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Annachiara De Sandre-giovannoli - One of the best experts on this subject based on the ideXlab platform.
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Restrictive Dermopathy in a Turkish Newborn
Pediatric dermatology, 2010Co-Authors: Gözde Yesil, Annachiara De Sandre-giovannoli, Vera Esteves-vieira, Nicolas Lévy, Lhan Hatipoglu, Beyhan TüysüzAbstract:: A 4-day-old boy presented with tight, translucent skin, prominent vessels, skin erosions, and dysmorphic findings, including hypertelorism, antimongoloid axis, sparse eyelashes and eyebrows, pinched nose, natal teeth, microretrognathia, and an “o-shaped” mouth. Multiple joint contractures, dysplastic clavicles, and thin ribs were also observed. He died at 2 weeks of age of respiratory distress. The patient was diagnosed as being affected with Restrictive Dermopathy, which is a rare, lethal genodermatosis caused by recessive mutations of the zinc metalloproteinase ZMPSTE24 gene or less frequently, by dominant lamin A/C gene mutations. Direct sequencing of the ZMPSTE24 gene was performed, and the most common, homozygous, inactivating mutation in exon 9 was identified in the patient (c.1085_1086insT; p.Leu362PhefsX19). Autosomal recessive transmission was confirmed by parental DNA analysis. After genetic counseling, a prenatal diagnosis could be performed during the subsequent pregnancy. ZMPSTE24 screening was performed by direct sequencing and fluorescent fragment analysis on DNA derived from a chorionic villus sample after exclusion of maternal contamination. The fetus had inherited both normal parental alleles, avoiding the recurrence of the disease.
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Novel frameshifting mutations of the ZMPSTE24 gene in two siblings affected with Restrictive Dermopathy and review of the mutations described in the literature
American Journal of Medical Genetics Part A, 2010Co-Authors: Robert Smigiel, Vera Esteves-vieira, Nicolas Lévy, Aleksandra Jakubiak, Katarzyna Szela, Tomasz Jurek, Agnieszka Hałoń, Annachiara De Sandre-giovannoliAbstract:Restrictive Dermopathy (RD) is a rare, severe, lethal genodermatosis in which tautness of the skin causes fetal akinesia or hypokinesia deformation sequence. To date, about 60 cases of RD were described. The signs of the disease are very characteristic and include intrauterine growth retardation, thin, tightly adherent translucent skin, superficial vessels, typical facial dysmorphism as well as generalized joint contractures. The syndrome is caused in most cases by ZMPSTE24 autosomal recessive mutations, or, less frequently, by LMNA autosomal dominant mutations. We report on two brothers affected with RD, who died in the neonatal period. Molecular analyses were performed in the second child, for whom biological material was available, and both parents. Compound heterozygous frameshifting mutations were identified in exon 1 (c.50delA) and exon 5 (c.584_585delAT) of the ZMPSTE24 gene. The autosomal recessive inheritance was confirmed by the parents' genomic analysis. Besides, a review of the mutations causing RD is made. © 2010 Wiley-Liss, Inc.
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Novel frameshifting mutations of the ZMPSTE24 gene in two siblings affected with Restrictive Dermopathy and review of the mutations described in the literature.
American journal of medical genetics. Part A, 2010Co-Authors: Robert Smigiel, Vera Esteves-vieira, Nicolas Lévy, Aleksandra Jakubiak, Katarzyna Szela, Agnieszka Halon, Tomasz Jurek, Annachiara De Sandre-giovannoliAbstract:Restrictive Dermopathy (RD) is a rare, severe, lethal genodermatosis in which tautness of the skin causes fetal akinesia or hypokinesia deformation sequence. To date, about 60 cases of RD were described. The signs of the disease are very characteristic and include intrauterine growth retardation, thin, tightly adherent translucent skin, superficial vessels, typical facial dysmorphism as well as generalized joint contractures. The syndrome is caused in most cases by ZMPSTE24 autosomal recessive mutations, or, less frequently, by LMNA autosomal dominant mutations. We report on two brothers affected with RD, who died in the neonatal period. Molecular analyses were performed in the second child, for whom biological material was available, and both parents. Compound heterozygous frameshifting mutations were identified in exon 1 (c.50delA) and exon 5 (c.584_585delAT) of the ZMPSTE24 gene. The autosomal recessive inheritance was confirmed by the parents' genomic analysis. Besides, a review of the mutations causing RD is made.
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HGPS and related premature aging disorders: from genomic identification to the first therapeutic approaches.
Mechanisms of ageing and development, 2008Co-Authors: Sandrine Pereira, Claire Navarro, Annachiara De Sandre-giovannoli, Vera Esteves-vieira, Patrice Bourgeois, Pierre Cau, Nicolas LévyAbstract:Progeroid syndromes are heritable human disorders displaying features that recall premature ageing. In these syndromes, premature aging is defined as "segmental" since only some of its features are accelerated. A number of cellular biological pathways have been linked to aging, including regulation of the insulin/growth hormone axis, pathways involving ROS metabolism, caloric restriction, and DNA repair. The number of identified genes associated with progeroid syndromes has increased in recent years, possibly shedding light as well on mechanisms underlying ageing in general. Among these, premature aging syndromes related to alterations of the LMNA gene have recently been identified. This review focuses on Hutchinson-Gilford Progeria syndrome and Restrictive Dermopathy, two well-characterized Lamin-associated premature aging syndromes, pointing out the current knowledge concerning their pathophysiology and the development of possible therapeutic approaches.
