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Fatal cardiac arrhythmia and long-QT syndrome in a new form of congenital generalized lipodystrophy with muscle rippling (CGL4) due to PTRF-CAVIN mutations.

Rajab A, Straub V, McCann LJ, Seelow D, Varon R, Barresi R, Schulze A, Lucke B, Lützkendorf S, Karbasiyan M, Bachmann S, Spuler S, Schuelke M - PLoS Genet. (2010)

Bottom Line: Additionally, we found impaired bone formation with osteopenia, osteoporosis, and atlanto-axial instability.Absence of PTRF-CAVIN did not influence abundance of its binding partner caveolin-1 and caveolin-3.In patient fibroblasts, however, caveolin-1 failed to localize toward the cell surface and electron microscopy revealed reduction of caveolae to less than 3%.

View Article: PubMed Central - PubMed

Affiliation: Genetics Unit, Ministry of Health, Directorate General of Health Affairs, Royal Hospital, Muscat, Oman.

ABSTRACT
We investigated eight families with a novel subtype of congenital generalized lipodystrophy (CGL4) of whom five members had died from sudden cardiac death during their teenage years. ECG studies revealed features of long-QT syndrome, bradycardia, as well as supraventricular and ventricular tachycardias. Further symptoms comprised myopathy with muscle rippling, skeletal as well as smooth-muscle hypertrophy, leading to impaired gastrointestinal motility and hypertrophic pyloric stenosis in some children. Additionally, we found impaired bone formation with osteopenia, osteoporosis, and atlanto-axial instability. Homozygosity mapping located the gene within 2 Mbp on chromosome 17. Prioritization of 74 candidate genes with GeneDistiller for high expression in muscle and adipocytes suggested PTRF-CAVIN (Polymerase I and transcript release factor/Cavin) as the most probable candidate leading to the detection of homozygous mutations (c.160delG, c.362dupT). PTRF-CAVIN is essential for caveolae biogenesis. These cholesterol-rich plasmalemmal vesicles are involved in signal-transduction and vesicular trafficking and reside primarily on adipocytes, myocytes, and osteoblasts. Absence of PTRF-CAVIN did not influence abundance of its binding partner caveolin-1 and caveolin-3. In patient fibroblasts, however, caveolin-1 failed to localize toward the cell surface and electron microscopy revealed reduction of caveolae to less than 3%. Transfection of full-length PTRF-CAVIN reestablished the presence of caveolae. The loss of caveolae was confirmed by Atomic Force Microscopy (AFM) in combination with fluorescent imaging. PTRF-CAVIN deficiency thus presents the phenotypic spectrum caused by a quintessential lack of functional caveolae.

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Abnormal fat distribution in patients with PTRF-CAVIN mutations.T1-weighted MR-images of patient FI:201 (B,D) and of patient FII:201 (F). On the left, the corresponding images of normal controls (A,C,E) are shown for comparison. T1-weighted images depict fat with high signal intensity thus giving an overview of the fat distribution. Subcutaneous fat is nearly completely lost over the peripheries, thoracic and abdominal walls and on both temporal regions. There is relative preservation of fat within the orbits. Paraspinal and perirenal fat is also reduced in bulk but relatively preserved. Fat in the bone marrow of the ribs and the humerus seems to be normal.
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pgen-1000874-g003: Abnormal fat distribution in patients with PTRF-CAVIN mutations.T1-weighted MR-images of patient FI:201 (B,D) and of patient FII:201 (F). On the left, the corresponding images of normal controls (A,C,E) are shown for comparison. T1-weighted images depict fat with high signal intensity thus giving an overview of the fat distribution. Subcutaneous fat is nearly completely lost over the peripheries, thoracic and abdominal walls and on both temporal regions. There is relative preservation of fat within the orbits. Paraspinal and perirenal fat is also reduced in bulk but relatively preserved. Fat in the bone marrow of the ribs and the humerus seems to be normal.

