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Zsolt Urban - One of the best experts on this subject based on the ideXlab platform.
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Novel defect in phosphatidylinositol 4‐kinase type 2‐alpha (PI4K2A) at the membrane‐enzyme interface is associated with metabolic Cutis Laxa
Journal of inherited metabolic disease, 2020Co-Authors: Miski Mohamed, Thatjana Gardeitchik, Zsolt Urban, Shanti Balasubramaniam, Sergio Guerrero-castillo, Daisy Dalloyaux, Sanne Van Kraaij, Hanka Venselaar, Alexander Hoischen, Ulrich BrandtAbstract:Inherited Cutis Laxa, or inelastic, sagging skin is a genetic condition of premature and generalised connective tissue ageing, affecting various elastic components of the extracellular matrix. Several Cutis Laxa syndromes are inborn errors of metabolism and lead to severe neurological symptoms. In a patient with Cutis Laxa, a choreoathetoid movement disorder, dysmorphic features and intellectual disability we performed exome sequencing to elucidate the underlying genetic defect. We identified the amino acid substitution R275W in phosphatidylinositol 4-kinase type IIα, caused by a homozygous missense mutation in the PI4K2A gene. We used lipidomics, complexome profiling and functional studies to measure phosphatidylinositol 4-phosphate synthesis in the patient and evaluated PI4K2A deficient mice to define a novel metabolic disorder. The R275W residue, located on the surface of the protein, is involved in forming electrostatic interactions with the membrane. The catalytic activity of PI4K2A in patient fibroblasts was severely reduced and lipid mass spectrometry showed that particular acyl-chain pools of PI4P and PI(4,5)P2 were decreased. Phosphoinositide lipids play a major role in intracellular signalling and trafficking and regulate the balance between proliferation and apoptosis. Phosphatidylinositol 4-kinases such as PI4K2A mediate the first step in the main metabolic pathway that generates PI4P, PI(4,5)P2 and PI(3,4,5)P3 . Although neurologic involvement is common, Cutis Laxa has not been reported previously in metabolic defects affecting signalling. Here we describe a patient with a complex neurological phenotype, premature ageing and a mutation in PI4K2A, illustrating the importance of this enzyme in the generation of inositol lipids with particular acylation characteristics.
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efemp2 related Cutis Laxa
GeneReviews®, 2015Co-Authors: Bart Loeys, Anne De Paepe, Zsolt UrbanAbstract:Clinical characteristics EFEMP2-related Cutis Laxa, or autosomal recessive Cutis Laxa type 1B (ARCL1B), is characterized by Cutis Laxa and systemic involvement, most commonly arterial tortuosity, aneurysms, and stenosis; retrognathia; joint laxity; and arachnodactyly. Severity ranges from perinatal lethality as a result of cardiopulmonary failure to manifestations limited to the vascular and craniofacial systems. Diagnosis/testing The diagnosis of EFEMP2-related Cutis Laxa is established in a proband with suggestive findings and biallelic pathogenic variants in EFEMP2 identified by molecular genetic testing. Management Treatment of manifestations: Treatment of aortic root dilatation with beta-blockers or angiotensin receptor inhibitors can be considered. Aortic aneurysm replacement has been performed successfully. Symptomatic treatment of pulmonary emphysema; muscle-reinforcing physical therapy for joint hypermobility; routine repair of hernias. Tracheostomy may be necessary when retrognathia leads to upper-airway obstruction. Surveillance: Follow-up evaluations with a cardiologist and pulmonologist at least annually starting from the time of diagnosis. Annual MR angiography from head to pelvis. Agents/circumstances to avoid: Sun tanning to avoid damaging the skin; cigarette smoking to avoid worsening of emphysema. Genetic counseling EFEMP2-related Cutis Laxa is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an EFEMP2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the EFEMP2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.
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a novel elastin gene mutation in a vietnamese patient with Cutis Laxa
Pediatric Dermatology, 2014Co-Authors: L Mark M D Siefring, C Elizabeth B A Lawrence, C Tom M D Nguyen, M Giang D Pham, B Christa S Lorenchick, L Kara M S Levine, Zsolt UrbanAbstract:We report a 3-year-old girl from Vietnam with severe congenital Cutis Laxa; no cardiovascular, pulmonary, neurologic, or visceral involvement; and no family history of Cutis Laxa. Mutational analysis of the elastin gene identified heterozygosity for a previously unreported de novo c.2184delT mutation in exon 30 not present in either parent.
