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01-06-2004 | Regular Paper

Emerin expression in tubular aggregates

Authors: Panagiota Manta, Gerasimos Terzis, Constantinos Papadimitriou, Chrysanthi Kontou, Demetris Vassilopoulos

Published in: Acta Neuropathologica | Issue 6/2004

Abstract

Emerin is an inner nuclear membrane protein that is mutated or not expressed in patients with X-linked Emery-Dreifuss muscular dystrophy (X-EDMD/EMD). Cytoplasmic localization of emerin in cultured cells or tissues has been reported, although this remains a controversial issue. Tubular aggregates (TAs) are pathological structures seen in the sarcoplasm of human skeletal muscle fibers in various disorders. The TAs derive from the sarcoplasmic reticulum (SR) and represent, probably, an adaptive response of the SR to various insults to the muscle fibers. In the present study, we present immunohistochemical evidence of emerin expression in TAs. Muscle biopsies with tubular aggregates from four male, unrelated patients were studied. The percentage of muscle fibers containing TAs varied between 5 and 20%. Routine histochemistry revealed intense reaction of TAs with NADH-TR, AMPDA, and NSE, but not with COX, SDH, myosin ATPase (pH 9.4, 4.3, 4.6), PAS, and Oil red O staining. Immunohistochemical study revealed strong immunostaining of TAs with antibodies against emerin and7 SERCA2-ATPase. Immunostaining of TAs was also seen with antibodies against heat shock protein and dysferlin, but not with antibodies to lamin A, dystrophin, adhalin, β, γ, δ sarcoglycans, and merosin. These results suggest that emerin, an inner nuclear membrane protein, is present at the TAs. The interpretation and significance of this finding is discussed in relation to experimental data suggesting that normal emerin localization at the inner nuclear membrane depends on lamin A and mutations in the N-terminal domain of emerin cause mislocalization of the protein to the sarcoplasmic membranes.

Bionne S, Maestrini E, Rivella S, Mancini M, Regis S, Romeo G, Toniolo D (1994) Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy. Nat Genet 8:323–332PubMed

Bonne G, Barletta MR di, Varnous S, Becane HM, Hammouda EH, Merlini L, Muntoni F, Greenberg CR, Gary F, Urtizberea JA, Duboc D, Fardeau M, Toniolo D, Schwartz K (1999) Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat Genet 21:285–288CrossRefPubMed

Bradley WG (1969) Ultrastructural changes in adynamia episodica hereditaria and normokalaemic periodic paralysis. Brain 92:379–390PubMed

Cartegni L, Di Barletta MR, Barresi R, Squarzoni S, Sabatelli P, Maraldi NM, Mora M, Blasi C di, Cornelio F, Merlini L, Villa A, Cobianchi F, Toniolo D (1997) Heat specific localization of emerin: new insights into Emery-Dreifuss muscular dystrophy. Hum Mol Genet 6:2257–2264CrossRefPubMed

Clements L, Manilal S, Love DR, Morris GE (2000) Direct interaction between emerin and lamin A. Biochem Biophys Res Commun 267:709–714CrossRefPubMed

Doriguzzi C, Mongini T, Jeantet A, Monga G (1984) Tubular aggregates in a case of osteomalacic myopathy due to anti-convulsant drugs. Clin Neuropathol 3:42–45PubMed

Ellis JA, Craxton M, Yates JRW, Kendrick-Jones J, Brown C (1998) Abberant intracellular targeting and cell cycle-dependent phosphorylation of emerin contribute to EDMD phenotype. J Cell Sci 111:781–792PubMed

Engel WK, Bishop DW, Cunningham GG (1970) Tubular aggregates in type II muscle fibers: ultrastructural and histochemical correlation. J Ultrastuct Res 31:507–525

Fairly EAL, Kendrick-Jones J, Ellis JA (1999) The Emery-Dreifuss muscular dystrophy phenotype arises from aberrant targeting and binding of emerin at the inner nuclear membrane. J Cell Sci 112:2571–2582PubMed

10.

Fatkin D, MacRae G, Sasaki T, Wolff MR, Porcu M, Frenneaux M, Atherton J, Vidaillet HJ Jr, Spudich S, Girolami U de, Seidman JG, Seidman CE (1999) Missence mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction system disease. N Engl J Med 1:1715–1724CrossRef

11.

