title: Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy.
abstract: Caveolae are invaginations of the plasma membrane involved in many cellular processes, including clathrin-independent endocytosis, cholesterol transport, and signal transduction. They are characterized by the presence of caveolin proteins. Mutations that cause deficiency in caveolin-3, which is expressed exclusively in skeletal and cardiac muscle, have been linked to muscular dystrophy. Polymerase I and transcript release factor (PTRF; also known as cavin) is a caveolar-associated protein suggested to play an essential role in the formation of caveolae and the stabilization of caveolins. Here, we identified PTRF mutations in 5 nonconsanguineous patients who presented with both generalized lipodystrophy and muscular dystrophy. Muscle hypertrophy, muscle mounding, mild metabolic complications, and elevated serum creatine kinase levels were observed in these patients. Skeletal muscle biopsies revealed chronic dystrophic changes, deficiency and mislocalization of all 3 caveolin family members, and reduction of caveolae structure. We generated expression constructs recapitulating the human mutations; upon overexpression in myoblasts, these mutations resulted in PTRF mislocalization and disrupted physical interaction with caveolins. Our data confirm that PTRF is essential for formation of caveolae and proper localization of caveolins in human cells and suggest that clinical features observed in the patients with PTRF mutations are associated with a secondary deficiency of caveolins.
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan. hayasi_y@ncnp.go.jp
authors.forename: Yukiko K
authors.initials: YK
authors.lastname: Hayashi
authors.forename: Chie
authors.initials: C
authors.lastname: Matsuda
authors.forename: Megumu
authors.initials: M
authors.lastname: Ogawa
authors.forename: Kanako
authors.initials: K
authors.lastname: Goto
authors.forename: Kayo
authors.initials: K
authors.lastname: Tominaga
authors.forename: Satomi
authors.initials: S
authors.lastname: Mitsuhashi
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Park
authors.forename: Ikuya
authors.initials: I
authors.lastname: Nonaka
authors.forename: Naomi
authors.initials: N
authors.lastname: Hino-Fukuyo
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Haginoya
authors.forename: Hisashi
authors.initials: H
authors.lastname: Sugano
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D051244:Caveolin 3 / Q000172:deficiency*; D002460:Cell Line; D002648:Child; D002522:Chlorocebus aethiops; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D054643:INDEL Mutation; D008060:Lipodystrophy / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009136:Muscular Dystrophies / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016254:Mutagenesis, Insertional; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: C417736:CAV3 protein, human; C497835:CAVIN1 protein, human; D051244:Caveolin 3; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D004247:DNA