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A new LMNA mutation causing limb girdle muscular dystrophy 1B

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A new LMNA mutation causing limb girdle muscular dystrophy 1B
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  J Neurol (2005) 252:621–623DOI 10.1007/s00415-005-0719-x Simone SpulerChristian GeierKarl JosefOsterzielMatthias GutberletJanine GenschelThomas-Nicolas LehmannSophie Zinn-JustinBernard GilquinHartmut Schmidt A new LMNA mutationcausing limb girdlemuscular dystrophy 1B Received:17 May 2004Received in revised form:22 October 2004Accepted:5 November 2004Published online:29 March 2005 Sirs:We describe a family withadult-onset limb girdle musculardystrophy 1B (LGMD1B) due to anew mutation in LMNA encodingfor lamin A/C.Lamins A/C main-tain nuclear shape and provide astructural support for chromo-somes [7].Mutations in LMNA cause a variety ofdiseases,now called laminopathies:autosomal-dominant and autosomal-recessiveEmery-Dreifuss muscular dystro-phy (AD-EDMD and AR-EDMD)[1],limb girdle muscular dystro-phy 1B (LGMD1B) [8],dilatedcardiomyopathy (DCM) withconduction defect [3],familialpartial lipodystrophy typeDunnigan (FPLP) [11],Charcot-Marie-Tooth neuropathy 2B1(CMT2B1) [10],and severalprogeria syndromes [2,9].Themolecular mechanisms leading tothese different clinical phenotypesare not understood.It appears thatdifferent parts ofthe moleculeplay different roles in their interac-tion with other molecules andstability ofthe protein [4,7].The48 year old female index patientwas well until she was 35 years of age when she noticed difficulty inclimbing stairs.The muscularweakness was slowly progressiveand was accompanied by milddyspnea.She denied any stiffnessor rigidity ofher back,elbows orankles.The family history revealedthat the father had died at a youngage because oflung cancer butmuscle weakness could not berecalled.Her mother was in goodhealth.On physical examinationmanual muscle testing revealed amoderate limb-girdle weaknesswith the pelvic girdle being pre-dominantly affected (hip-flexorparesis 3–4/5).There were nocontractures (Fig.A and B).The 19year old daughter had minimallimb girdle weakness withoutcontractures.Cardiac examinationwas normal.The creatinkinase was10-times above normal.Metaboli-cally,there were no signs ofin-sulin-resistance,hyperlipidemia orother abnormalities typical of lipodystrophy The muscle speci-men showed signs ofa milddystrophy with a normal immuno-histochemical analysis.Cardiacexamination revealed permanentatrial fibrillation and AV-block III°after cardioversion.A pacemakerwas implanted at age 49.CardiacMRI was performed using aphased array cardiac surface coil.On CINE-MRI images wall motionabnormalities could be detected atthe apex and inferoseptal wall of the left ventricle,as well as adelayed contrast enhancement inthe same regions (Fig.C).Thephenomenon ofdelayed myocar-dial enhancement on MRI was firstused to detect areas ofnon-viablemyocardium in chronic myocar-dial infarction [5].To our knowl-edge,we are the first to describethis phenomenon in a patient withmuscular dystrophy.For mutationanalysis of  LMNA all exons andthe promoter region were ampli-fied [3].The analysis was con-firmed by sequencing in bothdirections (Fig.D) and subse-quently by restriction enzymeanalysis (Fig.E).The identifiedmissense mutation exchangestryptophan at position 498 forcysteine (W498C).The mutationwas found in the index patient and in both ofher children.Hermother did not carry themutation.LGMD1B is rare withinthe LMNA -associated neuromus-cular disorders.Whereas only eight mutations have been foundleading to LGMD1B the EDMDphenotype is caused by more than40 mutations spread out over theentire gene [6,12–14].On theprotein level,tryptophan 498 islocated at the C-terminus ofbeta-strand 6 within the globulardomain oflamin A/C.At this posi-tion there is a conserved aromaticresidue in lamins.The side chainoftryptophan 498 is located at thecenter ofa cavity,surrounded by mainly hydrophobic side chains of different beta-strands that are notclose in the lamin sequence but intertiary structure.Interestingly,another mutation associated withthe rare LGMD1B phenotype isalso found in the globular domainoflamin A/C,Y481H [6].Y481 islocated on beta 5 in a cavity closeto W498 (Fig.E).This might becoincidental but could also repre-sent a mutational hotspot in LMNA for LGMD1B. References 1.Bonne G,Di Barletta MR,Varnous S,Becane HM,Hammouda EH,MerliniL,Muntoni F,Greenberg CR,Gary F,Urtizberea JA,Duboc D,Fardeau M,Toniolo D,Schwartz K (1999) Muta-tions in the gene encoding lamin A/Ccause autosomal dominant Emery-Dreifuss muscular dystrophy.NatGenet 21:285–2882.Chen L,Lee L,Kudlow BA,Dos SantosHG,Sletvold O,Shafeghati Y,Botha EG,Garg A,Hanson NB,Martin GM,MianIS,Kennedy BK,Oshima J (2003)LMNA mutations in