**2.4 Type 4 CGL (CGL4) and PTRF**

CGL4 (OMIM #613327) is an autosomal recessive condition caused by mutations in the *PTRF* gene that is located on chromosome 17q21. *PTRF* gene encodes cavin-1 protein. The coincidence of generalized lipodystrophy and muscular dystrophy was found in some Omani patients as early as 2002 [83, 84]; however, the genetic basis underlies this new subtype of generalized lipodystrophy was not identified until 2009 [85]. CGL4 patients normally do not have severe lipodystrophy at birth but gradually develop progressive fat loss from infancy or early childhood [85]. Similar to CGL3, CGL4 subjects lose metabolically active adipose tissue but preserve mechanical adipose tissue and fat in bone marrow [83]. In contrast to the "classic" lipodystrophies, CGL4 is comprising congenital myopathy with high circulating creatine kinase, smooth and skeletal muscle hypertrophy, cardiac arrhythmias, osteopenia, distal metaphyseal deformation with joint stiffness, pyloric stenosis, atlantoaxial instability, as well as percussion-induced muscle mounding and local protracted muscle contractions [78, 83, 86, 87]. Since 2013, a few homozygous *PTRF* mutations identified in CGL4 patients have been reported: c.259C>T (p.Gln87\*) and c.481–c.482insGTGA (p.Lys161Serfs\*41) in two female Turkish teenagers [43, 88]; c.176A>T (p.Asp59Val) and c.471G>C (p.Gln157Hisfs\*52) in patients from Switzerland and Egypt, respectively [89]; c.550G>T (p.Glu184\*) in a Saudi family [90]; c.947delA in child of Moroccan origin [76]; and c.696\_697insC in a Japanese boy [91].

As mentioned before, cavin-1 interacts with caveolin proteins to form caveolae and to mediate cellular trafficking and lipid turnover [70, 85]. Cavin-1 can stabilize

#### *Lipodystrophy - A Rare Condition with Serious Metabolic Abnormalities DOI: http://dx.doi.org/10.5772/intechopen.88667*

caveolae and caveolin proteins probably via its interactions with cytoskeleton [20]. In agreement with this finding, *Ptrf*<sup>−</sup>/<sup>−</sup> mice do not possess morphologically detectable caveolae and exhibit dramatically impaired expression of all three caveolin isoforms [92]. Specifically, cavin-1 colocalizes with caveolin-1 in adipocytes [93]. Paradoxically, it is believed that PTRF deficiency, as seen with loss of *CAV1*, causes generalized lipodystrophy due to the defects in caveolar formation [1, 20]. Recently, Liu and Pilch have demonstrated that the insulin-induced phosphorylation of cavin-1 results in its translocation to the nucleus where it regulates ribosomal transcription [94]. Primary and cultured cavin-1-deficient adipocytes have much lower levels of ribosomal RNA and proteins, resulting in ribosomal stress, which in turn leads to fat loss over time. This caveolae-independent cavin-1 function provides a novel explanation to CGL4 phenotype [95]. *PTRF* also serves as a terminator transcription factor via its interactions with both the thyroid transcription factor 1 (TFF-1) and RNA polymerase 1. cDNA cloning and functional characterization were initially reported by Jansa et al. in 1998 [94].

*Ptrf*<sup>−</sup>/<sup>−</sup> mice are viable with no overt change in body weight; nonetheless, they exhibit considerably reduced adipose tissue mass, high circulating triglyceride levels, glucose intolerance, and hyperinsulinemia, phenocopying lipodystrophy as seen in humans [92]. Notably, there is no morphologically detectable caveolae in *Ptrf*<sup>−</sup>/<sup>−</sup> mice, due to the absence of cavin-1 protein [85, 92]. Epididymal white adipocytes from *Ptrf*<sup>−</sup>/<sup>−</sup> mice were smaller as the result of reduced triglyceride accumulation due to decreased fatty acid uptake and incorporation [92]. In addition, they are insensitive to insulin; as a result, lacked insulin-stimulated glucose transport [96]. Both *Cav1*<sup>−</sup>/<sup>−</sup> and *Ptrf*<sup>−</sup>/<sup>−</sup> white adipocytes are resistant to lipolytic stimulation due to impaired perilipin phosphorylation [72, 96]. Much as *Ptrf*<sup>−</sup>/<sup>−</sup> mice are resistant to diet-induced obesity as seen in cav1<sup>−</sup>/<sup>−</sup> mice, BAT and liver exhibited abnormal lipid metabolism [96].
