Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene

Bonne, Gisèle; Mercuri, Eugenio; Muchir, Antoine; Urtizberea, Andoni; Hm, Bécane; Récan, Dominique; Merlini, Luciano; Wehnert, Manfred; Boor, Rainer; Reuner, Ulrike; Vorgerd, Matthias; Em, Wicklein; Eymard, B.; Duboc, Denis; Pénisson-Besnier, I.; Jm, Cuisset; Ferrer, Xavier; Desguerre, Isabelle; Lacombe, Didier; Bushby, K.; Pollitt, C; Toniolo, Daniela; Fardeau, Michel; Schwartz, Ketty; Muntoni, Francesco

doi:10.1002/1531-8249(200008)48:2<170::aid-ana6>3.0.co;2-j

Cited by 450 publications

(314 citation statements)

References 32 publications

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“…In cases with muscle weakness, spinal rigidity, contractures and cardiac involvement, lamin A/C and emerin related EDMD must be considered in the differential diagnosis. However, although the patients we report here had rigidity of the spine and ankle contractures, they did not have elbow contractures and the degree of atrophy, especially severe atrophy in the hands and finger contractures were not compatible with any known EDMD phenotype [4,18]. In addition, pedigree was not compatible with an X-linked disorder.…”

Section: Discussioncontrasting

confidence: 57%

“…An important group of muscular dystrophies is limb-girdle muscular dystrophies, which predominantly present with proximal weakness with sparing of the facial and distal muscles, and cardiomyopathy in some subtypes [2]; however even when the disease begins with limb-girdle weakness, additional clinical features lead to consider other myopathic disorders. When limb-girdle weakness is combined with early distal muscle involvement, contractures and cardiac involvement, the phenotype is usually categorized as Emery-Dreifuss muscular dystrophy (EDMD) [3,4]. On the other hand, additional characteristic features of the phenotype such as early and non-proportional weakness, and atrophy of the distal muscles, are indicative of myopathies with predominantly distal muscle involvement [5,6].…”

Section: Introductionmentioning

confidence: 99%

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Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies

Kayman-Kurekci

Talim

Korkusuz

et al. 2014

Neuromuscular Disorders

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We performed genome-wide homozygosity mapping and mapped a novel myopathic phenotype to chromosomal region 1q25 in a consanguineous family with three affected individuals manifesting proximal and distal weakness and atrophy, rigid spine and contractures of the proximal and distal interphalangeal hand joints. Additionally, cardiomyopathy and respiratory involvement were noted. DNA sequencing of torsinA-interacting protein 1 (TOR1AIP1) gene encoding lamina-associated polypeptide 1B (LAP1B), showed a homozygous c.186delG mutation that causes a frameshift resulting in a premature stop codon (p.E62fsTer25). We observed that expression of LAP1B was absent in the patient skeletal muscle fibres. Ultrastructural examination showed intact sarcomeric organization but alterations of the nuclear envelope including nuclear fragmentation, chromatin bleb formation and naked chromatin. LAP1B is a type-2 integral membrane protein localized in the inner nuclear membrane that binds to both A-and B-type lamins, and is involved in the regulation of torsinA ATPase. Interestingly, luminal domain-like LAP1 (LULL1)-an endoplasmic reticulum-localized partner of torsinA-was overexpressed in the patient's muscle in the absence of LAP1B. Therefore, the findings suggest that LAP1 and LULL1 might have a compensatory effect on each other. This study expands the spectrum of genes associated with nuclear envelopathies and highlights the critical function for LAP1B in striated muscle.

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Section: Discussioncontrasting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies

Kayman-Kurekci

Talim

Korkusuz

et al. 2014

Neuromuscular Disorders

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“…Cells were transfected with these constructs and the integrity of the GFP-lamin polymers was examined using the FLIP technique in living cells. We chose to examine two different LMNA mutations occurring in the autosomal form of EDMD, R386K and R453W [18,19], and a LMNA mutation, R482W, characteristic for patients with FPLD [20,21]. The R386K mutation is in the rod domain of lamin A/C, while the other two mutations are localized in its tail domain [22].…”

Section: Introductionmentioning

confidence: 99%

Both lamin A and lamin C mutations cause lamina instability as well as loss of internal nuclear lamin organization

Broers

Kuijpers

Östlund

et al. 2005

Experimental Cell Research

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We have applied the fluorescence loss of intensity after photobleaching (FLIP) technique to study the molecular dynamics and organization of nuclear lamin proteins in cell lines stably transfected with green fluorescent protein (GFP)-tagged A-type lamin cDNA. Normal lamin A and C proteins show abundant decoration of the inner layer of the nuclear membrane, the nuclear lamina, and a generally diffuse localization in the nuclear interior. Bleaching studies revealed that, while the GFP-tagged lamins in the lamina were virtually immobile, the intranuclear fraction of these molecules was partially mobile. Intranuclear lamin C was significantly more mobile than intranuclear lamina A.In search of a structural cause for the variety of inherited diseases caused by A-type lamin mutations, we have studied the molecular organization of GFP-tagged lamin A and lamin C mutants R453W and R386K, found in Emery-Dreifuss muscular dystrophy (EDMD), and lamin A and lamin C mutant R482W, found in patients with Dunnigan-type familial partial lipodystrophy (FPLD). In all mutants, a prominent increase in lamin mobility was observed, indicating loss of structural stability of lamin polymers, both at the perinuclear lamina and in the intranuclear lamin organization. While the lamin rod domain mutant showed overall increased mobility, the tail domain mutants showed mainly intranuclear destabilization, possibly as a result of loss of interaction with chromatin. Decreased stability of lamin mutant polymers was confirmed by flow cytometric analyses and immunoblotting of nuclear extracts.Our findings suggest a loss of function of A-type lamin mutant proteins in the organization of intranuclear chromatin and predict the loss of gene regulatory function in laminopathies.

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“…Carriers of the T528M mutation alone (subjects CII and CV) were not clinically lipodystrophic, although both had slightly increased fasting triglycerides and subject CII was noted to be diabetic and hypertensive at the time of screening. Interestingly, a more substantial amino acid change involving a charge change at this residue (threonine-528-lysine) is known to produce a form of EmeryDreifuss muscular dystrophy [7]. None of the T528M carriers reported muscular weakness or palpitations.…”

mentioning

confidence: 99%

Familial partial lipodystrophy associated with compound heterozygosity for novel mutations in the LMNA gene

et al. 2004

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Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene

Cited by 450 publications

References 32 publications

Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies

Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies

Both lamin A and lamin C mutations cause lamina instability as well as loss of internal nuclear lamin organization

Familial partial lipodystrophy associated with compound heterozygosity for novel mutations in the LMNA gene

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