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Altered splicing in prelamin A-associated premature aging phenotypes.
Progress in molecular and subcellular biology, 2006Co-Authors: Annachiara De Sandre-giovannoli, Nicolas LévyAbstract:Hutchinson-Gilford progeria (HGPS), a rare and severe developmental disorder characterized by features recalling premature aging, and Restrictive Dermopathy (RD), a neonatal lethal genodermatosis, have recently been identified as being primary or secondary "laminopathies." These are heterogeneous disorders due to altered function of lamins A/C or related proteins. In physiological conditions, mature lamin A is obtained through a series of post-translational processing steps performed on a protein precursor, prelamin A. The major pathophysiological mechanism involved in progeria is an aberrant splicing of pre-mRNAs issued from the LMNA gene, due to a de novo heterozygous point mutation, leading to the production and accumulation of truncated lamin A precursors. Aberrant splicing of prelamin A pre-mRNAs causing the production of more extensively truncated precursors is involved in the allelic disease Restrictive Dermopathy. Other Restrictive Dermopathy cases are due to the inactivation of a key enzyme involved in the maturation of lamin A precursors (ZMPSTE24). In functional terms, all these conditions share the same pathophysiological basis: intranuclear accumulation of lamin A precursors, which cannot be fully processed (due to primary or secondary events) and exert toxic, dominant negative effects on nuclear homeostasis. Most other laminopathies are due to autosomal dominant LMNA point mutations inferred to cause single amino acid substitutions. In any case, the impact of these mutations on pre-mRNA splicing has rarely been assessed. These disorders affect different tissues and organs, mainly including bone, skin, striated muscles, adipose tissue, vessels, and peripheral nerves in isolated or combined fashions, giving rise to syndromes whose severity ranges from mild to perinatally lethal. In this chapter we review the structure and functions of lamins A/C in physiological and pathological conditions, describe their known or putative roles, namely, in the pathogenesis of HGPS and RD in relation to existing animal models, and envisage possible targeted therapeutic strategies on the basis of recent research results.
Abhimanyu Garg - One of the best experts on this subject based on the ideXlab platform.
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Progeroid syndrome patients with ZMPSTE24 deficiency could benefit when treated with rapamycin and dimethylsulfoxide.
Cold Spring Harbor molecular case studies, 2016Co-Authors: Baris Akinci, Abhimanyu Garg, Shireesha Sankella, Christopher J. Gilpin, Keiichi Ozono, Anil K. AgarwalAbstract:Patients with progeroid syndromes such as mandibuloacral dysplasia, type B (MADB) and Restrictive Dermopathy (RD) harbor mutations in zinc metalloproteinase (ZMPSTE24), an enzyme essential for posttranslational proteolysis of prelamin A to form mature lamin A. Dermal fibroblasts from these patients show increased nuclear dysmorphology and reduced proliferation; however, the efficacy of various pharmacological agents in reversing these cellular phenotypes remains unknown. In this study, fibroblasts from MADB patients exhibited marked nuclear abnormalities and reduced proliferation that improved upon treatment with rapamycin and dimethylsulfoxide but not with other agents, including farnesyl transferase inhibitors. Surprisingly, fibroblasts from an RD patient with a homozygous null mutation in ZMPSTE24, resulting in exclusive accumulation of prelamin A with no lamin A on immunoblotting of cellular lysate, exhibited few nuclear abnormalities and near-normal cellular proliferation. An unbiased proteomic analysis of the cellular lysate from RD fibroblasts revealed a lack of processing of vimentin, a cytoskeletal protein. Interestingly, the assembly of the vimentin microfibrils in MADB fibroblasts improved with rapamycin and dimethylsulfoxide. We conclude that rapamycin and dimethylsulfoxide are beneficial for improving nuclear morphology and cell proliferation of MADB fibroblasts. Data from a single RD patient's fibroblasts also suggest that prelamin A accumulation by itself might not be detrimental and requires additional alterations at the cellular level to manifest the phenotype.