atypical Werner’ssyndrome.Lancet 362:440–445 LETTER TO THE EDITORS  J   O N 1  7 1  9   622 3.Fatkin D,MacRae C,Sasaki T,Wolff MR,Porcu M,Frenneaux M,AthertonJ,Vidaillet HJ Jr,Spudich S,De Giro-lami U,Seidman JG,Seidman C,Muntoni F,Muehle G,Johnson W,McDonough B (1999) Missense muta-tions in the rod domain ofthe laminA/C gene as causes ofdilated cardio-myopathy and conduction-systemdisease.N Engl J Med 341:1715–17244.Holt I,Ostlund C,Stewart CL,Man NN,Worman HJ,Morris GE (2003) Effectofpathogenic mis-sense mutations inlamin A on its interaction with emerinin vivo.J Cell Sci116:3027–30355.Kim RJ,Fieno DS,Parrish TB,HarrisK,Chen EL,Simonetti O,Bundy J,FinnJP,Klocke FJ,Judd RM (1999) Relation-ship ofMRI delayed contrast enhance-ment to irreversible injury,infarct age,and contractile function.Circulation100:1992–20026.Kitaguchi T,Matsubara S,Sato M,Miyamoto K,Hirai S,Schwartz K,Bonne G (2001) A missense mutationin the exon 8 oflamin A/C gene in aJapanese case ofautosomal dominantlimb-girdle muscular dystrophy andcardiac conduction block.Neuromus-cul Disord 11:542–5467.Krimm I,Ostlund C,Gilquin B,Cou-prie J,Hossenlopp P,Mornon JP,BonneG,Courvalin JC,Worman HJ,Zinn-Justin S (2002) The Ig-like structure of the C-terminal domain oflamin A/C,mutated in muscular dystrophies,cardiomyopathy,and partial lipodys-trophy.Structure (Camb) 10:811–8238.Muchir A,Bonne G,van der Kooi AJ,van Meegen M,Baas F,Bolhuis PA,deVisser M,Schwartz K (2000) Identifica-tion ofmutations in the gene encodinglamins A/C in autosomal dominantlimb girdle muscular dystrophy withatrioventricular conduction distur-bances (LGMD1B).Hum Mol Genet9:1453–14599.Sandre-Giovannoli A,Bernard R,CauP,Navarro C,Amiel J,Boccaccio I,Lyonnet S,Stewart CL,Munnich A,LeMerrer M,Levy N (2003) Lamin atruncation in Hutchinson-Gilfordprogeria.Science 300:2055 Fig.A and B: Absence of contractures in limb girdle muscular dystrophy in Achilles tendon ( A ) and elbow ( B ). C: Late contrast enhancement (circle) at the apex and in-feroseptal wall of the left ventricle on cardiac MRI. D: Sequence of codon 496 to 499 in exon 9 of the LMNA gene. Position 3 of codon 498 is mutated from TGG to TGT. TheW498C mutation was not detected in 130 controls alleles. E: Restriction endonuclease digestion with Bsl I produced four fragments of 90, 43, 39 and 20 bp. The mutationin codon 498 destroys one of the restriction sites for the restriction endonuclease Bsl I. F: Solution structure of the C-terminal globular domain of human lamin A/C [7]. Thebackbone is displayed as a green ribbon. The two side chains mutated in LGMD 1B patients, Y481 and W498, are displayed in pink and red sticks, respectively. The hy-drophobic side chains surrounding W498 are orange: F451 (beta 3), T496 (beta 6), A504 (loop between beta 6 and beta 7), D511 and V513 (beta 7).  623 10.Sandre-Giovannoli A,Chaouch M,Kozlov S,Vallat JM,Tazir M,KassouriN,Szepetowski P,Hammadouche T,Vandenberghe A,Stewart CL,Grid D,Levy N (2002) Homozygous defects inLMNA,encoding lamin A/C nuclear-envelope proteins,cause autosomalrecessive axonal neuropathy in human(Charcot-Marie-Tooth disorder type 2)and mouse.Am J Hum Genet 70:726–73611.Shackleton S,Lloyd DJ,Jackson SN,Evans R,Niermeijer MF,Singh BM,Schmidt H,Brabant G,Kumar S,Durrington PN,Gregory S,O’Rahilly S,Trembath RC (2000) LMNA,encodinglamin A/C,is mutated in partiallipodystrophy.Nat Genet 24:153–15612.Todorova A,Halliger-Keller B,WalterMC,Dabauvalle MC,Lochmuller H,Muller CR (2003) A synonymouscodon change in the LMNA gene altersmRNA splicing and causes limb girdlemuscular dystrophy type 1B.J MedGenet 40:e11513.van der Kooi AJ,van Meegen M,LedderhofTM,McNally EM,de VisserM,Bolhuis PA (1997) Genetic localiza-tion ofa newly recognized autosomaldominant limb-girdle muscular dys-trophy with cardiac involvement(LGMD1B) to chromosome 1q11–21.Am J Hum Genet 60:891–89514.Vytopil M,Benedetti S,Ricci E,Galluzzi G,Dello RA,Merlini L,Bori-ani G,Gallina M,Morandi L,PolitanoL,Moggio M,Chiveri L,Hausmanova-Petrusewicz I,Ricotti R,Vohanka S,Toman J,Toniolo D (2003) Mutationanalysis ofthe lamin A/C gene(LMNA) among patients with differentcardiomuscular phenotypes.J MedGenet 40:e132S.Spuler,M.D.(  )Dept.ofNeurology Charité University HospitalAugustenburger Platz 113353 Berlin,Germany Tel.:+49-30/450-560193Fax:+49-30/450-560982E-Mail:simone.spuler@charite.deCh.Geier,M.D.· K.J.Osterziel,M.D.Dept.ofCardiology Charité University HospitalBerlin,Germany M.Gutberlet,M.D.Dept.ofRadiology Charité University HospitalBerlin,Germany J.Genschel,Ph.D.· H.Schmidt,M.D.Dept.ofGastroenterology,Hepatology and Endocrinology Charité University HospitalBerlin,Germany T.-N.Lehmann,M.D.Dept.ofNeurosurgery Charité University HospitalBerlin,Germany S.Zinn-Justin,Ph.D.· B.Gilquin,Ph.D.Laboratoire de Structure des ProteinesGif-sur-Yvette,France
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