title: Novel and recurrent mutations in lamin A/C in patients with Emery-Dreifuss muscular dystrophy.
abstract: Emery-Dreifuss muscular dystrophy (EDMD) is characterized by slowly progressive muscle wasting and weakness; early contractures of the elbows, Achilles 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 envelope protein emerin, are responsible for X-linked EDMD, while mutations in the LMNA gene encoding lamins A and C by alternative splicing have been found in patients with autosomal dominant, autosomal recessive, and sporadic forms of EDMD. We report mutations in LMNA found in four familial and seven sporadic cases of EDMD, including seven novel mutations. Nine missense mutations and two small in-frame deletions were detected distributed throughout the gene. Most mutations (7/11) were detected within the LMNA exons encoding the central rod domain common to both lamins A/C. All of these missense mutations alter residues in the lamin A/C proteins conserved throughout evolution, implying an essential structural and/or functional role of these residues. One severely affected patient possesed two mutations, one specific to 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 disease phenotype among patients harboring mutations within lamin A/C and to determine the effect of various mutations on lamin A/C structure and function.
authors.affiliation: Department of Pediatric Research, Carolinas Medical Center, Charlotte, NC 28232-2861, USA. cbrown@carolinas.org
authors.forename: C A
authors.initials: CA
authors.lastname: Brown
authors.forename: R W
authors.initials: RW
authors.lastname: Lanning
authors.forename: K Q
authors.initials: KQ
authors.lastname: McKinney
authors.forename: A R
authors.initials: AR
authors.lastname: Salvino
authors.forename: E
authors.initials: E
authors.lastname: Cherniske
authors.forename: C A
authors.initials: CA
authors.lastname: Crowe
authors.forename: B T
authors.initials: BT
authors.lastname: Darras
authors.forename: S
authors.initials: S
authors.lastname: Gominak
authors.forename: C R
authors.initials: CR
authors.lastname: Greenberg
authors.forename: C
authors.initials: C
authors.lastname: Grosmann
authors.forename: P
authors.initials: P
authors.lastname: Heydemann
authors.forename: J R
authors.initials: JR
authors.lastname: Mendell
authors.forename: B R
authors.initials: BR
authors.lastname: Pober
authors.forename: T
authors.initials: T
authors.lastname: Sasaki
authors.forename: F
authors.initials: F
authors.lastname: Shapiro
authors.forename: D A
authors.initials: DA
authors.lastname: Simpson
authors.forename: O
authors.initials: O
authors.lastname: Suchowersky
authors.forename: J E
authors.initials: JE
authors.lastname: Spence
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D034904:Lamin Type A; D034882:Lamins; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009136:Muscular Dystrophies / Q000235:genetics*; D020389:Muscular Dystrophy, Emery-Dreifuss; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D010375:Pedigree
chemical_list: D034904:Lamin Type A; D034882:Lamins; D009687:Nuclear Proteins