Novel and recurrent mutations in lamin A/C in patients with Emery-Dreifussmuscular dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by slowly progres sive muscle wasting and weakness; early contractures of the elbows, Achille s tendons, and spine; and cardiomyopathy associated with cardiac conduction defects. Clinically indistinguishable X-linked and autosomal forms of EDMD have been described. Mutations in the STA gene, encoding the nuclear envel ope protein emerin, are responsible for X-linked EDMD, while mutations in t he LMNA gene encoding lamins A and C by alternative splicing have been foun d in patients with autosomal dominant, autosomal recessive, and sporadic fo rms of EDMD. We report mutations in LMNA found in four familial and seven s poradic cases of EDMD, including seven novel mutations. Nine missense mutat ions and two small in-frame deletions were detected distributed throughout the gene. Most mutations (7/11) were detected within the LMNA exons encodin g the central rod domain common to both lamins A/C. All of these missense m utations alter residues in the lamin A/C proteins conserved throughout evol ution, implying an essential structural and/or functional role of these res idues. One severely affected patient possesed two mutations, one specific t o lamin A that may modify the phenotype of this patient. Mutations in LMNA were frequently identified among patients with sporadic and familial forms of EDMD. Further studies are needed to identify the factors modifying disea se phenotype among patients harboring mutations within lamin A/C and to det ermine the effect of various mutations on lamin A/C structure and function. (C) 2001 Wiley-Liss, Inc.