Mentions: The girl (Figure 2A) was born to healthy first degree cousins (FII:201, Figure 2D) from the UK. She showed neonatal hypotonia and elevated serum creatine kinase levels (1,300 IU/l). Her appetite in early childhood was poor. At 2 years of age her weight was between the 3rd–10th percentile with normal height. Lack of subcutaneous fat (Figure 3F) and pronounced muscle bulk led to the diagnosis of lipodystrophy. She complained of stiff legs, neck flexor weakness, dizziness and involuntary muscle movements, which were later diagnosed as rippling muscle disease. Her cognitive functions were normal. At 7 years of age she experienced periodic episodes of headache, abdominal pain, constipation and vomiting. At 10 years of age she developed proximal muscle weakness and had problems climbing stairs. Muscle stiffness, exercise-induced myalgia, PIRCs and spontaneous muscle rippling progressed over the next two years, without any evidence of myotonia. Cardiac loop recording after two syncopes revealed sinus arrhythmia, supraventricular and ventricular tachycardias and ventricular extrasystoles. The corrected QT-time was between 430–501 ms (Figure 2E). At 12 years of age, an acute ileus after appendectomy required a partial bowel resection and histology of the colon wall revealed massive smooth muscle hypertrophy. She suffered from frequent infections (tonsillitis) from which she was slow to recover. Atlanto-axial instability with subluxation was verified by X-ray (Figure 2B and 2C) as well as magnetic resonance imaging and a DEXA-scan revealed severe osteoporosis (Z-score -5.7) and a total whole body fat of 9.7%. At 12 years of age her symptoms were accompanied by hepatomegaly with elevated transaminases (ALT 128 U/l, AST 105 U/l) and signs of fatty infiltration on ultrasound, elevated C-peptide (2,569 pmol/l; N 190–990) and insulin levels (331 pmol/l) at a fasting glucose of 5.8 mmol/l. Insulin resistance was considerably increased with HOMA-IR indices ranging between 5.4 and 11.8 without evidence of acanthosis nigricans. A glucose tolerance test showed a fasting glucose of 5.6 mmol/l and elevated glucose (8.0 mmol/l) and insulin levels (1,241 pmol/l) two hours after glucose administration. Dyslipidemia was present with elevated triglycerides (3.7–8.5 mmol/l), an abnormal cholesterol profile (HDL 0.4–0.7 mmol/l, LDL 2.1–2.3 mmol/l) and reduced apolipoprotein A1 (0.53–0.81 g/l). Serum leptin levels (between <0.1 to 0.2 µg/l) were below normal. At the age of 13 years the patient collapsed while playing and died from sudden cardiac death due to ventricular fibrillation, which was still seen in the ambulance but impossible to cardiovert.


Fatal cardiac arrhythmia and long-QT syndrome in a new form of congenital generalized lipodystrophy with muscle rippling (CGL4) due to PTRF-CAVIN mutations.

Rajab A, Straub V, McCann LJ, Seelow D, Varon R, Barresi R, Schulze A, Lucke B, Lützkendorf S, Karbasiyan M, Bachmann S, Spuler S, Schuelke M - PLoS Genet. (2010)

Abnormal fat distribution in patients with PTRF-CAVIN mutations.T1-weighted MR-images of patient FI:201 (B,D) and of patient FII:201 (F). On the left, the corresponding images of normal controls (A,C,E) are shown for comparison. T1-weighted images depict fat with high signal intensity thus giving an overview of the fat distribution. Subcutaneous fat is nearly completely lost over the peripheries, thoracic and abdominal walls and on both temporal regions. There is relative preservation of fat within the orbits. Paraspinal and perirenal fat is also reduced in bulk but relatively preserved. Fat in the bone marrow of the ribs and the humerus seems to be normal.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2837386&req=5

