Congenital generalized lipodystrophy, type 4 (CGL4) associated with myopathy due to novel PTRF mutations

Abstract

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near total absence of body fat since birth with predisposition to insulin resistance, diabetes, hypertriglyceridemia and hepatic steatosis. Three CGL loci, AGPAT2, BSCL2 and CAV1 have been identified previously. Recently, mutations in polymerase I and transcript release factor (PTRF) were reported in five Japanese patients presenting with myopathy and CGL (CGL4). We report on novel PTRF mutations and detailed phenotype of two male and three female patients with CGL4 belonging to two pedigrees of Mexican origin (CGL7100 and CGL178) and one pedigree of Turkish origin (CGL180). All patients had near total loss of body fat and congenital myopathy manifesting as weakness, percussion-induced muscle mounding and high serum creatine kinase levels. Four of them had hypertriglyceridemia. Three of them had atlantoaxial instability. Two patients belonging to CGL178 pedigree required surgery for pyloric stenosis in the first month of life. None of them had prolonged QT interval on electrocardiography but both siblings belonging to CGL7100 had exercise-induced arrhythmias. Three of them had mild acanthosis nigricans but had normal glucose tolerance. Two of them had hepatic steatosis. All patients had novel null mutations in PTRF gene. In conclusion, mutations in PTRF result in a novel phenotype that includes generalized lipodystrophy with mild metabolic derangements, myopathy, cardiac arrhythmias, atlantoaxial instability and pyloric stenosis. It is unclear how mutations in PTRF, which plays an essential role in formation of caveolae, affect a wide variety of tissues resulting in a variable phenotype.

Cavin-1: caveolae-dependent signalling and cardiovascular disease

“…Membrane curvature is critical for the regulation of signal transduction, for example, non-caveolae caveolin-1 is unable to inhibit eNOS [6]. Loss of caveolae results in a broad-range of disease states such as lipodystrophy [7], muscular dystrophy [7], cardiovascular disease [8], and cancer [9][10][11][12], possibly due to the plethora of signalling components which it regulates.…”

Seipin: from human disease to molecular mechanism

“…Cavin-1-defi cient patients have a secondary defi ciency of caveolin-1 in adipocytes and therefore present a similar pattern of generalized lipodystrophy with bone marrow preservation, although they retain some mechanical adipose tissue and have vestigial dorsal subcutaneous fat. In addition, cavin-1-defi cient patients manifest features of muscular dystrophy, impaired bone formation, smooth-muscle hypertrophy, and occasional cardiac arrhythmia; this phenotype is probably due to secondary defi ciency of muscle-specifi c caveolin-3 and a more global defect in caveolae ( 24,(30)(31)(32).…”

Muscular dystrophy in PTFR/cavin-1 null mice

“…Most of the mutated genes causing MDs are involved in sarcolemmal functions, the maintenance of membrane integrity, and/or communication with the extracellular matrix (2). Two such MD genes, caveolin-3 (CAV3) (3,4) and polymerase I transcription release factor (PTRF) (5)(6)(7)(8), encode protein components of cell surface domains called caveolae in humans and mice (Cav3 and Ptrf).…”

“…In humans, mutations in the CAV3 gene cause a number of different muscle pathologies depending on the mutation, including autosomal dominant limb-girdle muscular dystrophy 1C (LGMD1C), rippling muscle disease, hyperCKemia, and myalgia (16). More recently, human mutations in PTRF have been reported and they result in congenital generalized lipodystrophy type 4 (CGL4), a rare autosomal recessive disorder characterized by near total absence of body fat (5,7,8,(17)(18)(19)(20). While CGL4 is the defining pathology of these patients, they also exhibit MD and cardiac abnormalities including arrhythmias that can be fatal.…”