Gant TM, Wilson KL (1997) Nuclear assembly. Annu Rev Cell Dev Biol 13:669–695PubMed

12.

Harborth J, Elbashir SM, Beckert K, Tuschl T, Weber K (2001) Identification of essential genes in cultured mammalian cells using small interfering RNAs. J Cell Sci 114:4557–4565PubMed

13.

Ikezoe K, Furuya H, Ohyagi Y, Osoegawa M, Nishino I, Nonaka I, Kira J (2003) Dysferlin expression in tubular aggregates: their possible relationship to endoplasmic reticulum stress. Acta Neuropathol 105:603–609PubMed

14.

Jacques TS, Holton J, Watts PM, Wills AJ, Smoth SE, Hanna MG (2002) Tubular aggregates myopathy with abnormal pupils and skeletal deformities. J Neurol Neurosurg Psychiatry 73:324–326CrossRefPubMed

15.

Kitaguchi T, Matsubara S, Sato M, Miyamoto K, Hirai S, Schwrtz K, Bonne G (2001) A missense mutation in the exon 8 of lamin A/C gene in a Japanese case of autosomal dominant limb-girdle muscular dystrophy and cardiac conduction block. Neuromusc Disord 11:542–546CrossRefPubMed

16.

Kuncl RW, Pestronk A, Lane J, Alexander E (1989) The MRL +/+ mouse: a new model of tubular aggregates which are gender- and age-related. Acta Neuropathol 78:615–620PubMed

17.

Lee KK, Haragushi T, Lee RS, Koujin T, Hiraoka Y, Wilson KL (2001) Distinct functional domains in emerin bind to lamin A and DNA-bridging protein BAF. J Cell Sci 114:4567–4573PubMed

18.

Manilal S, Nguyen TM, Sewry C, Morris GE (1996) The Emery-Dreifuss muscular dystrophy protein, emerin, is a nuclear membrane protein. Hum Mol Genet 5:801–808CrossRefPubMed

19.

Manilal S, Recan D, Sewry CA, Hoeltzenbein M, Liense S, Leturcq F, Deburgrave N, Barbot J, Man N, Muntoni F, Wehnert M, Kaplan J, Morris GE (1998) Mutations in Emery–Dreifuss muscular dystrophy and their effect on emerin protein expression. Hum Mol Genet 7:855–864CrossRefPubMed

20.

Manilal S, Sewry C, Pereboev A, Man N, Gobbi P, Hawkes S, Love DR, Morris GE (1999) Distribution of emerin and lamins in the heart and implications for Emery–Dreifuss muscular dystrophy. Hum Mol Genet 8:353–359CrossRefPubMed

21.

Martin JE, Mather K, Swash M, Gray AB (1991) Expression of heat-shock protein epitopes in tubular aggregates. Muscle Nerve 14:219–225PubMed

22.

Martin JJ, Ceuterick C, Van Goethem G (1997) On a dominantly inherited myopathy With tubular aggregates. Neuromusc Disord 7:512–520CrossRefPubMed

23.

Morris GE, Manilal S (1999) Heart to heart from nuclear proteins to Emery-Dreifuss muscular dystrophy. Hum Mol Genet 8:1847–1851CrossRefPubMed

24.

Muchir A, Bonne G, van der Kooi AJ, van Meegen M, Baas F, Bolhuis PA, de Visser M, Schwartz K (2000) Identification of mutations in the gene encode lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum Mol Genet 9:1453–1459CrossRefPubMed

25.

Nagano A, Koga R, Ogawa M, Kurano Y, Kawada J, Okada R, Hayashi YK, Tsukahara T, Arahata K (1996) Emerin deficiency at the nuclear membrane in patients with Emery-Dreifuss muscular dystrophy. Nat Genet 12:254–259PubMed

26.

Negro ADV, Angulo JM, Pomar JMR, Errasti CA (1982) Tubular aggregates in skeletal muscle of chronic alcoholic patients. Acta Neuropathol 56:250–254PubMed

27.

Ostlund C, Ellenberg J, Hallberg E, Lippincott-Schwartz J, Worman HJ (1999) Intracellular trafficking of emerin, the Emery-Dreifuss muscular dystrophy protein. J Cell Sci 112:1709–1719PubMed

28.

