Fatal Cardiac Arrhythmia and Long-QT Syndrome in a New Form of Congenital Generalized Lipodystrophy with Muscle Rippling (CGL4) Due to Mutations
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.
Vyšlo v časopise:
Fatal Cardiac Arrhythmia and Long-QT Syndrome in a New Form of Congenital Generalized Lipodystrophy with Muscle Rippling (CGL4) Due to Mutations. PLoS Genet 6(3): e32767. doi:10.1371/journal.pgen.1000874
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1000874
Souhrn
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.
Zdroje
1. GargA
2004 Acquired and inherited lipodystrophies. N Engl J Med 350 1220 1234
2. GargA
AgarwalAK
2009 Lipodystrophies: Disorders of adipose tissue biology. Biochim Biophys Acta 1791 507 513
3. MagreJ
DelepineM
KhalloufE
Gedde-DahlTJr
Van MaldergemL
2001 Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 28 365 370
4. AgarwalAK
AriogluE
De AlmeidaS
AkkocN
TaylorSI
2002 AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet 31 21 23
5. KimCA
DelepineM
BoutetE
El MourabitH
Le LayS
2008 Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J Clin Endocrinol Metab 93 1129 1134
6. CaoH
AlstonL
RuschmanJ
HegeleRA
2008 Heterozygous CAV1 frameshift mutations (MIM 601047) in patients with atypical partial lipodystrophy and hypertriglyceridemia. Lipids Health Dis 7:3.:3
7. RajabA
HeathcoteK
JoshiS
JefferyS
PattonM
2002 Heterogeneity for congenital generalized lipodystrophy in seventeen patients from Oman. Am J Med Genet 110 219 225
8. HeathcoteK
RajabA
MagreJ
SyrrisP
BestiM
2002 Molecular analysis of Berardinelli-Seip congenital lipodystrophy in Oman: evidence for multiple loci. Diabetes 51 1291 1293
9. SimhaV
AgarwalAK
AroninPA
IannacconeST
GargA
2008 Novel subtype of congenital generalized lipodystrophy associated with muscular weakness and cervical spine instability. Am J Med Genet A 146A 2318 2326
10. CrottiL
CelanoG
DagradiF
SchwartzPJ
2008 Congenital long QT syndrome. Orphanet J Rare Dis 3 18
11. SlaughterMH
LohmanTG
BoileauRA
HorswillCA
StillmanRJ
1988 Skinfold equations for estimation of body fatness in children and youth. Hum Biol 60 709 723
12. SinhaR
FischG
TeagueB
TamborlaneWV
BanyasB
2002 Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med 346 802 810
13. HayashiYK
MatsudaC
OgawaM
GotoK
TominagaK
2009 Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy. J Clin Invest 119 2623 2633
14. SeelowD
SchuelkeM
HildebrandtF
NurnbergP
2009 HomozygosityMapper-an interactive approach to homozygosity mapping. Nucleic Acids Res 37 W593 W599
15. SeelowD
SchwarzJM
SchuelkeM
2008 GeneDistiller-distilling candidate genes from linkage intervals. PLoS One 3 e3874 doi:10.1371/journal.pone.0003874
16. HillMM
BastianiM
LuetterforstR
KirkhamM
KirkhamA
2008 PTRF-Cavin, a conserved cytoplasmic protein required for caveola formation and function. Cell 132 113 124
17. BetzRC
SchoserBG
KasperD
RickerK
RamirezA
2001 Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease. Nat Genet 28 218 219
18. LiuL
BrownD
McKeeM
LebrasseurNK
YangD
2008 Deletion of Cavin/PTRF causes global loss of caveolae, dyslipidemia, and glucose intolerance. Cell Metab 8 310 317
19. AboulaichN
VainonenJP
StralforsP
VenerAV
2004 Vectorial proteomics reveal targeting, phosphorylation and specific fragmentation of polymerase I and transcript release factor (PTRF) at the surface of caveolae in human adipocytes. Biochem J 383 237 248