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Homozygous null mutations in ZMPSTE24 in Restrictive Dermopathy: Evidence of genetic heterogeneity
Clinical genetics, 2010Co-Authors: Zahid Ahmad, Anil K. Agarwal, Shubha R. Phadke, Ellen Arch, Jonathan Glass, Abhimanyu GargAbstract:Restrictive Dermopathy (RD) results in stillbirth or early neonatal death. RD is characterized by prematurity, intrauterine growth retardation, fixed facial expression, micrognathia, mouth in the “o” position, rigid and tense skin with erosions and denudations and multiple joint contractures. Nearly all 25 previously reported neonates with RD had homozygous or compound heterozygous null mutations in the ZMPSTE24 gene. Here, we report 3 new cases of RD; all died within three weeks of birth. One of them had a previously reported homozygous c.1085dupT (p.Leu362PhefsX19) mutation, a second case had a novel homozygous c.1020G>A (p.Trp340X) null mutation in ZMPSTE24, and finally, a stillborn with features of RD except for the presence of tapering rather than rounded, bulbous digits, harbored no disease-causing mutations in LMNA or ZMPSTE24. In the newborn with a novel ZMPSTE24 mutation, unique features included butterfly-shaped thoracic 5th vertebra and the bulbous appearance of the distal clavicles. Skin biopsies from both the stillborn fetus and the newborn with c.1020G>A ZMPSTE24 mutation showed absence of elastic fibers throughout the dermis. This report provides evidence of genetic heterogeneity among RD and concludes that there may be an additional locus for RD which remains to be identified.
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a homozygous mutation in the lamin a c gene associated with a novel syndrome of arthropathy tendinous calcinosis and progeroid features
The Journal of Clinical Endocrinology and Metabolism, 2006Co-Authors: Hilde Van Esch, Anil K. Agarwal, Jean-pierre Fryns, Philippe Debeer, Abhimanyu GargAbstract:Context: Mutations in the lamin A/C (LMNA) gene have been reported in a wide variety of disorders, including lipodystrophies, cardiomyopathy, muscular dystrophies, neuropathy, mandibuloacral dysplasia, Restrictive Dermopathy, and progeria. Objective: The objective of this study was to carry out mutational analysis of LMNA in a patient with a novel syndrome of arthropathy, tendinous calcinosis, and progeroid features. Design: The study design was a descriptive case report. Setting: The study was performed at a referral center. Patient: A 44-yr-old male of European descent with an autosomal recessive arthropathy syndrome affecting predominantly the distal femora and proximal tibia in the knee with tendinous calcifications was studied. He also had progeroid features, such as pinched nose and micrognathia, cataract, alopecia, generalized lipodystrophy, and sclerodermatous skin. Main Outcome Measures: The main outcome measures were mutational analysis of lamin A/C (LMNA) and its processing enzyme, zinc metallo...
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Laminopathies: multisystem dystrophy syndromes.
Molecular genetics and metabolism, 2005Co-Authors: Katherine N. Jacob, Abhimanyu GargAbstract:Laminopathies are a heterogeneous group of genetic disorders due to abnormalities in type A lamins and can manifest varied clinical features affecting many organs including the skeletal and cardiac muscle, adipose tissue, nervous system, cutaneous tissue, and bone. Mutations in the gene encoding lamins A and C (LMNA) cause primary laminopathies, including various types of lipodystrophies, muscular dystrophies and progeroid syndromes, mandibuloacral dysplasia, dilated cardiomyopathies, and Restrictive Dermopathy. The secondary laminopathies are due to mutations in ZMPSTE24 gene which encodes for a zinc metalloproteinase involved in processing of prelamin A into mature lamin A and cause mandibuloacral dysplasia and Restrictive Dermopathy. Skin fibroblast cells from many patients with laminopathies show a range of abnormal nuclear morphology including bleb formation, honeycombing, and presence of multi-lobulated nuclei. The mechanisms by which mutations in LMNA gene cause multisystem dystrophy are an active area of current investigation. Further studies are needed to understand the underlying mechanisms of marked pleiotropy in laminopathies.
Nicolas Lévy - One of the best experts on this subject based on the ideXlab platform.
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A Heterozygous ZMPSTE24 Mutation Associated with Severe Metabolic Syndrome, Ectopic Fat Accumulation, and Dilated Cardiomyopathy
Cells, 2016Co-Authors: Damien Galant, Patrice Roll, Bénédicte Gaborit, Camille Desgrouas, Inès Abdesselam, Monique Bernard, Nicolas Lévy, Françoise Merono, Catherine Coirault, Arnaud LagardeAbstract:ZMPSTE24 encodes the only metalloprotease, which transforms prelamin into mature lamin A. Up to now, mutations in ZMPSTE24 have been linked to Restrictive Dermopathy (RD), Progeria or Mandibulo-Acral Dysplasia (MAD). We report here the phenotype of a patient referred for severe metabolic syndrome and cardiomyopathy, carrying a mutation in ZMPSTE24. The patient presented with a partial lipodystrophic syndrome associating hypertriglyceridemia, early onset type 2 diabetes, and android obesity with truncal and abdominal fat accumulation but without subcutaneous lipoatrophy. Other clinical features included acanthosis nigricans, liver steatosis, dilated cardiomyopathy, and high myocardial and hepatic triglycerides content. Mutated fibroblasts from the patient showed increased nuclear shape abnormalities and premature senescence as demonstrated by a decreased Population Doubling Level, an increased beta-galactosidase activity and a decreased BrdU incorporation rate. Reduced prelamin A expression by siRNA targeted toward LMNA transcripts resulted in decreased nuclear anomalies. We show here that a central obesity without subcutaneous lipoatrophy is associated with a laminopathy due to a heterozygous missense mutation in ZMPSTE24. Given the high prevalence of metabolic syndrome and android obesity in the general population, and in the absence of familial study, the causative link between mutation and phenotype cannot be formally established. Nevertheless, altered lamina architecture observed in mutated fibroblasts are responsible for premature cellular senescence and could contribute to the phenotype observed in this patient.
