Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations

Juergen Scharner (1) , Charlotte A Brown (2) , Matthew Bower (3) , Susan T Iannaccone (4) , Ismail A Khatri (5) , Diana Escolar (6) , Erynn Gordon (7) , Kevin Felice (8) , Carol A Crowe (9) , Carla Grosmann (10) , Matthew N Meriggioli (11) , Alexander Asamoah (12) , Ora Gordon (13) , Viola F Gnocchi (1) , Juliet A Ellis (1) , Jerry R Mendell (14) , Peter S Zammit (15)

1 Randall Division of Cell and Molecular Biophysics
2 BD Diagnostics
3 Department of Pediatrics
4 Texas Scottish Rite Hospital for Children
5 Division of Neurology
6 Research Center for Genetic Medicine
7 Coriell Institute for Medical Research
8 Department of Neuromuscular Medicine
9 Department of Pediatrics
10 Department of Neurology
11 Department of Neurology and Rehabilitation
12 Department of Pediatrics
13 Medical Genetics Institute
14 Departments of Pediatrics and Neurology
15 Randall Division of Cell and Molecular Biophysics

Mutations in LMNA cause a variety of diseases affecting striated muscle including autosomal-Emery-Dreifuss muscular dystrophy (EDMD), LMNA-associated congenital muscular dystrophy (L-CMD) and limb-girdle muscular dystrophy type 1B (LGMD1B). Here, we describe novel and recurrent LMNA mutations identified in 50 patients from the USA and Canada, which is the first report of the distribution of LMNA mutations from a large cohort outside Europe. This augments the number of LMNA mutations known to cause EDMD by 16.5%, equating to an increase of 5.9% in the total known LMNA mutations. Eight patients presented with p.R249W/Q or p.E358K mutations and an early onset EDMD phenotype: two mutations recently associated with L-CMD. Importantly, 15 mutations are novel and include eight missense mutations (p.R189P, p.F206L, p.S268P, p.S295P, p.E361K, p.G449D, p.L454P and p.W467R), three splice site mutations (c.IVS4+1G>A, c.IVS6-2A>G, c.IVS8+1G>A), one duplication/in frame insertion (p.R190dup), one deletion (p.Q355del) and two silent mutations (p.R119R and p.K270K). Analysis of 4 of our lamin A mutations showed that some caused nuclear deformations and lamin B re-distribution in a mutation specific manner. Together, this study significantly augments the number of EDMD patients on the database and describes 15 novel mutations that underlie EDMD, which will contribute to establishing genotype-phenotype correlations.

Mots clés: Life Sciences

Juergen Scharner, Charlotte A Brown, Matthew Bower, Susan T Iannaccone, Ismail A Khatri, et al.. Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations. Human Mutation, 2011, 32 (2), pp.152. ⟨10.1002/humu.21361⟩. ⟨hal-00610794⟩