20. FrankPG
PavlidesS
CheungMW
DaumerK
LisantiMP
2008 Role of caveolin-1 in the regulation of lipoprotein metabolism. Am J Physiol Cell Physiol 295 C242 C248
21. ChenL
ChuW
XuY
ChenP
LaoF
2009 Time-series investigation of fused vesicles in microvessel endothelial cells with atomic force microscopy. Microsc Res Tech DOI 10.1002/jemt.20766
22. HuangPL
DawsonTM
BredtDS
SnyderSH
FishmanMC
1993 Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75 1273 1286
23. SatoY
SagamiI
ShimizuT
2004 Identification of caveolin-1-interacting sites in neuronal nitric-oxide synthase. Molecular mechanism for inhibition of NO formation. J Biol Chem 279 8827 8836
24. Garcia-CardenaG
MartasekP
MastersBS
SkiddPM
CouetJ
1997 Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo. J Biol Chem 272 25437 25440
25. SunadaY
OhiH
HaseA
OhiH
HosonoT
2001 Transgenic mice expressing mutant caveolin-3 show severe myopathy associated with increased nNOS activity. Hum Mol Genet 10 173 178
26. LöhnM
FürstenauM
SagachV
ElgerM
SchulzeW
2000 Ignition of calcium sparks in arterial and cardiac muscle through caveolae. Circ Res 87 1034 1039
27. BalijepalliRC
KampTJ
2008 Caveolae, ion channels and cardiac arrhythmias. Prog Biophys Mol Biol 98 149 160
28. VorgerdM
BolzH
PatzoldT
KubischC
MalinJP
1999 Phenotypic variability in rippling muscle disease. Neurology 52 1453 1459
29. LambGD
2005 Rippling muscle disease may be caused by “silent” action potentials in the tubular system of skeletal muscle fibers. Muscle Nerve 31 652 658
30. HansenCG
BrightNA
HowardG
NicholsBJ
2009 SDPR induces membrane curvature and functions in the formation of caveolae. Nat Cell Biol 11 807 814
31. MedinaFA
WilliamsTM
SotgiaF
TanowitzHB
LisantiMP
2006 A novel role for caveolin-1 in B lymphocyte function and the development of thymus-independent immune responses. Cell Cycle 5 1865 1871
32. HartungA
Bitton-WormsK
RechtmanMM
WenzelV
BoergermannJH
2006 Different routes of bone morphogenic protein (BMP) receptor endocytosis influence BMP signaling. Mol Cell Biol 26 7791 7805
33. SawadaN
TaketaniY
AmizukaN
IchikawaM
OgawaC
2007 Caveolin-1 in extracellular matrix vesicles secreted from osteoblasts. Bone 41 52 58
34. MillerSA
DykesDD
PoleskyHF
1988 A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16 1215
35. AllanVJ
2000 Basic immunofluorescence.
AllanVK
Protein localization by fluorescence mciroscopy Oxford Oxford University Press 1 26
36. PartonRG
MoleroJC
FloetenmeyerM
GreenKM
JamesDE
2002 Characterization of a distinct plasma membrane macrodomain in differentiated adipocytes. J Biol Chem 277 46769 46778
37. LuciusH
FriedrichsonT
KurzchaliaTV
LewinGR
2003 Identification of caveolae-like structures on the surface of intact cells using scanning force microscopy. J Membr Biol 194 97 108
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2010 Číslo 3
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Papillorenal Syndrome-Causing Missense Mutations in / Result in Hypomorphic Alleles in Mouse and Human
- Fatal Cardiac Arrhythmia and Long-QT Syndrome in a New Form of Congenital Generalized Lipodystrophy with Muscle Rippling (CGL4) Due to Mutations
- Deciphering Normal Blood Gene Expression Variation—The NOWAC Postgenome Study
- HAP2(GCS1)-Dependent Gamete Fusion Requires a Positively Charged Carboxy-Terminal Domain