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the complexity of elastic fibre biogenesis in the skin a perspective to the clinical heterogeneity of Cutis Laxa
Experimental Dermatology, 2013Co-Authors: Jouni Uitto, Zsolt UrbanAbstract:Elastic fibres are critical connective tissue components providing elasticity and resilience to skin and other tissues. These fibres are composed of elastin and a number of elastin-associated microfibrillar proteins that assemble in a complex fibre network in a multi-step process. Multiple cellular processes, including mitochondrial function, specific molecules in the secretory pathways and temporally and spatially ordered production of elastic fibre components, are required for the biogenesis of functional elastic fibres. Abnormalities in these processes can lead to loss of functional elastic fibres manifesting phenotypically as a skin disease. The paradigm of elastic fibre diseases affecting the skin is Cutis Laxa, a clinically and genetically heterogeneous group of disorders characterized by loose and sagging skin, frequently associated with extracutaneous manifestations in the lungs and the arterial blood vessels. The complexity of Cutis Laxa is emphasized by the fact that as many as 10 distinct genes can harbour mutations in this and related disorders. Understanding of the pathomechanistic pathways involved in perturbed elastic fibre assembly in Cutis Laxa provides information potentially helpful for the development of molecular strategies towards treatment of these, currently intractable, diseases.
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Cutis Laxa a review
Journal of The American Academy of Dermatology, 2012Co-Authors: David R Berk, Danette D Bentley, Susan J Bayliss, Anne C Lind, Zsolt UrbanAbstract:Cutis Laxa is a rare disorder of elastic tissue resulting in loose, redundant, hypoelastic skin. Both acquired and inherited forms exist, some of which have significant systemic manifestations. Here, we review the various forms of Cutis Laxa, with focus on the inherited forms. Recent molecular studies have provided many new insights into the causes of Cutis Laxa and revealed greater genetic heterogeneity than previously appreciated.
Shanti Balasubramaniam - One of the best experts on this subject based on the ideXlab platform.
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Novel defect in phosphatidylinositol 4‐kinase type 2‐alpha (PI4K2A) at the membrane‐enzyme interface is associated with metabolic Cutis Laxa
Journal of inherited metabolic disease, 2020Co-Authors: Miski Mohamed, Thatjana Gardeitchik, Zsolt Urban, Shanti Balasubramaniam, Sergio Guerrero-castillo, Daisy Dalloyaux, Sanne Van Kraaij, Hanka Venselaar, Alexander Hoischen, Ulrich BrandtAbstract:Inherited Cutis Laxa, or inelastic, sagging skin is a genetic condition of premature and generalised connective tissue ageing, affecting various elastic components of the extracellular matrix. Several Cutis Laxa syndromes are inborn errors of metabolism and lead to severe neurological symptoms. In a patient with Cutis Laxa, a choreoathetoid movement disorder, dysmorphic features and intellectual disability we performed exome sequencing to elucidate the underlying genetic defect. We identified the amino acid substitution R275W in phosphatidylinositol 4-kinase type IIα, caused by a homozygous missense mutation in the PI4K2A gene. We used lipidomics, complexome profiling and functional studies to measure phosphatidylinositol 4-phosphate synthesis in the patient and evaluated PI4K2A deficient mice to define a novel metabolic disorder. The R275W residue, located on the surface of the protein, is involved in forming electrostatic interactions with the membrane. The catalytic activity of PI4K2A in patient fibroblasts was severely reduced and lipid mass spectrometry showed that particular acyl-chain pools of PI4P and PI(4,5)P2 were decreased. Phosphoinositide lipids play a major role in intracellular signalling and trafficking and regulate the balance between proliferation and apoptosis. Phosphatidylinositol 4-kinases such as PI4K2A mediate the first step in the main metabolic pathway that generates PI4P, PI(4,5)P2 and PI(3,4,5)P3 . Although neurologic involvement is common, Cutis Laxa has not been reported previously in metabolic defects affecting signalling. Here we describe a patient with a complex neurological phenotype, premature ageing and a mutation in PI4K2A, illustrating the importance of this enzyme in the generation of inositol lipids with particular acylation characteristics.
