| *603198 | |||||||||||||||||||||||||||||||||
| RNA POLYMERASE I AND TRANSCRIPT RELEASE FACTOR; PTRF | |||||||||||||||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||||||||||||||
| CAVIN | |||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: PTRF | |||||||||||||||||||||||||||||||||
| Cytogenetic location: 17q21.2 Genomic coordinates (GRCh37): 17:40,554,466 - 40,575,337 (from NCBI) | |||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | |||||||||||||||||||||||||||||||||
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| TEXT | |||||||||||||||||||||||||||||||||
| Description | |||||||||||||||||||||||||||||||||
| The PTRF gene encodes cavin, an essential factor in the biogenesis of caveolae, which are 50- to 100-nm invaginations of cell-surface membranes putatively involved in numerous processes, including signal transduction and membrane and lipid trafficking (summary by Liu et al., 2008). | |||||||||||||||||||||||||||||||||
| Cloning | |||||||||||||||||||||||||||||||||
| Termination of RNA polymerase I (Pol I; see 602000) transcription is a 2-step process that involves pausing of transcription elongation complexes and release of both the pre-rRNA and Pol I from the template. In mouse, pausing is mediated by Ttf1 (see 600777). Mason et al. (1997) demonstrated that an additional trans-acting factor is required for dissociation of the paused complex. Jansa et al. (1998) designated this factor PTRF for 'Pol I and transcript release factor'. Using a yeast 2-hybrid screen with mouse Ttf1 as the bait, these authors isolated a partial human cDNA encoding PTRF. They cloned a full-length mouse Ptrf cDNA using a PCR-based approach. The predicted mouse and truncated human PTRF proteins are 94% identical. By Northern blot analysis, Miyoshi et al. (2001) determined that the mouse Ptrf gene is expressed as a 3.2-kb transcript. Highest expression was detected in lung and heart, with lower levels in all other tissues examined. Hayashi et al. (2009) noted that the PTRF gene encodes a 390-amino acid protein. Immunoblotting detected PTRF as an approximately 50-kD band in human muscle and 3T3 cells. In C2C12 myoblasts cotransfected with PTRF and caveolin-3 (CAV3; 601253) or caveolin-1 (CAV1; 601047), PTRF was detected at the cell membrane and colocalized with CAV3. | |||||||||||||||||||||||||||||||||
| Gene Structure | |||||||||||||||||||||||||||||||||
| Hayashi et al. (2009) noted that the PTRF gene contains 2 coding exons. Miyoshi et al. (2001) determined that the mouse Ptrf gene contains 2 exons and spans 12 kb. | |||||||||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||||||||
| Miyoshi et al. (2001) mapped the mouse Ptrf gene to chromosome 11. The order and orientation of genes at this locus, Ptrf--Stat3 (102582)--Stat5a (601511)--Stat5b (604260)--Lgp1 (608587)--Hcrt (602358), are identical in the syntenic region of human chromosome 17q21. | |||||||||||||||||||||||||||||||||
| Gene Function | |||||||||||||||||||||||||||||||||
| Jansa et al. (1998) demonstrated that Ptrf interacts with both TTF1 and Pol I, and binds to transcripts containing the 3-prime end of pre-rRNA in vitro. Recombinant Ptrf induced the dissociation of ternary Pol I transcription complexes in vitro, releasing both Pol I and nascent transcripts from the template. By comparative proteomic screening of Cav1-knockout and wildtype mouse embryonic fibroblasts, Hill et al. (2008) identified Ptrf as a putative caveolar coat protein. Ptrf associated with mature caveolae in the plasma membrane, but not with Golgi-localized caveolin. In PC3 human prostate cancer cells and during development of zebrafish notochord, lack of PTRF expression correlated with lack of caveolae, and caveolin redistributed to noncaveolar plasma membrane. Expression of PTRF in PC3 cells was sufficient to cause formation of caveolae. Knockdown of PTRF reduced caveolae density, both in mammalian cells and in zebrafish. Caveolin remained on the plasma membrane in PTRF-knockdown cells, but it exhibited increased lateral mobility and accelerated lysosomal degradation. Hill et al. (2008) concluded that PTRF is required for caveola formation and sequestration of mobile caveolin into immobile caveolae. Zhu et al. (2011) showed that mouse Mg53 (TRIM72; 613288) and Ptrf interacted with each other and functioned together in muscle membrane repair. Ptrf was required for the translocation of Mg53 to the site of membrane