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Published online before print March 21, 2007, doi:10.1212/01.wnl.0000261254.87181.80)
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Received July 12, 2006
Accepted February 7, 2007

Phenotypic clustering of lamin A/C mutations in neuromuscular patients

S. Benedetti PhD*, I. Menditto BS, M. Degano PhD, C. Rodolico MD, L. Merlini MD, A. D’Amico MD, L. Palmucci MD, A. Berardinelli MD, E. Pegoraro PhD, C. P. Trevisan MD, L. Morandi MD, I. Moroni MD, G. Galluzzi MD, E. Bertini MD, A. Toscano MD, M. Olivè MD, G. Bonne PhD, F. Mari MD, R. Caldara MD, R. Fazio MD, I. Mammì MD, P. Carrera PhD, D. Toniolo PhD, G. Comi MD, A. Quattrini MD, M. Ferrari MD, and S. C. Previtali MD

From the Laboratory of Clinical Molecular Biology (S.B., I. Menditto, P.C., M.F.), Diagnostica e Ricerca San Raffaele, Milan; Biocrystallography Unit (M.D.), Department of Medicine (R.C.), and Neuropathology Unit and Department of Neurology and INSPE (R.F., G.C., A.Q., S.C.P.), San Raffaele Scientific Institute, Milan; Department of Neurosciences, Psychiatry and Anesthesiology (C.R., A.T.), AOU "G. Martino," Messina; Neuromuscular Unit (L. Merlini), Department of Medical Genetics, University of Ferrara; Unit of Molecular Medicine (A.D., E.B.), Ospedale Bambino Gesù Research Hospital, Rome; P. Peirolo Centre for Neuromuscular Diseases (L.P.), Department of Neuroscience, University of Torino; Department of Child Neurology and Psychiatry (A.B.), IRCCS "C. Mondino" Foundation, Pavia; Departments of Neurosciences (E.P.) and Neurological and Psychiatric Sciences (C.P.T.), University of Padova; Division of Neuromuscular Diseases (L. Morandi, I. Moroni), Istituto Nazionale Neurologico C. Besta, Bicocca Laboratories, Milan; Laboratory of Molecular Genetics (G.G.), UILDM-Sez. Laziale, Rome, Italy; Institute of Neuropathology (M.O.), IDIBELL-Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain; Inserm, U582 (G.B.), Institut de Myologie; Université Pierre et Marie Curie-Paris 6, UMR S582 (G.B.), IFR14; and AP-HP, Groupe Hospitalier Pitié-Salpêtrière (G.B.), UF Cardiogenetic and Myogenetics, Paris, France; Medical Genetics (F.M.), University of Siena, Policlinico "S. Maria alle Scotte," Siena; Ambulatorio Genetica Medica (I. Mammì), USSL 13, Ospedale di Dolo, Venezia; Unit for Genomics for Human Disease Diagnosis (P.C., M.F.), San Raffaele Scientific Institute, Milan; Dibit-San Raffaele Scientific Institute (D.T.), Milan; and Università Vita-Salute San Raffaele (G.C., S.C.P.), Milan, Italy.


* To whom correspondence should be addressed. E-mail: benedetti.sara{at}hsr.it.

Abstract-- Background: Mutations in the LMNA gene, encoding human lamin A/C, have been associated with an increasing number of disorders often involving skeletal and cardiac muscle, but no clear genotype/phenotype correlation could be established to date. Methods: We analyzed the LMNA gene in a large cohort of patients mainly affected by neuromuscular or cardiac disease and clustered mutated patients in two groups to unravel possible correlations. Results: We identified 28 variants, 9 of which reported for the first time. The two groups of patients were characterized by clinical and genetic differences: 1) patients with childhood onset displayed skeletal muscle involvement with predominant scapuloperoneal and facial weakness associated with missense mutations; 2) patients with adult onset mainly showed cardiac disorders or myopathy with limb girdle distribution, often associated with frameshift mutations presumably leading to a truncated protein. Conclusions: Our findings, supported by meta-analysis of previous literature, suggest the presence of two different pathogenetic mechanisms: late onset phenotypes may arise through loss of function secondary to haploinsufficiency, while dominant negative or toxic gain of function mechanisms may explain the severity of early phenotypes. This model of patient stratification may help patient management and facilitate future studies aimed at deciphering lamin A/C pathogenesis.




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