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novel defect in phosphatidylinositol 4 kinase type 2 alpha pi4k2a at the membrane enzyme interface is associated with metabolic Cutis Laxa
Journal of Inherited Metabolic Disease, 2020Co-Authors: Miski Mohamed, Thatjana Gardeitchik, Shanti Balasubramaniam, Daisy Dalloyaux, Sanne Van Kraaij, Hanka Venselaar, Sergio Guerrerocastillo, Alexander HoischenAbstract:Inherited Cutis Laxa, or inelastic, sagging skin is a genetic condition of premature and generalised connective tissue ageing, affecting various elastic components of the extracellular matrix. Several Cutis Laxa syndromes are inborn errors of metabolism and lead to severe neurological symptoms. In a patient with Cutis Laxa, a choreoathetoid movement disorder, dysmorphic features and intellectual disability we performed exome sequencing to elucidate the underlying genetic defect. We identified the amino acid substitution R275W in phosphatidylinositol 4-kinase type II alpha, caused by a homozygous missense mutation in thePI4K2Agene. We used lipidomics, complexome profiling and functional studies to measure phosphatidylinositol 4-phosphate synthesis in the patient and evaluated PI4K2A deficient mice to define a novel metabolic disorder. The R275W residue, located on the surface of the protein, is involved in forming electrostatic interactions with the membrane. The catalytic activity of PI4K2A in patient fibroblasts was severely reduced and lipid mass spectrometry showed that particular acyl-chain pools of PI4P and PI(4,5)P(2)were decreased. Phosphoinositide lipids play a major role in intracellular signalling and trafficking and regulate the balance between proliferation and apoptosis. Phosphatidylinositol 4-kinases such as PI4K2A mediate the first step in the main metabolic pathway that generates PI4P, PI(4,5)P(2)and PI(3,4,5)P-3. Although neurologic involvement is common, Cutis Laxa has not been reported previously in metabolic defects affecting signalling. Here we describe a patient with a complex neurological phenotype, premature ageing and a mutation inPI4K2A, illustrating the importance of this enzyme in the generation of inositol lipids with particular acylation characteristics.
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unique presentation of Cutis Laxa with leigh like syndrome due to echs1 deficiency
Journal of Inherited Metabolic Disease, 2017Co-Authors: Shanti Balasubramaniam, Lisa G Riley, Drago Bratkovic, D Ketteridge, N Manton, Mark J Cowley, Velimir Gayevskiy, Tony RoscioliAbstract:Clinical finding of Cutis Laxa, characterized by wrinkled, redundant, sagging, nonelastic skin, is of growing significance due to its occurrence in several different inborn errors of metabolism (IEM). Metabolic Cutis Laxa results from Menkes syndrome, caused by a defect in the ATPase copper transporting alpha (ATP7A) gene; congenital disorders of glycosylation due to mutations in subunit 7 of the component of oligomeric Golgi (COG7)-congenital disorders of glycosylation (CDG) complex; combined disorder of N- and O-linked glycosylation, due to mutations in ATPase H+ transporting V0 subunit a2 (ATP6VOA2) gene; pyrroline-5-carboxylate reductase 1 deficiency; pyrroline-5-carboxylate synthase deficiency; macrocephaly, alopecia, Cutis Laxa, and scoliosis (MACS) syndrome, due to Ras and Rab interactor 2 (RIN2) mutations; transaldolase deficiency caused by mutations in the transaldolase 1 (TALDO1) gene; Gerodermia osteodysplastica due to mutations in the golgin, RAB6-interacting (GORAB or SCYL1BP1) gene; and mitogen-activated pathway (MAP) kinase defects, caused by mutations in several genes [protein tyrosine phosphatase, non-receptor-type 11 (PTPN11), RAF, NF, HRas proto-oncogene, GTPase (HRAS), B-Raf proto-oncogene, serine/threonine kinase (BRAF), MEK1/2, KRAS proto-oncogene, GTPase (KRAS), SOS Ras/Rho guanine nucleotide exchange factor 2 (SOS2), leucine rich repeat scaffold protein (SHOC2), NRAS proto-oncogene, GTPase (NRAS), and Raf-1 proto-oncogene, serine/threonine kinase (RAF1)], which regulate the Ras-MAPK cascade. Here, we further expand the list of inborn errors of metabolism associated with Cutis Laxa by describing the clinical presentation of a 17-month-old girl with Leigh-like syndrome due to enoyl coenzyme A hydratase, short chain, 1, mitochondria (ECHS1) deficiency, a mitochondrial matrix enzyme that catalyzes the second step of the beta-oxidation spiral of fatty acids and plays an important role in amino acid catabolism, particularly valine.
Thatjana Gardeitchik - One of the best experts on this subject based on the ideXlab platform.