pgen-1000874-g003: Abnormal fat distribution in patients with PTRF-CAVIN mutations.T1-weighted MR-images of patient FI:201 (B,D) and of patient FII:201 (F). On the left, the corresponding images of normal controls (A,C,E) are shown for comparison. T1-weighted images depict fat with high signal intensity thus giving an overview of the fat distribution. Subcutaneous fat is nearly completely lost over the peripheries, thoracic and abdominal walls and on both temporal regions. There is relative preservation of fat within the orbits. Paraspinal and perirenal fat is also reduced in bulk but relatively preserved. Fat in the bone marrow of the ribs and the humerus seems to be normal.
Mentions: The girl (Figure 2A) was born to healthy first degree cousins (FII:201, Figure 2D) from the UK. She showed neonatal hypotonia and elevated serum creatine kinase levels (1,300 IU/l). Her appetite in early childhood was poor. At 2 years of age her weight was between the 3rd–10th percentile with normal height. Lack of subcutaneous fat (Figure 3F) and pronounced muscle bulk led to the diagnosis of lipodystrophy. She complained of stiff legs, neck flexor weakness, dizziness and involuntary muscle movements, which were later diagnosed as rippling muscle disease. Her cognitive functions were normal. At 7 years of age she experienced periodic episodes of headache, abdominal pain, constipation and vomiting. At 10 years of age she developed proximal muscle weakness and had problems climbing stairs. Muscle stiffness, exercise-induced myalgia, PIRCs and spontaneous muscle rippling progressed over the next two years, without any evidence of myotonia. Cardiac loop recording after two syncopes revealed sinus arrhythmia, supraventricular and ventricular tachycardias and ventricular extrasystoles. The corrected QT-time was between 430–501 ms (Figure 2E). At 12 years of age, an acute ileus after appendectomy required a partial bowel resection and histology of the colon wall revealed massive smooth muscle hypertrophy. She suffered from frequent infections (tonsillitis) from which she was slow to recover. Atlanto-axial instability with subluxation was verified by X-ray (Figure 2B and 2C) as well as magnetic resonance imaging and a DEXA-scan revealed severe osteoporosis (Z-score -5.7) and a total whole body fat of 9.7%. At 12 years of age her symptoms were accompanied by hepatomegaly with elevated transaminases (ALT 128 U/l, AST 105 U/l) and signs of fatty infiltration on ultrasound, elevated C-peptide (2,569 pmol/l; N 190–990) and insulin levels (331 pmol/l) at a fasting glucose of 5.8 mmol/l. Insulin resistance was considerably increased with HOMA-IR indices ranging between 5.4 and 11.8 without evidence of acanthosis nigricans. A glucose tolerance test showed a fasting glucose of 5.6 mmol/l and elevated glucose (8.0 mmol/l) and insulin levels (1,241 pmol/l) two hours after glucose administration. Dyslipidemia was present with elevated triglycerides (3.7–8.5 mmol/l), an abnormal cholesterol profile (HDL 0.4–0.7 mmol/l, LDL 2.1–2.3 mmol/l) and reduced apolipoprotein A1 (0.53–0.81 g/l). Serum leptin levels (between <0.1 to 0.2 µg/l) were below normal. At the age of 13 years the patient collapsed while playing and died from sudden cardiac death due to ventricular fibrillation, which was still seen in the ambulance but impossible to cardiovert.

Bottom Line: Additionally, we found impaired bone formation with osteopenia, osteoporosis, and atlanto-axial instability.Absence of PTRF-CAVIN did not influence abundance of its binding partner caveolin-1 and caveolin-3.In patient fibroblasts, however, caveolin-1 failed to localize toward the cell surface and electron microscopy revealed reduction of caveolae to less than 3%.

View Article: PubMed Central - PubMed

Affiliation: Genetics Unit, Ministry of Health, Directorate General of Health Affairs, Royal Hospital, Muscat, Oman.

ABSTRACT
We investigated eight families with a novel subtype of congenital generalized lipodystrophy (CGL4) of whom five members had died from sudden cardiac death during their teenage years. ECG studies revealed features of long-QT syndrome, bradycardia, as well as supraventricular and ventricular tachycardias. Further symptoms comprised myopathy with muscle rippling, skeletal as well as smooth-muscle hypertrophy, leading to impaired gastrointestinal motility and hypertrophic pyloric stenosis in some children. Additionally, we found impaired bone formation with osteopenia, osteoporosis, and atlanto-axial instability. Homozygosity mapping located the gene within 2 Mbp on chromosome 17. Prioritization of 74 candidate genes with GeneDistiller for high expression in muscle and adipocytes suggested PTRF-CAVIN (Polymerase I and transcript release factor/Cavin) as the most probable candidate leading to the detection of homozygous mutations (c.160delG, c.362dupT). PTRF-CAVIN is essential for caveolae biogenesis. These cholesterol-rich plasmalemmal vesicles are involved in signal-transduction and vesicular trafficking and reside primarily on adipocytes, myocytes, and osteoblasts. Absence of PTRF-CAVIN did not influence abundance of its binding partner caveolin-1 and caveolin-3. In patient fibroblasts, however, caveolin-1 failed to localize toward the cell surface and electron microscopy revealed reduction of caveolae to less than 3%. Transfection of full-length PTRF-CAVIN reestablished the presence of caveolae. The loss of caveolae was confirmed by Atomic Force Microscopy (AFM) in combination with fluorescent imaging. PTRF-CAVIN deficiency thus presents the phenotypic spectrum caused by a quintessential lack of functional caveolae.

Show MeSH
Related in: MedlinePlus