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Restrictive Dermopathy in a Turkish Newborn
Pediatric dermatology, 2010Co-Authors: Gözde Yesil, Annachiara De Sandre-giovannoli, Vera Esteves-vieira, Nicolas Lévy, Lhan Hatipoglu, Beyhan TüysüzAbstract:: A 4-day-old boy presented with tight, translucent skin, prominent vessels, skin erosions, and dysmorphic findings, including hypertelorism, antimongoloid axis, sparse eyelashes and eyebrows, pinched nose, natal teeth, microretrognathia, and an “o-shaped” mouth. Multiple joint contractures, dysplastic clavicles, and thin ribs were also observed. He died at 2 weeks of age of respiratory distress. The patient was diagnosed as being affected with Restrictive Dermopathy, which is a rare, lethal genodermatosis caused by recessive mutations of the zinc metalloproteinase ZMPSTE24 gene or less frequently, by dominant lamin A/C gene mutations. Direct sequencing of the ZMPSTE24 gene was performed, and the most common, homozygous, inactivating mutation in exon 9 was identified in the patient (c.1085_1086insT; p.Leu362PhefsX19). Autosomal recessive transmission was confirmed by parental DNA analysis. After genetic counseling, a prenatal diagnosis could be performed during the subsequent pregnancy. ZMPSTE24 screening was performed by direct sequencing and fluorescent fragment analysis on DNA derived from a chorionic villus sample after exclusion of maternal contamination. The fetus had inherited both normal parental alleles, avoiding the recurrence of the disease.
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Prelamin A processing and functional effects in Restrictive Dermopathy.
Cell cycle (Georgetown Tex.), 2010Co-Authors: Marta Columbaro, Claire Navarro, Nicolas Lévy, Elisabetta Mattioli, Cristina Capanni, Stefano Squarzoni, Vittoria Cenni, Elisa Schena, Rosalba Del Coco, Daria CamozziAbstract:Laminopathies are an heterogeneous group of human disorders caused by mutations in the lamin A/C gene or in genes coding for lamin-binding proteins. They include several tissue-specific disorders (e.g., Emery-Dreifuss muscular distrophy and dilated cardiomyopathy with conduction defects) or systemic forms including the most severe phenotypes: Hutchinson-Gilford progeria syndrome (HGPS) and Restrictive Dermopathy (RD).1 RD is a lethal neonatal laminopathy causing bone resorption of clavicles, tight translucent skin, anomalous facial features and arthrogryposis.2 RD is a secondary laminopathy, since it is associated with mutations of a lamin-binding protein, the endoprotease ZMPSTE24 involved in lamin A precursor (prelamin A) post-translational processing.3 A common mutation in the ZMPSTE24 gene (c.1085_1086InsT) has been characterized in most RD patients leading to impaired protein expression and prelamin A accumulation in cells. Prelamin A processing consists of four steps: farnesylation of the C-terminal CaaX motif by the enzyme protein farnesyl-transferase, cleavage of the last three aminoacids by ZMPSTE24, carboxymethylation of the C-terminal cysteine by Icmt methyl-transferase and proteolytic removal of the last 18 aminoacids by ZMPSTE24. Thus, four processing intermediates are formed during prelamin A maturation.4 Since also the RCE1 endoprotease catalyses the first cleavage step,3 ZMPSTE24 absence should cause accumulation of farnesylated-carboxymethylated prelamin A. Accumulation of different prelamin A forms causes different effects on nuclear organization:5,6 accumulating farnesylated prelamin A causes nuclear enlargement and mis-shapening, along with changes in the localization pattern of heterochromatin-associated proteins HP1 and tri-H3K9,7 while accumulating non-farnesylated prelamin A produces intranuclear prelamin A and heterochromatin clusters, with re-localization of heterochromatin markers, without nuclear enlargement.5 Also, impaired lamin maturation promotes DNA damage accumulation.8,9 We analyzed prelamin A processing in four different RD cell lines bearing the same ZMPSTE24 mutation2 using an antibody (Sc-6214) directed to a C-terminal epitope of prelamin A.10 The experiments were performed at low (5–12) and at high (16–22) culture passage numbers. Low passage RD cells showed high prelamin A levels, but undetectable mature lamin A; prelamin A was localized exclusively at the nuclear rim by both immunofluorescence and colloidal gold-immunoelectron microscopy; western blot analysis confirmed this data (part A). TEM analysis showed severe nuclear morphology defects (enlarged size, envelope invaginations) and heterochromatin disorganization (areas devoid of heterochromatin) in 10–30% of cells, while most of RD nuclei were normally shaped, though presented nuclear envelope duplications and severe heterochromatin loss (part A). Surprisingly, at high passage numbers, labeling by Sc-6214 was reduced in about 90% of nuclei and undetectable in several cells; only highly dysmorphic nuclei showed intense prelamin A staining. Ultrastructural analysis of high passage fibroblasts revealed improved peripheral heterochromatin