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Novel defect in phosphatidylinositol 4‐kinase type 2‐alpha (PI4K2A) at the membrane‐enzyme interface is associated with metabolic Cutis Laxa
Journal of inherited metabolic disease, 2020Co-Authors: Miski Mohamed, Thatjana Gardeitchik, Zsolt Urban, Shanti Balasubramaniam, Sergio Guerrero-castillo, Daisy Dalloyaux, Sanne Van Kraaij, Hanka Venselaar, Alexander Hoischen, Ulrich BrandtAbstract:Inherited Cutis Laxa, or inelastic, sagging skin is a genetic condition of premature and generalised connective tissue ageing, affecting various elastic components of the extracellular matrix. Several Cutis Laxa syndromes are inborn errors of metabolism and lead to severe neurological symptoms. In a patient with Cutis Laxa, a choreoathetoid movement disorder, dysmorphic features and intellectual disability we performed exome sequencing to elucidate the underlying genetic defect. We identified the amino acid substitution R275W in phosphatidylinositol 4-kinase type IIα, caused by a homozygous missense mutation in the PI4K2A gene. We used lipidomics, complexome profiling and functional studies to measure phosphatidylinositol 4-phosphate synthesis in the patient and evaluated PI4K2A deficient mice to define a novel metabolic disorder. The R275W residue, located on the surface of the protein, is involved in forming electrostatic interactions with the membrane. The catalytic activity of PI4K2A in patient fibroblasts was severely reduced and lipid mass spectrometry showed that particular acyl-chain pools of PI4P and PI(4,5)P2 were decreased. Phosphoinositide lipids play a major role in intracellular signalling and trafficking and regulate the balance between proliferation and apoptosis. Phosphatidylinositol 4-kinases such as PI4K2A mediate the first step in the main metabolic pathway that generates PI4P, PI(4,5)P2 and PI(3,4,5)P3 . Although neurologic involvement is common, Cutis Laxa has not been reported previously in metabolic defects affecting signalling. Here we describe a patient with a complex neurological phenotype, premature ageing and a mutation in PI4K2A, illustrating the importance of this enzyme in the generation of inositol lipids with particular acylation characteristics.
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novel defect in phosphatidylinositol 4 kinase type 2 alpha pi4k2a at the membrane enzyme interface is associated with metabolic Cutis Laxa
Journal of Inherited Metabolic Disease, 2020Co-Authors: Miski Mohamed, Thatjana Gardeitchik, Shanti Balasubramaniam, Daisy Dalloyaux, Sanne Van Kraaij, Hanka Venselaar, Sergio Guerrerocastillo, Alexander HoischenAbstract:Inherited Cutis Laxa, or inelastic, sagging skin is a genetic condition of premature and generalised connective tissue ageing, affecting various elastic components of the extracellular matrix. Several Cutis Laxa syndromes are inborn errors of metabolism and lead to severe neurological symptoms. In a patient with Cutis Laxa, a choreoathetoid movement disorder, dysmorphic features and intellectual disability we performed exome sequencing to elucidate the underlying genetic defect. We identified the amino acid substitution R275W in phosphatidylinositol 4-kinase type II alpha, caused by a homozygous missense mutation in thePI4K2Agene. We used lipidomics, complexome profiling and functional studies to measure phosphatidylinositol 4-phosphate synthesis in the patient and evaluated PI4K2A deficient mice to define a novel metabolic disorder. The R275W residue, located on the surface of the protein, is involved in forming electrostatic interactions with the membrane. The catalytic activity of PI4K2A in patient fibroblasts was severely reduced and lipid mass spectrometry showed that particular acyl-chain pools of PI4P and PI(4,5)P(2)were decreased. Phosphoinositide lipids play a major role in intracellular signalling and trafficking and regulate the balance between proliferation and apoptosis. Phosphatidylinositol 4-kinases such as PI4K2A mediate the first step in the main metabolic pathway that generates PI4P, PI(4,5)P(2)and PI(3,4,5)P-3. Although neurologic involvement is common, Cutis Laxa has not been reported previously in metabolic defects affecting signalling. Here we describe a patient with a complex neurological phenotype, premature ageing and a mutation inPI4K2A, illustrating the importance of this enzyme in the generation of inositol lipids with particular acylation characteristics.
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mutations in atp6v1e1 or atp6v1a cause autosomal recessive Cutis Laxa
American Journal of Human Genetics, 2017Co-Authors: Tim Van Damme, Miski Mohamed, Thatjana Gardeitchik, Daisy Dalloyaux, Sanne Van Kraaij, Ariana Kariminejad, Sergio Guerrerocastillo, Peter Freisinger, Brecht Guillemyn, Dirk LefeberAbstract:Defects of the V-type proton (H+) ATPase (V-ATPase) impair acidification and intracellular trafficking of membrane-enclosed compartments, including secretory granules, endosomes, and lysosomes. Whole-exome sequencing in five families affected by mild to severe Cutis Laxa, dysmorphic facial features, and cardiopulmonary involvement identified biallelic missense mutations in ATP6V1E1 and ATP6V1A, which encode the E1 and A subunits, respectively, of the V1 domain of the heteromultimeric V-ATPase complex. Structural modeling indicated that all substitutions affect critical residues and inter- or intrasubunit interactions. Furthermore, complexome profiling, a method combining blue-native gel electrophoresis and liquid chromatography tandem mass spectrometry, showed that they disturb either the assembly or the stability of the V-ATPase complex. Protein glycosylation was variably affected. Abnormal vesicular trafficking was evidenced by delayed retrograde transport after brefeldin A treatment and abnormal swelling and fragmentation of the Golgi apparatus. In addition to showing reduced and fragmented elastic fibers, the histopathological hallmark of Cutis Laxa, transmission electron microscopy of the dermis also showed pronounced changes in the structure and organization of the collagen fibers. Our findings expand the clinical and molecular spectrum of metabolic Cutis Laxa syndromes and further link defective extracellular matrix assembly to faulty protein processing and cellular trafficking caused by genetic defects in the V-ATPase complex.
