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 clathrinindependent 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.

Not Just Fat: The Structure and Function of the Lipid Droplet

“…The functions of caveolins are closely linked to a family of cytoplasmic proteins termed cavins (Hill et al 2008;Bastiani et al 2009;Hansen et al 2009;McMahon et al 2009). PTRF/ cavin-1 is essential for the formation of caveolae (Hill et al 2008;Liu et al 2008) and, like caveolin, has been shown to be associated with LD function and lipid storage in cultured adipocytes (Aboulaich et al 2006), mice (Liu et al 2008), and human patients (Hayashi et al 2009;Rajab et al 2010). …”

“…Genetic mutation of LD-related proteins such as, seipin (Magre et al 2001), caveolin-1 (Kim et al 2008), PTRF/cavin1 (Hayashi et al 2009;Rajab et al 2010), and 1-acylglycerol-3-phosphate-O-acyltransferase 2 (Agarwal et al 2002), which is a critical enzyme in TG and phospholipid synthesis, has been shown to cause lipodystrophies. The mechanism that seipin mutation leads to lipodystrophy may not be directly related to its effect on LD formation because it also affects a transcriptional cascade that drives adipogenesis (Payne et al 2008;Chen et al 2009).…”

Lipodystrophy: metabolic insights from a rare disorder

“…It is therefore to be expected that the loss of this protein should disrupt adipose tissue function, both through impairments in fatty acid uptake, and thus TAG synthesis, and (more speculatively) through the loss of insulin signalling into the cell (Cohen et al 2003, Saltiel & Pessin 2003. In addition, mutations in PTRF (encoding polymerase 1 and transcript release factor, also known as cavin-1) have recently been identified in several kindreds with an autosomal recessive disorder characterised by generalised lipodystrophy and muscular dystrophy , Hayashi et al 2009). Unlike BSCL2 and AGPAT2 mutations, in which somatic overgrowth is a common feature, CAV1 defects were associated with short stature (albeit in a single kindred so far).…”

An inhibitor of transforming growth factor beta type I receptor ameliorates muscle atrophy in a mouse model of caveolin 3-deficient muscular dystrophy

“…29,49 Caveolin 3-deficient myoblasts formed thin myotubes upon activation of the TGF-b effector, Smad2. 29 Activated Smad2 was also observed in skeletal muscle from patients with muscular dystrophy with generalized lipodystrophy caused by deficiency of cavin, an assembly molecule for caveolin 3.…”

“…29 Activated Smad2 was also observed in skeletal muscle from patients with muscular dystrophy with generalized lipodystrophy caused by deficiency of cavin, an assembly molecule for caveolin 3. 49 To confirm the novel concept of the caveolin 3-TGF-b-p21 axis in the pathobiology of muscle atrophy, further characterization of both satellite cells and myoblasts will be required in skeletal muscle samples from patients with LGMD1C and cavin 1 deficiency.…”