organization in 50% of the normally shaped nuclei and peripheral heterochromatin clumps in 5% of nuclei. At this stage (p.16–22), western blot analysis revealed prelamin A as a doublet (part B). To characterize prelamin A forms, we used selective antibodies: 1188-1 (directed to the full-length prelamin A-specific C-terminus sequence) detects both non-farnesylated and farnesylated prelamin A, provided that the CSIM terminal sequence is maintained; 1188-2 (directed to the farnesylated prelamin A-specific C-terminus lacking the SIM sequence) detects farnesylated-carboxymethylated prelamin A.4 1188-1 revealed intense fluorescence at low passage number in both normally shaped and dysmorphic nuclei indicating high levels of full-length prelamin A accumulation, while 1188-2 labelled only dysmorphic nuclei, suggesting that farnesylated-carboxymethylated prelamin A was less represented. At high passage numbers, 1188-2 labelled the normally shaped nuclei, while both antibodies revealed intense fluorescence in highly dysmorphic enlarged nuclei (part C). 1188-1 and SC-6214, but not 1188-2, revealed the prelamin A band in western blot analysis at low passages, confirming the small amount of farnesylated-carboxymethylated prelamin A (non-farnesylated, full-length prelamin A-accumulating control was obtained with Mevinolin11). On the contrary, 1188-2 revealed a faint band in very high passage (p.25) cells, which did not accumulate the prelamin A form(s) detectable by 1188-1 or Sc-6214 (part C). We then immunoprecipitated the whole prelamin A exploiting an anti-lamin A/C N-terminus antibody and revealed the immunoprecipitated bands with anti-prelamin A or anti-farnesyl antibodies confirming farnesylation of prelamin A bands (panel D). Searching for functional defects in RD nuclei, we labeled prelamin A and the heterochromatin marker tri-H3K9 or tri-H4K20. At any passage, dysmorphic nuclei accumulating both prelamin A forms, showed altered distribution (i.e., without clusters) or loss (in some nuclei) of tri-H3K9 fluorescence and disorganization of heterochromatic areas (part D); normally shaped nuclei accumulating prelamin A, showed mostly unaffected tri-H3K9, which was only slightly more clustered in a low percentage of nuclei. Analogous alterations were revealed by tri-H4K20 labelling. In conclusion, we detected significant changes in prelamin A levels and post-translational modifications in all cell lines, depending on the passage number. So far, increased prelamin A levels have been observed in progeroid laminopathies, depending on the passage number or on the patient's age.7,12 We show that accumulation of full-length, farnesylated protein form prevails in RD fibroblasts, and that a subpopulation of cells accumulates high levels of both full-length and farnesylated-carboxymethylated prelamin A. Finally, we demonstrate that accumulation of both forms is associated with the most severe abnormalities, i.e., nuclear enlargement and mis-shaping and severe chromatin defects. Our data suggest that the first cleavage step in prelamin A post-translational processing is mostly carried out by the ZMPSTE24 endoprotease, which is not efficiently replaced by other enzyme(s) in RD cells. However, our results suggest activation of alternative endoproteolytic processes, probably when high prelamin A levels are reached.
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Novel frameshifting mutations of the ZMPSTE24 gene in two siblings affected with Restrictive Dermopathy and review of the mutations described in the literature
American Journal of Medical Genetics Part A, 2010Co-Authors: Robert Smigiel, Vera Esteves-vieira, Nicolas Lévy, Aleksandra Jakubiak, Katarzyna Szela, Tomasz Jurek, Agnieszka Hałoń, Annachiara De Sandre-giovannoliAbstract:Restrictive Dermopathy (RD) is a rare, severe, lethal genodermatosis in which tautness of the skin causes fetal akinesia or hypokinesia deformation sequence. To date, about 60 cases of RD were described. The signs of the disease are very characteristic and include intrauterine growth retardation, thin, tightly adherent translucent skin, superficial vessels, typical facial dysmorphism as well as generalized joint contractures. The syndrome is caused in most cases by ZMPSTE24 autosomal recessive mutations, or, less frequently, by LMNA autosomal dominant mutations. We report on two brothers affected with RD, who died in the neonatal period. Molecular analyses were performed in the second child, for whom biological material was available, and both parents. Compound heterozygous frameshifting mutations were identified in exon 1 (c.50delA) and exon 5 (c.584_585delAT) of the ZMPSTE24 gene. The autosomal recessive inheritance was confirmed by the parents' genomic analysis. Besides, a review of the mutations causing RD is made. © 2010 Wiley-Liss, Inc.
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Novel frameshifting mutations of the ZMPSTE24 gene in two siblings affected with Restrictive Dermopathy and review of the mutations described in the literature.