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further characterization of atp6v0a2 related autosomal recessive Cutis Laxa
Human Genetics, 2012Co-Authors: Bjoern Fischer, Thatjana Gardeitchik, Hulya Kayserili, Aikaterini Dimopoulou, Johannes Egerer, Alexa Kidd, D Jost, Yasemin Alanay, Iliana TantchevapoorAbstract:Autosomal recessive Cutis Laxa (ARCL) syndromes are phenotypically overlapping, but genetically heterogeneous disorders. Mutations in the ATP6V0A2 gene were found to underlie both, autosomal recessive Cutis Laxa type 2 (ARCL2), Debre type, and wrinkly skin syndrome (WSS). The ATP6V0A2 gene encodes the a2 subunit of the V-type H(+)-ATPase, playing a role in proton translocation, and possibly also in membrane fusion. Here, we describe a highly variable phenotype in 13 patients with ARCL2, including the oldest affected individual described so far, who showed strikingly progressive dysmorphic features and heterotopic calcifications. In these individuals we identified 17 ATP6V0A2 mutations, 14 of which are novel. Furthermore, we demonstrate a localization of ATP6V0A2 at the Golgi-apparatus and a loss of the mutated ATP6V0A2 protein in patients' dermal fibroblasts. Investigation of brefeldin A-induced Golgi collapse in dermal fibroblasts as well as in HeLa cells deficient for ATP6V0A2 revealed a delay, which was absent in cells deficient for the ARCL-associated proteins GORAB or PYCR1. Furthermore, fibroblasts from patients with ATP6V0A2 mutations displayed elevated TGF-β signalling and increased TGF-β1 levels in the supernatant. Our current findings expand the genetic and phenotypic spectrum and suggest that, besides the known glycosylation defect, alterations in trafficking and signalling processes are potential key events in the pathogenesis of ATP6V0A2-related ARCL.
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Metabolic Cutis Laxa syndromes
Journal of Inherited Metabolic Disease, 2011Co-Authors: Miski Mohamed, Thatjana Gardeitchik, Ron A Wevers, Dorus Kouwenberg, Uwe Kornak, Eva MoravaAbstract:Cutis Laxa is a rare skin disorder characterized by wrinkled, redundant, inelastic and sagging skin due to defective synthesis of elastic fibers and other proteins of the extracellular matrix. Wrinkled, inelastic skin occurs in many cases as an acquired condition. Syndromic forms of Cutis Laxa, however, are caused by diverse genetic defects, mostly coding for structural extracellular matrix proteins. Surprisingly a number of metabolic disorders have been also found to be associated with inherited Cutis Laxa. Menkes disease was the first metabolic disease reported with old-looking, wrinkled skin. Cutis Laxa has recently been found in patients with abnormal glycosylation. The discovery of the COG7 defect in patients with wrinkled, inelastic skin was the first genetic link with the Congenital Disorders of Glycosylation (CDG). Since then several inborn errors of metabolism with Cutis Laxa have been described with variable severity. These include P5CS, ATP6V0A2-CDG and PYCR1 defects. In spite of the evolving number of Cutis Laxa-related diseases a large part of the cases remain genetically unsolved. In metabolic Cutis Laxa syndromes the clinical and laboratory features might partially overlap, however there are some distinct, discriminative features. In this review on metabolic diseases causing Cutis Laxa we offer a practical approach for the differential diagnosis of metabolic Cutis Laxa syndromes.
Miski Mohamed - One of the best experts on this subject based on the ideXlab platform.
