title: The muscle dystrophy-causing ΔK32 lamin A/C mutant does not impair the functions of the nucleoplasmic lamin-A/C-LAP2α complex in mice.
abstract: A-type lamins are components of the nuclear lamina, a filamentous network of the nuclear envelope in metazoans that supports nuclear architecture. In addition, lamin A/C can also be found in the interior of the nucleus. This nucleoplasmic lamin pool is soluble in physiological buffer, depends on the presence of the lamin-binding protein, lamina-associated polypeptide 2α (LAP2α) and regulates cell cycle progression in tissue progenitor cells. ΔK32 mutations in A-type lamins cause severe congenital muscle disease in humans and a muscle maturation defect in Lmna(ΔK32/ΔK32) knock-in mice. Mutant ΔK32 lamin A/C protein levels were reduced and all mutant lamin A/C was soluble and mislocalized to the nucleoplasm. To test the role of LAP2α in nucleoplasmic ΔK32 lamin A/C regulation and functions, we deleted LAP2α in Lmna(ΔK32/ΔK32) knock-in mice. In double mutant mice the Lmna(ΔK32/ΔK32)-linked muscle defect was unaffected. LAP2α interacted with mutant lamin A/C, but unlike wild-type lamin A/C, the intranuclear localization of ΔK32 lamin A/C was not affected by loss of LAP2α. In contrast, loss of LAP2α in Lmna(ΔK32/ΔK32) mice impaired the regulation of tissue progenitor cells as in lamin A/C wild-type animals. These data indicate that a LAP2α-independent assembly defect of ΔK32 lamin A/C is the predominant cause of the mouse pathology, whereas the LAP2α-linked functions of nucleoplasmic lamin A/C in the regulation of tissue progenitor cells are not affected in Lmna(ΔK32/ΔK32) mice.
authors: Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University of Vienna, Dr. Bohr-Gasse 9, A-1030 Vienna, Austria.
authors: Ursula
authors: U
authors: Pilat
authors: Thomas
authors: T
authors: Dechat
authors: Anne T
authors: AT
authors: Bertrand
authors: Nikola
authors: N
authors: Woisetschläger
authors: Ivana
authors: I
authors: Gotic
authors: Rita
authors: R
authors: Spilka
authors: Katarzyna
authors: K
authors: Biadasiewicz
authors: Gisèle
authors: G
authors: Bonne
authors: Roland
authors: R
authors: Foisner
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D004268:DNA-Binding Proteins; D034904:Lamin Type A; D008565:Membrane Proteins; C440308:lamin C; C093413:lamina-associated polypeptide 2
keywords: Congenital muscular dystrophy; Lamin A/C; Lamina associated polypeptide 2α; Nuclear envelope; Nucleoplasmic lamins