American journal of medical genetics. Part A, 2010Co-Authors: Robert Smigiel, Vera Esteves-vieira, Nicolas Lévy, Aleksandra Jakubiak, Katarzyna Szela, Agnieszka Halon, Tomasz Jurek, Annachiara De Sandre-giovannoliAbstract:Restrictive Dermopathy (RD) is a rare, severe, lethal genodermatosis in which tautness of the skin causes fetal akinesia or hypokinesia deformation sequence. To date, about 60 cases of RD were described. The signs of the disease are very characteristic and include intrauterine growth retardation, thin, tightly adherent translucent skin, superficial vessels, typical facial dysmorphism as well as generalized joint contractures. The syndrome is caused in most cases by ZMPSTE24 autosomal recessive mutations, or, less frequently, by LMNA autosomal dominant mutations. We report on two brothers affected with RD, who died in the neonatal period. Molecular analyses were performed in the second child, for whom biological material was available, and both parents. Compound heterozygous frameshifting mutations were identified in exon 1 (c.50delA) and exon 5 (c.584_585delAT) of the ZMPSTE24 gene. The autosomal recessive inheritance was confirmed by the parents' genomic analysis. Besides, a review of the mutations causing RD is made.
Claire Navarro - One of the best experts on this subject based on the ideXlab platform.
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New ZMPSTE24 (FACE1) mutations in patients affected with Restrictive Dermopathy or related progeroid syndromes and mutation update
European Journal of Human Genetics, 2013Co-Authors: Claire Navarro, Patrice Roll, Vera Esteves-vieira, Sebastien Courrier, Amandine Boyer, Thuy Duong Nguyen, Le Thi Thanh Huong, Peter Meinke, Winnie Schröder, Valérie Cormier-daireAbstract:Restrictive Dermopathy (RD) is a rare and extremely severe congenital genodermatosis, characterized by a tight rigid skin with erosions at flexure sites, multiple joint contractures, low bone density and pulmonary insufficiency generally leading to death in the perinatal period. RD is caused in most patients by compound heterozygous or homozygous ZMPSTE24 null mutations. This gene encodes a metalloprotease specifically involved in lamin A post-translational processing. Here, we report a total of 16 families for whom diagnosis and molecular defects were clearly established. Among them, we report seven new ZMPSTE24 mutations, identified in classical RD or Mandibulo-acral dysplasia (MAD) affected patients. We also report nine families with one or two affected children carrying the common, homozygous thymine insertion in exon 9 and demonstrate the lack of a founder effect. In addition, we describe several new ZMPSTE24 variants identified in unaffected controls or in patients affected with non-classical progeroid syndromes. In addition, this mutation update includes a comprehensive search of the literature on previously described ZMPSTE24 mutations and associated phenotypes. Our comprehensive analysis of the molecular pathology supported the general rule: complete loss-of-function of ZMPSTE24 leads to RD, whereas other less severe phenotypes are associated with at least one haploinsufficient allele.
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Prelamin A processing and functional effects in Restrictive Dermopathy.
Cell cycle (Georgetown Tex.), 2010Co-Authors: Marta Columbaro, Claire Navarro, Nicolas Lévy, Elisabetta Mattioli, Cristina Capanni, Stefano Squarzoni, Vittoria Cenni, Elisa Schena, Rosalba Del Coco, Daria CamozziAbstract:Laminopathies are an heterogeneous group of human disorders caused by mutations in the lamin A/C gene or in genes coding for lamin-binding proteins. They include several tissue-specific disorders (e.g., Emery-Dreifuss muscular distrophy and dilated cardiomyopathy with conduction defects) or systemic forms including the most severe phenotypes: Hutchinson-Gilford progeria syndrome (HGPS) and Restrictive Dermopathy (RD).1 RD is a lethal neonatal laminopathy causing bone resorption of clavicles, tight translucent skin, anomalous facial features and arthrogryposis.2 RD is a secondary laminopathy, since it is associated with mutations of a lamin-binding protein, the endoprotease ZMPSTE24 involved in lamin A precursor (prelamin A) post-translational processing.3 A common mutation in the ZMPSTE24 gene (c.1085_1086InsT) has been characterized in most RD patients leading to impaired protein expression and prelamin A accumulation in cells. Prelamin A processing consists of four steps: farnesylation of the C-terminal CaaX motif by the enzyme protein farnesyl-transferase, cleavage of the last three aminoacids by ZMPSTE24, carboxymethylation of the C-terminal cysteine by Icmt methyl-transferase and proteolytic removal of the last 18 aminoacids by ZMPSTE24. Thus, four processing intermediates are formed during prelamin A maturation.4 Since also the RCE1 endoprotease catalyses the first cleavage step,3 ZMPSTE24 absence should cause accumulation of farnesylated-carboxymethylated prelamin A. Accumulation of different prelamin A forms causes different effects on nuclear organization:5,6 accumulating farnesylated prelamin A causes nuclear enlargement and mis-shapening, along with changes in the localization pattern of heterochromatin-associated proteins HP1 and tri-H3K9,7 while accumulating non-farnesylated prelamin A produces intranuclear prelamin A and heterochromatin clusters, with re-localization of heterochromatin markers, without nuclear enlargement.5 Also, impaired lamin maturation promotes DNA damage accumulation.8,9 We analyzed prelamin A processing in four different RD cell lines bearing the same ZMPSTE24 mutation2 using an antibody (Sc-6214) directed to a C-terminal epitope of prelamin A.10 The experiments were performed at low (5–12) and at high (16–22) culture passage numbers. Low passage RD cells showed high prelamin A levels, but undetectable mature lamin A; prelamin A was localized exclusively at the nuclear rim by both immunofluorescence and colloidal gold-immunoelectron microscopy; western blot analysis confirmed this data (part A). TEM analysis showed severe nuclear morphology defects (enlarged size, envelope invaginations) and heterochromatin disorganization (areas devoid of heterochromatin) in 10–30% of cells, while most of RD nuclei were normally shaped, though presented nuclear envelope duplications and severe heterochromatin loss (part A). Surprisingly, at high passage numbers, labeling by Sc-6214 was reduced in about 90% of nuclei and undetectable in several cells; only highly dysmorphic nuclei showed intense prelamin A staining. Ultrastructural analysis of high passage fibroblasts revealed improved peripheral heterochromatin organization in 50% of the normally shaped nuclei and peripheral heterochromatin clumps in 5% of nuclei. At this stage (p.16–22), western blot analysis revealed prelamin A as a doublet (part B). To characterize prelamin A forms, we used selective antibodies: 1188-1 (directed to the full-length prelamin A-specific C-terminus sequence) detects both non-farnesylated and farnesylated prelamin A, provided that the CSIM terminal sequence is maintained; 1188-2 (directed to the farnesylated prelamin A-specific C-terminus lacking the SIM sequence) detects farnesylated-carboxymethylated prelamin A.4 1188-1 revealed intense fluorescence at low passage number in both normally shaped and dysmorphic nuclei indicating high levels of full-length prelamin A accumulation, while 1188-2 labelled only dysmorphic nuclei, suggesting that farnesylated-carboxymethylated prelamin A was less represented. At high passage numbers, 1188-2 labelled the normally shaped nuclei, while both antibodies revealed intense fluorescence in highly dysmorphic enlarged nuclei (part C). 1188-1 and SC-6214, but not 1188-2, revealed the prelamin A band in western blot analysis at low passages, confirming the small amount of farnesylated-carboxymethylated prelamin A (non-farnesylated, full-length prelamin A-accumulating control was obtained with Mevinolin11). On the contrary, 1188-2 revealed a faint band in very high passage (p.25) cells, which did not accumulate the prelamin A form(s) detectable by 1188-1 or Sc-6214 (part C). We then immunoprecipitated the whole prelamin A exploiting an anti-lamin A/C N-terminus antibody and revealed the immunoprecipitated bands with anti-prelamin A or anti-farnesyl antibodies confirming farnesylation of prelamin A bands (panel D). Searching for functional defects in RD nuclei, we labeled prelamin A and the heterochromatin marker tri-H3K9 or tri-H4K20. At any passage, dysmorphic nuclei accumulating both prelamin A forms, showed altered distribution (i.e., without clusters) or loss (in some nuclei) of tri-H3K9 fluorescence and disorganization of heterochromatic areas (part D); normally shaped nuclei accumulating prelamin A, showed mostly unaffected tri-H3K9, which was only slightly more clustered in a low percentage of nuclei. Analogous alterations were revealed by tri-H4K20 labelling. In conclusion, we detected significant changes in prelamin A levels and post-translational modifications in all cell lines, depending on the passage number. So far, increased prelamin A levels have been observed in progeroid laminopathies, depending on the passage number or on the patient's age.7,12 We show that accumulation of full-length, farnesylated protein form prevails in RD fibroblasts, and that a subpopulation of cells accumulates high levels of both full-length and farnesylated-carboxymethylated prelamin A. Finally, we demonstrate that accumulation of both forms is associated with the most severe abnormalities, i.e., nuclear enlargement and mis-shaping and severe chromatin defects. Our data suggest that the first cleavage step in prelamin A post-translational processing is mostly carried out by the ZMPSTE24 endoprotease, which is not efficiently replaced by other enzyme(s) in RD cells. However, our results suggest activation of alternative endoproteolytic processes, probably when high prelamin A levels are reached.
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HGPS and related premature aging disorders: from genomic identification to the first therapeutic approaches.
Mechanisms of ageing and development, 2008Co-Authors: Sandrine Pereira, Claire Navarro, Annachiara De Sandre-giovannoli, Vera Esteves-vieira, Patrice Bourgeois, Pierre Cau, Nicolas LévyAbstract:Progeroid syndromes are heritable human disorders displaying features that recall premature ageing. In these syndromes, premature aging is defined as "segmental" since only some of its features are accelerated. A number of cellular biological pathways have been linked to aging, including regulation of the insulin/growth hormone axis, pathways involving ROS metabolism, caloric restriction, and DNA repair. The number of identified genes associated with progeroid syndromes has increased in recent years, possibly shedding light as well on mechanisms underlying ageing in general. Among these, premature aging syndromes related to alterations of the LMNA gene have recently been identified. This review focuses on Hutchinson-Gilford Progeria syndrome and Restrictive Dermopathy, two well-characterized Lamin-associated premature aging syndromes, pointing out the current knowledge concerning their pathophysiology and the development of possible therapeutic approaches.
