TY - JOUR AU - Hayashi, Yukiko K. AU - Matsuda, Chie AU - Ogawa, Megumu AU - Goto, Kanako AU - Tominaga, Kayo AU - Mitsuhashi, Satomi AU - Park, Young-Eun AU - Nonaka, Ikuya AU - Hino-Fukuyo, Naomi AU - Haginoya, Kazuhiro AU - Sugano, Hisashi AU - Nishino, Ichizo T1 - Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy PY - 2009/09/01/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI38660 VL - 119 IS - 9 UR - https://doi.org/10.1172/JCI38660 SP - 2623 EP - 2633 PB - The American Society for Clinical Investigation ER -