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Novel defect in phosphatidylinositol 4‐kinase type 2‐alpha (PI4K2A) at the membrane‐enzyme interface is associated with metabolic Cutis Laxa
Journal of inherited metabolic disease, 2020Co-Authors: Miski Mohamed, Thatjana Gardeitchik, Zsolt Urban, Shanti Balasubramaniam, Sergio Guerrero-castillo, Daisy Dalloyaux, Sanne Van Kraaij, Hanka Venselaar, Alexander Hoischen, Ulrich BrandtAbstract:Inherited Cutis Laxa, or inelastic, sagging skin is a genetic condition of premature and generalised connective tissue ageing, affecting various elastic components of the extracellular matrix. Several Cutis Laxa syndromes are inborn errors of metabolism and lead to severe neurological symptoms. In a patient with Cutis Laxa, a choreoathetoid movement disorder, dysmorphic features and intellectual disability we performed exome sequencing to elucidate the underlying genetic defect. We identified the amino acid substitution R275W in phosphatidylinositol 4-kinase type IIα, caused by a homozygous missense mutation in the PI4K2A gene. We used lipidomics, complexome profiling and functional studies to measure phosphatidylinositol 4-phosphate synthesis in the patient and evaluated PI4K2A deficient mice to define a novel metabolic disorder. The R275W residue, located on the surface of the protein, is involved in forming electrostatic interactions with the membrane. The catalytic activity of PI4K2A in patient fibroblasts was severely reduced and lipid mass spectrometry showed that particular acyl-chain pools of PI4P and PI(4,5)P2 were decreased. Phosphoinositide lipids play a major role in intracellular signalling and trafficking and regulate the balance between proliferation and apoptosis. Phosphatidylinositol 4-kinases such as PI4K2A mediate the first step in the main metabolic pathway that generates PI4P, PI(4,5)P2 and PI(3,4,5)P3 . Although neurologic involvement is common, Cutis Laxa has not been reported previously in metabolic defects affecting signalling. Here we describe a patient with a complex neurological phenotype, premature ageing and a mutation in PI4K2A, illustrating the importance of this enzyme in the generation of inositol lipids with particular acylation characteristics.
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novel defect in phosphatidylinositol 4 kinase type 2 alpha pi4k2a at the membrane enzyme interface is associated with metabolic Cutis Laxa
Journal of Inherited Metabolic Disease, 2020Co-Authors: Miski Mohamed, Thatjana Gardeitchik, Shanti Balasubramaniam, Daisy Dalloyaux, Sanne Van Kraaij, Hanka Venselaar, Sergio Guerrerocastillo, Alexander HoischenAbstract:Inherited Cutis Laxa, or inelastic, sagging skin is a genetic condition of premature and generalised connective tissue ageing, affecting various elastic components of the extracellular matrix. Several Cutis Laxa syndromes are inborn errors of metabolism and lead to severe neurological symptoms. In a patient with Cutis Laxa, a choreoathetoid movement disorder, dysmorphic features and intellectual disability we performed exome sequencing to elucidate the underlying genetic defect. We identified the amino acid substitution R275W in phosphatidylinositol 4-kinase type II alpha, caused by a homozygous missense mutation in thePI4K2Agene. We used lipidomics, complexome profiling and functional studies to measure phosphatidylinositol 4-phosphate synthesis in the patient and evaluated PI4K2A deficient mice to define a novel metabolic disorder. The R275W residue, located on the surface of the protein, is involved in forming electrostatic interactions with the membrane. The catalytic activity of PI4K2A in patient fibroblasts was severely reduced and lipid mass spectrometry showed that particular acyl-chain pools of PI4P and PI(4,5)P(2)were decreased. Phosphoinositide lipids play a major role in intracellular signalling and trafficking and regulate the balance between proliferation and apoptosis. Phosphatidylinositol 4-kinases such as PI4K2A mediate the first step in the main metabolic pathway that generates PI4P, PI(4,5)P(2)and PI(3,4,5)P-3. Although neurologic involvement is common, Cutis Laxa has not been reported previously in metabolic defects affecting signalling. Here we describe a patient with a complex neurological phenotype, premature ageing and a mutation inPI4K2A, illustrating the importance of this enzyme in the generation of inositol lipids with particular acylation characteristics.
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mutations in atp6v1e1 or atp6v1a cause autosomal recessive Cutis Laxa
American Journal of Human Genetics, 2017Co-Authors: Tim Van Damme, Miski Mohamed, Thatjana Gardeitchik, Daisy Dalloyaux, Sanne Van Kraaij, Ariana Kariminejad, Sergio Guerrerocastillo, Peter Freisinger, Brecht Guillemyn, Dirk LefeberAbstract:Defects of the V-type proton (H+) ATPase (V-ATPase) impair acidification and intracellular trafficking of membrane-enclosed compartments, including secretory granules, endosomes, and lysosomes. Whole-exome sequencing in five families affected by mild to severe Cutis Laxa, dysmorphic facial features, and cardiopulmonary involvement identified biallelic missense mutations in ATP6V1E1 and ATP6V1A, which encode the E1 and A subunits, respectively, of the V1 domain of the heteromultimeric V-ATPase complex. Structural modeling indicated that all substitutions affect critical residues and inter- or intrasubunit interactions. Furthermore, complexome profiling, a method combining blue-native gel electrophoresis and liquid chromatography tandem mass spectrometry, showed that they disturb either the assembly or the stability of the V-ATPase complex. Protein glycosylation was variably affected. Abnormal vesicular trafficking was evidenced by delayed retrograde transport after brefeldin A treatment and abnormal swelling and fragmentation of the Golgi apparatus. In addition to showing reduced and fragmented elastic fibers, the histopathological hallmark of Cutis Laxa, transmission electron microscopy of the dermis also showed pronounced changes in the structure and organization of the collagen fibers. Our findings expand the clinical and molecular spectrum of metabolic Cutis Laxa syndromes and further link defective extracellular matrix assembly to faulty protein processing and cellular trafficking caused by genetic defects in the V-ATPase complex.