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Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify Restrictive Dermopathy as a lethal neonatal laminopathy
Human Molecular Genetics, 2004Co-Authors: Claire Navarro, Annachiara De Sandre-giovannoli, Amandine Boyer, Rafaelle Bernard, Irène Boccaccio, David Geneviève, Smail Hadj-rabia, Caroline Gaudy-marqueste, Henk Smitt, Pierre VabresAbstract:Restrictive Dermopathy (RD), also called tight skin contracture syndrome (OMIM 275210), is a rare disorder mainly characterized by intrauterine growth retardation, tight and rigid skin with erosions, prominent superficial vasculature and epidermal hyperkeratosis, facial features (small mouth, small pinched nose and micrognathia), sparse/absent eyelashes and eyebrows, mineralization defects of the skull, thin dysplastic clavicles, pulmonary hypoplasia, multiple joint contractures and an early neonatal lethal course. Liveborn children usually die within the first week of life. The overall prevalence of consanguineous cases suggested an autosomal recessive inheritance. We explored nine fetuses/newborns children with RD. Two were found to have an heterozygous splicing mutation in the LMNA gene, leading to the complete or partial loss of exon 11 in mRNAs encoding Lamin A and resulting in a truncated Prelamin A protein. Lamins are major constituents of the nuclear lamina, a filamentous meshwork underlying the inner nuclear envelope. In the other seven patients, a unique heterozygous insertion leading to the creation of a premature termination codon was identified in the gene ZMPSTE24, also known as FACE-1 in human. This gene encodes a metalloproteinase specifically involved in the post-translational processing of Lamin A precursor. In all patients carrying a ZMPSTE24 mutation, loss of expression of Lamin A as well as abnormal patterns of nuclear sizes and shapes and mislocalization of Lamin-associated proteins was evidenced. Our results indicate that a common pathogenetic pathway, involving defects of the nuclear lamina and matrix, is involved in all RD cases. RD is thus one of the most deleterious laminopathies identified so far in humans caused by (primary or secondary) A-type Lamin defects and nuclear structural and functional alterations.
Jeffrey H. Miner - One of the best experts on this subject based on the ideXlab platform.
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Homozygous and compound heterozygous mutations in ZMPSTE24 cause the laminopathy Restrictive Dermopathy
The Journal of investigative dermatology, 2005Co-Authors: Casey L. Moulson, Jennifer M. Gardner, Allard C. Van Der Wal, J. Henk Sillevis Smitt, Johanna M. Van Hagen, Jeffrey H. MinerAbstract:Restrictive Dermopathy (RD) is a lethal human genetic disorder characterized by very tight, thin, easily eroded skin, rocker bottom feet, and joint contractures. This disease was recently reported to be associated with a single heterozygous mutation in ZMPSTE24 and hypothesized to be a digenic disorder (Navarro et al, Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify Restrictive Dermopathy as a lethal neonatal laminopathy. Hum Mol Genet 13:2493-2503, 2004). ZMPSTE24 encodes an enzyme necessary for the correct processing and maturation of lamin A, an intermediate filament component of the nuclear envelope. Here we present four unrelated patients with homozygous mutations in ZMPSTE24 and a fifth patient with compound heterozygous mutations in ZMPSTE24. Two of the three different mutations we found are novel, and all are single base insertions that result in messenger RNA frameshifts. As a consequence of the presumed lack of ZMPSTE24 activity, prelamin A, the unprocessed toxic form of lamin A, was detected in the nuclei of both cultured cells and tissue from RD patients, but not in control nuclei. Abnormally aggregated lamin A/C was also observed. These results indicate that RD is an autosomal recessive laminopathy caused by inactivating ZMPSTE24 mutations that result in defective processing and nuclear accumulation of prelamin A.
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Cloning of wrinkle-free, a previously uncharacterized mouse mutation, reveals crucial roles for fatty acid transport protein 4 in skin and hair development
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Casey L. Moulson, Daniel R. Martin, Jesse J. Lugus, Jean E. Schaffer, Anne C. Lind, Jeffrey H. MinerAbstract:Wrinkle-free (wrfr) is a previously uncharacterized, spontaneous, autosomal recessive mouse mutation resulting in very tight, thick skin. wrfr mutant mice exhibit severe breathing difficulties secondary to their tight skin and die shortly after birth. This phenotype is strikingly similar to a very rare human genetic disorder, Restrictive Dermopathy. wrfr mutant mice display a defective skin barrier, which is normally imparted by the cornified envelope, a composite of protein and lipid that prevents loss of water from within and entry of potentially harmful substances from without. In addition, hair growth from grafted wrfr skin is impaired. Positional cloning of the wrfr mutation revealed a retrotransposon insertion into a coding exon of Slc27a4, the gene encoding fatty acid transport protein (FATP)4. FATP4 is the primary intestinal FATP and is thought to play a major role in dietary fatty acid uptake; it therefore is viewed as a target to prevent or reverse obesity. However, its function in vivo had not been determined. Our results demonstrate an unexpected yet critical role for FATP4 in skin and hair development and suggest Slc27a4 to be a candidate gene for Restrictive Dermopathy.