injury in cell culture models and in mice irradiated with a UV laser to cause localized sarcolemma damage. A mouse mutant ortholog of the PTRF 525delG mutation (603198.0002) resulted in mislocalization of Ptrf to the nucleus in transfected human cell lines. Consequently, mutant Ptrf was unable to target Mg53 to the plasma membrane for repair of detergent-induced membrane damage. The authors also showed that cholesterol, which is exposed during membrane damage, was critical for membrane repair. Cholesterol, bound by Ptrf, functioned as a nucleation site for the recruitment of Mg53-containing vesicles. Zhu et al. (2011) hypothesized that, upon cell membrane disruption, PTRF recognizes exposed cholesterol at the site of injury and tethers MG53 and its associated intracellular vesicles to the damage site, allowing formation of a membrane repair patch. | |||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||
| In 4 unrelated Japanese patients with congenital generalized lipodystrophy type 4 (CGL4; 613327) and muscular dystrophy, Hayashi et al. (2009) identified a homozygous truncating mutation in the PTRF gene (696insC; 603198.0001). A fifth Japanese patient was compound heterozygous for the 696insC mutation and another truncating mutation (525delG; 603198.0002). In 10 patients from Oman with lipodystrophy, muscular dystrophy, and cardiac conduction defects, consistent with CGL4 (Rajab et al., 2002), Rajab et al. (2010) identified a homozygous truncating mutation in the PTRF gene (160delG; 603198.0003), resulting in complete loss of protein function. A girl from the U.K. with a similar phenotype was homozygous for another truncating mutation (362dupT; 603198.0004). Rajab et al. (2010) noted that the symptoms of the patients combine the features seen in individuals with mutations in CAV1 (601047), such as CGL3 (612526), and with those in CAV3 (601253), such as LGMD1C (607801) and rippling muscle disease (RMD; 606072), since the PTRF gene product in essential for caveolae biogenesis. PTRF is expressed in many tissues, but highest mRNA levels are found in adipocytes, smooth muscle, skeletal muscle, heart, and osteoblasts, consistent with the tissues affected in patients with CGL4. The nervous system is spared. In 3 patients, including 2 sibs, with CGL4, Shastry et al. (2010) identified 2 different homozygous truncating mutations in the PTRF gene (603198.0005-603198.0006). In addition, the affected sibs reported by Simha et al. (2008) were found to be compound heterozygous for 2 truncating PTRF mutations (603198.0007 and 603198.0008). Clinical information available from some of the parents, who carried heterozygous PTRF mutations, showed some metabolic abnormalities, including increased serum triglycerides and insulin intolerance, although none had lipodystrophy. | |||||||||||||||||||||||||||||||||
| Animal Model | |||||||||||||||||||||||||||||||||
| Liu et al. (2008) found that Ptrf-knockout mice were viable and of normal weight, but had a metabolic phenotype of significantly reduced adipose tissue mass, higher circulating triglyceride levels, glucose intolerance, and hyperinsulinemia, consistent with a lipodystrophy. Cells from various tissues of Ptrf-knockout mice, including lung epithelium, intestinal smooth muscle, skeletal muscle, and endothelial cells showed no detectable caveolae cells. These cells also had markedly decreased expression of all 3 caveolin isoforms, although some tissues showed increased mRNA, a possible compensatory response. The findings indicated that cavin is required for the formation and/or stabilization of morphologically defined caveolae. Liu et al. (2008) suggested that the absence of cavin impairs the ability of adipocytes to store triglycerides, which in turn leads an increase in circulating lipids, glucose intolerance, and insulin resistance. | |||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | |||||||||||||||||||||||||||||||||
| Table View | |||||||||||||||||||||||||||||||||
| .0001 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 4 | |||||||||||||||||||||||||||||||||
| PTRF, 1-BP INS, 696C | |||||||||||||||||||||||||||||||||
