title: LMNA variants cause cytoplasmic distribution of nuclear pore proteins in Drosophila and human muscle.
abstract: Mutations in the human LMNA gene, encoding A-type lamins, give rise to laminopathies, which include several types of muscular dystrophy. Here, heterozygous sequence variants in LMNA, which result in single amino-acid substitutions, were identified in patients exhibiting muscle weakness. To assess whether the substitutions altered lamin function, we performed in vivo analyses using a Drosophila model. Stocks were generated that expressed mutant forms of the Drosophila A-type lamin modeled after each variant. Larvae were used for motility assays and histochemical staining of the body-wall muscle. In parallel, immunohistochemical analyses were performed on human muscle biopsy samples from the patients. In control flies, muscle-specific expression of the wild-type A-type lamin had no apparent affect. In contrast, expression of the mutant A-type lamins caused dominant larval muscle defects and semi-lethality at the pupal stage. Histochemical staining of larval body wall muscle revealed that the mutant A-type lamin, B-type lamins, the Sad1p, UNC-84 domain protein Klaroid and nuclear pore complex proteins were mislocalized to the cytoplasm. In addition, cytoplasmic actin filaments were disorganized, suggesting links between the nuclear lamina and the cytoskeleton were disrupted. Muscle biopsies from the patients showed dystrophic histopathology and architectural abnormalities similar to the Drosophila larvae, including cytoplasmic distribution of nuclear envelope proteins. These data provide evidence that the Drosophila model can be used to assess the function of novel LMNA mutations and support the idea that loss of cellular compartmentalization of nuclear proteins contributes to muscle disease pathogenesis.
authors.affiliation: Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: George
authors.initials: G
authors.lastname: Dialynas
authors.forename: Kaitlin M
authors.initials: KM
authors.lastname: Flannery
authors.forename: Luka N
authors.initials: LN
authors.lastname: Zirbel
authors.forename: Peter L
authors.initials: PL
authors.lastname: Nagy
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Mathews
authors.forename: Steven A
authors.initials: SA
authors.lastname: Moore
authors.forename: Lori L
authors.initials: LL
authors.lastname: Wallrath
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002648:Child; D002675:Child, Preschool; D003593:Cytoplasm / Q000737:chemistry; D004330:Drosophila / Q000235:genetics / Q000254:growth & development; D029721:Drosophila Proteins / Q000032:analysis / Q000737:chemistry / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D034904:Lamin Type A / Q000032:analysis / Q000737:chemistry / Q000235:genetics*; D034921:Lamin Type B / Q000032:analysis; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009043:Motor Activity; D018908:Muscle Weakness / Q000235:genetics; D018482:Muscle, Skeletal / Q000737:chemistry* / Q000473:pathology; D009133:Muscular Atrophy / Q000235:genetics / Q000473:pathology; D009136:Muscular Dystrophies / Q000235:genetics* / Q000473:pathology; D028861:Nuclear Pore Complex Proteins / Q000032:analysis*; D017434:Protein Structure, Tertiary / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; C494847:LMNA protein, human; D034904:Lamin Type A; D034921:Lamin Type B; D028861:Nuclear Pore Complex Proteins