title: Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations.
abstract: 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 United States 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 either 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, and 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 redistribution 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.
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, United Kingdom.
authors.forename: Juergen
authors.initials: J
authors.lastname: Scharner
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Brown
authors.forename: Matthew
authors.initials: M
authors.lastname: Bower
authors.forename: Susan T
authors.initials: ST
authors.lastname: Iannaccone
authors.forename: Ismail A
authors.initials: IA
authors.lastname: Khatri
authors.forename: Diana
authors.initials: D
authors.lastname: Escolar
authors.forename: Erynn
authors.initials: E
authors.lastname: Gordon
authors.forename: Kevin
authors.initials: K
authors.lastname: Felice
authors.forename: Carol A
authors.initials: CA
authors.lastname: Crowe
authors.forename: Carla
authors.initials: C
authors.lastname: Grosmann
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Meriggioli
authors.forename: Alexander
authors.initials: A
authors.lastname: Asamoah
authors.forename: Ora
authors.initials: O
authors.lastname: Gordon
authors.forename: Viola F
authors.initials: VF
authors.lastname: Gnocchi
authors.forename: Juliet A
authors.initials: JA
authors.lastname: Ellis
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Mendell
authors.forename: Peter S
authors.initials: PS
authors.lastname: Zammit
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002170:Canada; D002460:Cell Line; D004252:DNA Mutational Analysis; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics*; D009154:Mutation; D016415:Sequence Alignment; D014481:United States
chemical_list: D034904:Lamin Type A