| In 4 unrelated Japanese patients with congenital generalized lipodystrophy type 4 (CGL4; 613327) and muscular dystrophy, Hayashi et al. (2009) identified a homozygous 1-bp insertion (696insC) in exon 2 of the PTRF gene. A fifth Japanese patient was compound heterozygous for the 696insC mutation and a 1-bp deletion in exon 2 (525delG; 603198.0002). The 696insC mutation substitutes the last 158 amino acids with an unrelated 191-amino acid sequence, and the 535delG mutation changes the last 275 amino acids to a 98-amino acid sequence. Neither mutation was found in 200 control individuals. Haplotype analysis of 696insC carriers suggested that a founder effect may not be likely but could not be ruled out. | |||||||||||||||||||||||||||||||||
| .0002 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 4 | |||||||||||||||||||||||||||||||||
| PTRF, 1-BP DEL, 525G | |||||||||||||||||||||||||||||||||
| See 603198.0001 and Hayashi et al. (2009) | |||||||||||||||||||||||||||||||||
| .0003 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 4 | |||||||||||||||||||||||||||||||||
| PTRF, 1-BP DEL, 160G | |||||||||||||||||||||||||||||||||
| In 11 patients from 8 consanguineous Omani families with CGL4 (613327), Rajab et al. (2010) identified a homozygous 1-bp deletion (160delG) in exon 1 of the PTRF gene, resulting in a frameshift, premature truncation, and complete absence of the protein from patient fibroblasts and muscle cells. The patients had previously been reported by Rajab et al. (2002). | |||||||||||||||||||||||||||||||||
| .0004 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 4 | |||||||||||||||||||||||||||||||||
| PTRF, 1-BP DUP, 362T | |||||||||||||||||||||||||||||||||
| In a 12-year-old girl from the U.K., born of first-cousin parents, with CGL4 (613327), Rajab et al. (2010) identified a homozygous 1-bp duplication (362dupT) in exon 1 of the PTRF gene, resulting in a frameshift, premature truncation, and complete loss of function. She had lack of subcutaneous fat, prominent musculature, exercise intolerance, muscle weakness, stiffness, and percussion-induced contractions. She also had atlanto-axial instability, osteoporosis, hepatomegaly with fatty infiltration, and insulin resistance. She died suddenly at age 13 years from sudden cardiac death to due ventricular fibrillation. There was a complete absence of caveolin-1 immunoreactivity and patchy and decreased caveolin-3 staining in patient adipose cells, and severely decreased caveolae on patient fibroblasts. PTRF staining was completely absent. | |||||||||||||||||||||||||||||||||
| .0005 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 4 | |||||||||||||||||||||||||||||||||
| PTRF, 1-BP DEL, 135G | |||||||||||||||||||||||||||||||||
| In a Mexican brother and sister with CGL4 (613327), Shastry et al. (2010) identified a homozygous 1-bp deletion (135delG) in the PTRF gene, resulting in a frameshift and premature truncation. Each parent was heterozygous for the mutation. The 43-year-old father had poorly controlled diabetes mellitus and increased serum triglycerides, and the 40-year-old mother had increased serum triglycerides; neither parent had lipodystrophy. | |||||||||||||||||||||||||||||||||
| .0006 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 4 | |||||||||||||||||||||||||||||||||
| PTRF, 4-BP INS, 481GTGA | |||||||||||||||||||||||||||||||||
| In a Turkish girl, born of consanguineous parents, with CGL4 (613327), Shastry et al. (2010) identified a homozygous 4-bp insertion (481insGTGA) in exon 2 of the PTRF gene, resulting in a frameshift and premature truncation. | |||||||||||||||||||||||||||||||||
| .0007 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 4 | |||||||||||||||||||||||||||||||||
| PTRF, 4-BP DEL, 518AAGA | |||||||||||||||||||||||||||||||||
| In 2 sibs with CGL4 (613327), originally reported by Simha et al. (2008), Shastry et al. (2010) identified compound heterozygosity for 2 mutations in the PTRF gene: a 4-bp deletion (518delAAGA), predicted to result in a frameshift and premature truncation, and a G-to-T transversion in intron 1, predicted to result in the inclusion of 143 nucleotides of intron 1, causing a frameshift and premature truncation. The parents, each of whom was heterozygous for 1 of the mutations, had slightly high serum triglycerides, but no lipodystrophy. | |||||||||||||||||||||||||||||||||
| .0008 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 4 | |||||||||||||||||||||||||||||||||
| PTRF, IVS1DS, G-T, +1 | |||||||||||||||||||||||||||||||||
| See 603198.0007 and Shastry et al. (2010). | |||||||||||||||||||||||||||||||||
| REFERENCES | |||||||||||||||||||||||||||||||||
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