title: FE65 and FE65L1 amyloid precursor protein-binding protein compound null mice display adult-onset cataract and muscle weakness.
abstract: FE65 and FE65L1 are cytoplasmic adaptor proteins that bind a variety of proteins, including the amyloid precursor protein, and that mediate the assembly of multimolecular complexes. We previously reported that FE65/FE65L1 double knockout (DKO) mice display disorganized laminin in meningeal fibroblasts and a cobblestone lissencephaly-like phenotype in the developing cortex. Here, we examined whether loss of FE65 and FE65L1 causes ocular and muscular deficits, 2 phenotypes that frequently accompany cobblestone lissencephaly. Eyes of FE65/FE65L1 DKO mice develop normally, but lens degeneration becomes apparent in young adult mice. Abnormal lens epithelial cell migration, widespread small vacuole formation, and increased laminin expression underneath lens capsules suggest impaired interaction between epithelial cells and capsular extracellular matrix in DKO lenses. Cortical cataracts develop in FE65L1 knockout (KO) mice aged 16 months or more but are absent in wild-type or FE65 KO mice. FE65 family KO mice show attenuated grip strength, and the nuclei of DKO muscle cells frequently locate in the middle of muscle fibers. These findings reveal that FE65 and FE65L1 are essential for the maintenance of lens transparency, and their loss produce phenotypes in brain, eye, and muscle that are comparable to the clinical features of congenital muscular dystrophies in humans.
authors.affiliation: *Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, and Molecular Aging and Development Laboratory, Boston University School of Medicine, Boston, Massachusetts, USA; and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA suh.jaehong@mgh.harvard.edu suzanne.guenette@gmail.com.
authors.forename: Jaehong
authors.initials: J
authors.lastname: Suh
authors.affiliation: *Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, and Molecular Aging and Development Laboratory, Boston University School of Medicine, Boston, Massachusetts, USA; and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Juliet A
authors.initials: JA
authors.lastname: Moncaster
authors.affiliation: *Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, and Molecular Aging and Development Laboratory, Boston University School of Medicine, Boston, Massachusetts, USA; and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Lirong
authors.initials: L
authors.lastname: Wang
authors.affiliation: *Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, and Molecular Aging and Development Laboratory, Boston University School of Medicine, Boston, Massachusetts, USA; and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Imran
authors.initials: I
authors.lastname: Hafeez
authors.affiliation: *Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, and Molecular Aging and Development Laboratory, Boston University School of Medicine, Boston, Massachusetts, USA; and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.affiliation: *Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, and Molecular Aging and Development Laboratory, Boston University School of Medicine, Boston, Massachusetts, USA; and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.affiliation: *Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, and Molecular Aging and Development Laboratory, Boston University School of Medicine, Boston, Massachusetts, USA; and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Lee E
authors.initials: LE
authors.lastname: Goldstein
authors.affiliation: *Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, and Molecular Aging and Development Laboratory, Boston University School of Medicine, Boston, Massachusetts, USA; and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA suh.jaehong@mgh.harvard.edu suzanne.guenette@gmail.com.
authors.forename: Suzanne Y
authors.initials: SY
authors.lastname: Guénette
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002386:Cataract / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007797:Laminin / Q000378:metabolism; D007903:Lens Capsule, Crystalline / Q000378:metabolism / Q000473:pathology; D007905:Lens Diseases / Q000235:genetics / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018908:Muscle Weakness / Q000235:genetics* / Q000378:metabolism; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C486243:Apbb1 protein, mouse; C101886:Apbb2 protein, mouse; D002352:Carrier Proteins; D007797:Laminin; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins
keywords: APP; congenital muscular dystrophy; extracellular matrix; laminin; lens