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Metabolic Cutis Laxa syndromes
Journal of Inherited Metabolic Disease, 2011Co-Authors: Miski Mohamed, Thatjana Gardeitchik, Ron A Wevers, Dorus Kouwenberg, Uwe Kornak, Eva MoravaAbstract:Cutis Laxa is a rare skin disorder characterized by wrinkled, redundant, inelastic and sagging skin due to defective synthesis of elastic fibers and other proteins of the extracellular matrix. Wrinkled, inelastic skin occurs in many cases as an acquired condition. Syndromic forms of Cutis Laxa, however, are caused by diverse genetic defects, mostly coding for structural extracellular matrix proteins. Surprisingly a number of metabolic disorders have been also found to be associated with inherited Cutis Laxa. Menkes disease was the first metabolic disease reported with old-looking, wrinkled skin. Cutis Laxa has recently been found in patients with abnormal glycosylation. The discovery of the COG7 defect in patients with wrinkled, inelastic skin was the first genetic link with the Congenital Disorders of Glycosylation (CDG). Since then several inborn errors of metabolism with Cutis Laxa have been described with variable severity. These include P5CS, ATP6V0A2-CDG and PYCR1 defects. In spite of the evolving number of Cutis Laxa-related diseases a large part of the cases remain genetically unsolved. In metabolic Cutis Laxa syndromes the clinical and laboratory features might partially overlap, however there are some distinct, discriminative features. In this review on metabolic diseases causing Cutis Laxa we offer a practical approach for the differential diagnosis of metabolic Cutis Laxa syndromes.
Eva Morava - One of the best experts on this subject based on the ideXlab platform.
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Metabolic Cutis Laxa syndromes
Journal of Inherited Metabolic Disease, 2011Co-Authors: Miski Mohamed, Thatjana Gardeitchik, Ron A Wevers, Dorus Kouwenberg, Uwe Kornak, Eva MoravaAbstract:Cutis Laxa is a rare skin disorder characterized by wrinkled, redundant, inelastic and sagging skin due to defective synthesis of elastic fibers and other proteins of the extracellular matrix. Wrinkled, inelastic skin occurs in many cases as an acquired condition. Syndromic forms of Cutis Laxa, however, are caused by diverse genetic defects, mostly coding for structural extracellular matrix proteins. Surprisingly a number of metabolic disorders have been also found to be associated with inherited Cutis Laxa. Menkes disease was the first metabolic disease reported with old-looking, wrinkled skin. Cutis Laxa has recently been found in patients with abnormal glycosylation. The discovery of the COG7 defect in patients with wrinkled, inelastic skin was the first genetic link with the Congenital Disorders of Glycosylation (CDG). Since then several inborn errors of metabolism with Cutis Laxa have been described with variable severity. These include P5CS, ATP6V0A2-CDG and PYCR1 defects. In spite of the evolving number of Cutis Laxa-related diseases a large part of the cases remain genetically unsolved. In metabolic Cutis Laxa syndromes the clinical and laboratory features might partially overlap, however there are some distinct, discriminative features. In this review on metabolic diseases causing Cutis Laxa we offer a practical approach for the differential diagnosis of metabolic Cutis Laxa syndromes.
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Autosomal recessive Cutis Laxa syndrome revisited
European Journal of Human Genetics, 2009Co-Authors: Eva Morava, Maïlys Guillard, Dirk J Lefeber, Ron A WeversAbstract:The clinical spectrum of the autosomal recessive Cutis Laxa syndromes is highly heterogeneous with respect to organ involvement and severity. One of the major diagnostic criteria is to detect abnormal elastin fibers. In several other clinically similar autosomal recessive syndromes, however, the classic histological anomalies are absent, and the definite diagnosis remains uncertain. In Cutis Laxa patients mutations have been demonstrated in elastin or fibulin genes, but in the majority of patients the underlying genetic etiology remains unknown. Recently, we found mutations in the ATP6V0A2 gene in families with autosomal recessive Cutis Laxa. This genetic defect is associated with abnormal glycosylation leading to a distinct combined disorder of the biosynthesis of N- and O-linked glycans. Interestingly, similar mutations have been found in patients with wrinkly skin syndrome, without the presence of severe skin symptoms of elastin deficiency. These findings suggest that the Cutis Laxa and wrinkly skin syndromes are phenotypic variants of the same disorder. Interestingly many phenotypically similar patients carry no mutations in the ATP6V0A2 gene. The variable presence of protein glycosylation abnormalities in the diverse clinical forms of the wrinkled skin-Cutis Laxa syndrome spectrum necessitates revisiting the diagnostic criteria to be able to offer adequate prognosis assessment and counseling. This paper aims at describing the spectrum of clinical features of the various forms of autosomal recessive Cutis Laxa syndromes. Based on the recently unraveled novel genetic entity we also review the genetic aspects in Cutis Laxa syndromes including genotype–phenotype correlations and suggest a practical diagnostic approach.
