with AD-EMD are underdiagnosed and that their number is likely higher than predicted from family studies. The number of isolated cases in our sample (11 of 13) also suggest that the frequency of new mutations may be higher for AD-EMD than X-EMD (Yates Yates, 1997Yates JR 43rd ENMC International Workshop on Emery-Dreifuss muscular dystrophy.Neuromuscul Disord. 1997; 7: 67-69Abstract Full Text PDF PubMed Scopus (23) Google Scholar). Among the dominant mutations described in this study and in Bonne et al. (Bonne et al., 1999Bonne G Raffaele di Barletta M Varnous S Becane HM Hammouda EH Merlini L Muntoni F et al.Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy.Nat Genet. 1999; 21: 285-288Crossref PubMed Scopus (1039) Google Scholar), the majority were amino acid changes that could result in a dominant negative effect. It is significant that recurrent changes were observed in AD-EMD patients: 11 of 16 (68%) dominant mutations causing AD-EMD were localized to the central region of the tail domain, and three of the remaining five patients carried the same mutation in the 2A rod domain (fig. 2). Fatkin et al. (Fatkin et al., 1999Fatkin D MacRae C Sasaki T Wolff MR Porcu M Frenneaux M Atherton J et al.Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction system disease.N Engl J Med. 1999; 341: 1715-1724Crossref PubMed Scopus (994) Google Scholar) recently described mutations in LMNA in patients affected with DCM and with conduction system disorders but who did not present with contractures or skeletal myopathy: four mutations were in rod domain 1 and one in the tail of lamin C. Lamins are involved in multiple interactions with themselves (Stuurman et al. Stuurman et al., 1998Stuurman N Heins S Aebi U Nuclear lamins: their structure, assembly and interactions.J Struct Biol. 1998; 122: 42-66Crossref PubMed Scopus (567) Google Scholar), with proteins of the nucleus of the nuclear envelope (Foisner and Gerace Foisner and Gerace, 1993Foisner R Gerace L Integral membrane proteins of the nuclear envelope interact with lamins and chromosomes, and binding is modulated by mitotic phosphorylation.Cell. 1993; 73: 1267-1279Abstract Full Text PDF PubMed Scopus (435) Google Scholar; Martin et al. Martin et al., 1995Martin L Crimaudo C Gerace L cDNA cloning and characterization of lamina-associated polypeptide 1C (LAP1C), an integral protein of the inner nuclear membrane.J Biol Chem. 1995; 270: 8822-8828Crossref PubMed Scopus (94) Google Scholar; Furukawa et al. Furukawa et al., 1997Furukawa K Glass C Kondo T Characterization of the chromatin binding activity of lamina-associated polypeptide (LAP) 2.Biochem Biophys Res Commun. 1997; 238: 240-246Crossref PubMed Scopus (42) Google Scholar; Worman et al. Worman et al., 1988Worman HJ Yuan J Blobel G Georgatos SD A lamin B receptor in the nuclear envelope.Proc Natl Acad Sci USA. 1988; 85: 8531-8534Crossref PubMed Scopus (288) Google Scholar), and with chromatin (Hoger et al. Hoger et al., 1991Hoger TH Krohne G Kleinschmidt JA Interaction of Xenopus lamins A and LII with chromatin in vitro mediated by a sequence element in the carboxyterminal domain.Exp Cell Res. 1991; 197: 280-289Crossref PubMed Scopus (106) Google Scholar; Glass et al. Glass et al., 1993Glass CA Glass JR Taniura H Hasel KW Blevitt JM Gerace L The α-helical rod domain of human lamins A and C contains a chromatin binding site.EMBO J. 1993; 12: 4413-4424Crossref PubMed Scopus (134) Google Scholar; Taniura et al. Taniura et al., 1995Taniura H Glass C Gerace L A chromatin binding site in the tail domain of nuclear lamins that interacts with core histone.J Cell Biol. 1995; 131: 33-44Crossref PubMed Scopus (228) Google Scholar). The different distribution along lamin A/C of the mutations in AD-EMD and DCM patients suggests that the tail domain and the two rod domains of lamin A/C participate in different interactions in skeletal or cardiac muscle. This interpretation can also explain the finding of a mutation in patients affected with Dunnigan-type familial partial lipodystrophy, a disorder of adipocytes associated with insulin resistance and diabetes but not with muscular or cardiac alterations (Cao and Hegele Cao and Hegele, 2000Cao H Hegele RA Nuclear lamin A/C R482 mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy.Hum Mol Genet. 2000; 9: 109-112Crossref PubMed Scopus (542) Google Scholar). This very unexpected finding suggests that the interactions of lamin A/C may be diverse in different cell types and that specific mutations may modify some of the interactions, eventually causing tissue or cell-type-specific alterations of the nuclear envelope. How does a lamin defect cause EMD? Most mutations affecting emerin are null (Morris and Manilal Morris and Manilal, 1999Morris GE Manilal S Heart to heart: from nuclear proteins to Emery-Dreifuss muscular dystrophy.Hum Mol Genet. 1999; 8: 1847-1851Crossref PubMed Scopus (83) Google Scholar), and lack of emerin seems to be the cause of X-EMD. It has been suggested that haploinsufficiency or a dominant negative effect caused by mutations in lamin A/C modifies the nuclear lamina and the nuclear envelope and causes, either directly or indirectly, misplacement or modifications of the distribution of emerin (Toniolo and Minetti Toniolo and Minetti, 1999Toniolo D Minetti C Muscular dystrophies: alterations in a limited number of cellular pathways?.Curr Opin Genet Dev. 1999; 9: 275-282Crossref PubMed Scopus (17) Google Scholar). Alternatively, a third component, in addition to emerin and lamin A/C, may exist, and its cellular distribution may be altered by lack of emerin and by mutations in lamin A/C. From this point of view, the recently published study of mice lacking lamin A (Sullivan et al. Sullivan et al., 1999Sullivan T Escalante-Alcade D Batt H Anver M Bhat N Nagashima K Stewart CL et al.Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy.J Cell Biol. 1999; 147: 913-920Crossref PubMed Scopus (913) Google Scholar) is of great interest. Soon after birth, the Lmna −/− mice develop severe muscular dystrophy; their phenotype is associated with ultrastructural perturbations of the nuclear envelope and mislocalization of emerin. Another nuclear envelope protein, LAP2, which is known to interact with chromatin and B-type lamins (Foisner and Gerace Foisner and Gerace, 1993Foisner R Gerace L Integral membrane proteins of the nuclear envelope interact with lamins and chromosomes, and binding is modulated by mitotic phosphorylation.Cell. 1993; 73: 1267-1279Abstract Full Text PDF PubMed Scopus (435) Google Scholar) but not with lamin A/C, was found at the nuclear envelope. Study of specific Lmna mutations in the mouse model in the heterozygotic and homozygotic state may help clarify the role of and the interactions of lamin A/C in different affected tissues. We thank the patients we studied and their families for their collaboration. We thank the European Neuromuscular Center for its support. We also thank Luisa Maestroni for providing the DNA of patient II-1 and Luisa Maestroni and Francesco Muntoni for unpublished data on the clinical characterization of the family of patient II-1. The research was funded by Telethon, Italy (D.T.), and by the Ministero dell'Università e della Ricerca Scientifica (E.R.)." @default.
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• W2073111593 title "Different Mutations in the LMNA Gene Cause Autosomal Dominant and Autosomal Recessive Emery-Dreifuss Muscular Dystrophy" @default.
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