Ostlund C, Bonne G, Schwartz K, Worman HJ (2001) Properties of lamin A mutants found in Emery–Dreifuss muscular dystrophy, cardiomyopathy and Dunnigun-type partial lipodystrophy. J Cell Sci 114:4435–4445PubMed

29.

Rahario WH, Enarson P, Sullivan T, Stewart CL, Burke B (2001) Nuclear envelope defects associated with LMNA mutations causing dilated cardiomyopathy and Emery-Dreifuss muscular dystrophy. J Cell Sci 114:4447–4457PubMed

30.

Reske-Nielson E, Haase J, Kelstrup J (1975) Malignant hyperthermia in a family. Acta Path Microbiol Scand 83:651–660

31.

Rosenberg NL, Neville HE, Ringel SP (1985) Tubular aggregates. Their association with neuromuscular diseases, including the syndrome of myalgia/cramps. Arch Neurol 42:973–976

32.

Salviati G, Pierobon-Bormioli S, Betto R, Damiani E, Angelini C, Ringel SP, Salvatori S, Margreth A (1985) Tubular aggregates: sarcoplasmic reticulum origin, calcium storage ability and functional implications. Muscle Nerve 8:299–306

33.

Schotland D (1968) Ultrastuctural abnormalities in myotonic dystrophy including an unusual T-system alteration. J Neuropathol Exp Neurol 27:109–110

34.

Sewry CA, Brown SC, Mercuri E, Bonne G, Feng L, Camici G, Morris GE, Muntoni F (2001) Skeletal muscle pathology in autosomal dominant muscular dystrophy with lamin A/C mutations. Neuropathol Appl Neurobiol 27:281–290CrossRefPubMed

35.

Sieb JP, Tolksdorf K, Dengler R, Jerusalem F (1996) An autosomal recessive congenital myasthenic syndrome with tubular aggregates in a Libyan family. Neuromusc Disord 6:115–119CrossRefPubMed

36.

Sipila I, Simell O, Rapola J, Sainio K, Tuuteri L (1979) Gyrate atrophy of the choroids and retina with hyperornithinaemia: tubular aggregates and atrophy in muscle. Neurology 29:996–1005PubMed

37.

Squarzoni S, Sabatelli P, Capanni C, Petrini S, Ognibene A, Toniolo D, Cobianchi F, Zauli G, Bassini A, Baracca A, Guarnieri C, Merlini L, Maraldi NM (2000) Emerin presence in platelets. Acta Neuropathol 100:291–298CrossRefPubMed

38.

Squarzoni S, Sabatelli P, Ognibese A, Toniolo D, Cartegni L, Cobianchi F, Petrini S, Merlini L, Maraldi NM (1998) Immunocytochemical detection of emerin within the nuclear matrix. Neuromusc Disord 8:338–344CrossRefPubMed

39.

Stamboulis E, Manta P, Kararizou E, Grivas I (1993) Whipple’s disease with tubular aggregates in asymptomatic muscle. Clin Neuropathol 12:121–124PubMed

40.

Stuurman N, Heins S, Aebi U (1998) Nuclear lamins: their structure, assembly and interactions. J Struct Biol 122:42–66CrossRefPubMed

41.

Sullivan T, Escalante–Alcalde D, Bhatt H, Anver N, Bhatt N, Nagashima K, Stewart CL, Burke B (1999) Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy. J Cell Biol 147:913–919CrossRefPubMed

42.

Tulinius MH, Lundberg A, Oldfors A (1996) Early-onset myopathy with tubular aggregates. Pediatr Neurol 15:68–71CrossRefPubMed

43.

Vaughman OA, Alvarez-Reyes M, Bridger JM, Broers JLV, Ramaekers FCS, Wehnert M, Morris GA, Whitfield WGF, Hutchison CJ (2001) Both emerin and lamin C depend on lamin A for localization at the nuclear envelope. J Cell Sci 114:2577–2590PubMed

44.

Yates JRW, Wehnert M (1999) The Emery-Dreifuss muscular dystrophy mutation database. Neuromusc Disord 9:199PubMed

Title: Emerin expression in tubular aggregates
Authors: Panagiota Manta
Gerasimos Terzis
Constantinos Papadimitriou
Chrysanthi Kontou
Demetris Vassilopoulos
Publication date: 01-06-2004
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 6/2004
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-004-0851-1

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Emerin expression in tubular aggregates

Abstract

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