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vacuolar h atpase meets glycosylation in patients with Cutis Laxa
Biochimica et Biophysica Acta, 2009Co-Authors: Maïlys Guillard, Eva Morava, Uwe Kornak, Dirk J Lefeber, Aikaterini Dimopoulou, Bjorn Fischer, Ron A WeversAbstract:Glycosylation of proteins is one of the most important post-translational modifications. Defects in the glycan biosynthesis result in congenital malformation syndromes, also known as congenital disorders of glycosylation (CDG). Based on the iso-electric focusing patterns of plasma transferrin and apolipoprotein C-III a combined defect in N- and O-glycosylation was identified in patients with autosomal recessive Cutis Laxa type II (ARCL II). Disease-causing mutations were identified in the ATP6V0A2 gene, encoding the a2 subunit of the vacuolar H(+)-ATPase (V-ATPase). The V-ATPases are multi-subunit, ATP-dependent proton pumps located in membranes of cells and organels. In this article, we describe the structure, function and regulation of the V-ATPase and the phenotypes currently known to result from V-ATPase mutations. A clinical overview of Cutis Laxa syndromes is presented with a focus on ARCL II. Finally, the relationship between ATP6V0A2 mutations, the glycosylation defect and the ARCLII phenotype is discussed.
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decreased bone density and treatment in patients with autosomal recessive Cutis Laxa
Acta Paediatrica, 2009Co-Authors: C Noordam, Ron A Wevers, Zsolt Urban, Simone Funke, Nine V A M Knoers, Petr E Jira, Eva MoravaAbstract:AIM: Due to the occasional association pathological fractures and osteoporosis we evaluated four patients with Cutis Laxa syndrome for skeletal anomalies. PATIENT/METHODS: We prospectively evaluated four patients, a male and a female child and a brother-sister sib pair, with dysmorphic features, growth delay, joint anomalies, psychomotor retardation and congenital Cutis Laxa. The clinical features and the family history were suggestive for autosomal recessive Cutis Laxa syndrome type II, partially overlapping with geroderma osteodysplastica. Skeletal survey, sequential bone density measurements, endocrine and metabolic investigations were performed including N- and O-linked glycosylation analysis. ATP6V0A2 and FBLN5 mutations were ruled out in all patients. RESULTS: All children were diagnosed with significantly decreased bone density, especially in the lumbar spine, including spontaneous vertebral and rib fractures in three children. Following 24 months of bisphosphonate treatment a total restitution of bone density was observed in three cases and no relapse was detected in the 2-year follow-up period. A spontaneous improvement was found in one female during puberty. CONCLUSION: Bone disease might occur early in the course in autosomal recessive Cutis Laxa syndrome. We report on a significant clinical improvement and stabilization in our patients following bisphosphonate therapy. We suggest early, systemic evaluation and follow up of bone density in all children presenting with inherited Cutis Laxa.
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Defining the phenotype in an autosomal recessive Cutis Laxa syndrome with a combined congenital defect of glycosylation
European Journal of Human Genetics, 2008Co-Authors: Eva Morava, Dirk J Lefeber, Z Urban, L De Meirleir, P Meinecke, G Gillessen Kaesbach, J Sykut-cegielska, M Adamowicz, I Salafsky, J RanellsAbstract:Autosomal recessive Cutis Laxa is a genetically heterogeneous condition. Its molecular basis is largely unknown. Recently, a combined disorder of N- and O-linked glycosylation was described in children with congenital Cutis Laxa in association with severe central nervous system involvement, brain migration defects, seizures and hearing loss. We report on seven additional patients with similar clinical features in combination with congenital disorder of glycosylation type IIx. On the basis of phenotype in 10 patients, we define an autosomal recessive Cutis Laxa syndrome. The patients have a complex phenotype of neonatal Cutis Laxa, transient feeding intolerance, late closure of the fontanel, characteristic facial features including down-slanting palpebral fissures, short nose and small mouth, and developmental delay. There is a variable degree of the central nervous system involvement and variable systemic presentation. The biochemical analysis using transferrin isoelectric focusing gives false negative results in some of the youngest patients. Analysis of the apolipoprotein C-III isoelectric focusing, however, is diagnostic in all cases.
