Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy
Yukiko K. Hayashi, … , Hisashi Sugano, Ichizo Nishino
Yukiko K. Hayashi, … , Hisashi Sugano, Ichizo Nishino
Published August 10, 2009
Citation Information: J Clin Invest. 2009;119(9):2623-2633. https://doi.org/10.1172/JCI38660.
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Research Article Genetics

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

Yukiko K. Hayashi, Chie Matsuda, Megumu Ogawa, Kanako Goto, Kayo Tominaga, Satomi Mitsuhashi, Young-Eun Park, Ikuya Nonaka, Naomi Hino-Fukuyo, Kazuhiro Haginoya, Hisashi Sugano, Ichizo Nishino

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Figure 1

Mutations in PTRF.

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Mutations in PTRF. (A) All 5 patients had a homozygous or compound h...
(A) All 5 patients had a homozygous or compound heterozygous mutation in PTRF (shown by arrows). P1–P4 had the same homozygous insertion mutation of c.696_697insC (InsC) in exon 2, whereas P5 had a compound heterozygous mutation of the same c.696_697insC insertion mutation and a deletion mutation of c.525delG (DelG) in exon 2. (B) Schema of the position of mutations in PTRF, putative proteins produced by mutations, and antibody recognition sites. The c.525delG mutant changes the last 275 amino acids to an unrelated 98–amino acid sequence, while the c.696_697insC mutant substitutes the last 158 amino acids with an unrelated 191–amino acid sequence.