Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2

Kornak, Uwe; Reynders, Ellen; Dimopoulou, Aikaterini; Reeuwijk, Jeroen van; Fischer, Bjoern; Rajab, Anna; Budde, Birgit; Nürnberg, Peter; Foulquier, François; Dobyns, William B.; Quelhas, Dulce; Vilarinho, Laura; Leão‐Teles, Elisa; Greally, Marie T.; Seemanová, E; Simandlová, Martina; Salih, Mustafa A.; Nanda, Arti; Basel‐Vanagaite, Lina; Kayserili, Hülya; Yüksel‐Apak, Memnune; Larrègue, M; Vigneron, Jacqueline; Giurgea, S.; Lefeber, Dirk; Urban, Zsolt; Gruenewald, S; Annaert, Wim; Brunner, Han G.; Bokhoven, Hans van; Wevers, Ron A.; Morava, Éva; Matthijs, Gert; Maldergem, Lionel Van; Mundlos, Stefan

doi:10.1038/ng.2007.45

Cited by 327 publications

(321 citation statements)

References 13 publications

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“…4,12,13,17,18,24,25,33 PCR products were Figure 2 Diagnostic flowchart for evaluation of a new CL patient with suspected autosomal recessive inheritance (non-type 1). The facial features of PYCR1, ALDH18A1 and GORAB-related syndromes are similar to each other and different from the ATP6V0A2-related ARCL2A.…”

Section: Metabolic Investigationsmentioning

confidence: 99%

“…ARCL2A (including ATP6V0A2-CDG, Debré-type CL and wrinkly skin syndrome) is caused by mutations in the ATP6V0A2 gene. 2,12,13 Generalized CL is already present at birth and intriguingly improves over time. Patients have suggestive facial features with hanging eyelids, down-slanting palpebral fissures, muscle hypotonia, epilepsy and mild-to-moderate developmental delay.…”

Section: Introductionmentioning

confidence: 99%

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Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

et al. 2013

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Patients with cutis laxa (CL) have wrinkled, sagging skin with decreased elasticity. Skin symptoms are associated with variable systemic involvement. The most common, genetically highly heterogeneous form of autosomal recessive CL, ARCL2, is frequently associated with variable metabolic and neurological symptoms. Progeroid symptoms, dysmorphic features, hypotonia and psychomotor retardation are highly overlapping in the early phase of these disorders. This makes the genetic diagnosis often challenging. In search for discriminatory symptoms, we prospectively evaluated clinical, neurologic, metabolic and genetic features in our patient cohort referred for suspected ARCL. From a cohort of 26 children, we confirmed mutations in genes associated with ARCL in 16 children (14 probands), including 12 novel mutations. Abnormal glycosylation and gyration abnormalities were mostly, but not always associated with ATP6V0A2 mutations. Epilepsy was most common in ATP6V0A2 defects. Corpus callosum dysgenesis was associated with PYCR1 and ALDH18A1 mutations. Dystonic posturing was discriminatory for PYCR1 and ALDH18A1 defects. Metabolic markers of mitochondrial dysfunction were found in one patient with PYCR1 mutations. So far unreported white matter abnormalities were found associated with GORAB and RIN2 mutations. We describe a large cohort of CL patients with neurologic involvement. Migration defects and corpus callosum hypoplasia were not always diagnostic for a specific genetic defect in CL. All patients with ATP6V0A2 defects had abnormal glycosylation. To conclude, central nervous system and metabolic abnormalities were discriminatory in this genetically heterogeneous group, although not always diagnostic for a certain genetic defect in CL.

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Section: Metabolic Investigationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

et al. 2013

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“…Autosomal-recessive forms of cutis laxa are associated with mutations in the genes encoding fibulin 4 and fibulin 5 (FBLN4 and FBLN5), 41,42 and more recently also with mutations in ATP6V0A2 and PYCR1. 43,44 The previously defined X-linked form of cutis laxa, or OHS, is caused by mutations in ATP7A and was discussed earlier.…”

Section: Cutis Laxa Syndromesmentioning

confidence: 99%

Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type

Malfait

Wenstrup

Paepe

2010

Genetics in Medicine

235

228

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“…These changes affect multiple classes of glycosylation as shown by the abnormal N-glycosylation and mucin type O-glycosylation of blood serum proteins. Clinically, mutations in ATP6V0A2 lead to multiple abnormalities including growth delay and psychomotor disability, but also to skin wrinkling and connective tissue alterations referred to as cutis laxa [73]. Skin and skeletal phenotypes are likely related to alterations of extracellular matrix secretion as indicated by changes of TGF- signaling observed in affected fibroblasts [71].…”

Section: Organelle Milieumentioning

confidence: 99%

Congenital disorders of glycosylation: a concise chart of glycocalyx dysfunction

Hennet

Cabalzar

2015

Trends in Biochemical Sciences

107

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Glycosylation is a ubiquitous modification of lipids and proteins. Despite the essential contribution of glycoconjugates to the viability of all living organisms, diseases of glycosylation in humans have only been identified over the past few decades. The recent development of next-generation DNA sequencing techniques has accelerated the pace of discovery of novel glycosylation defects. The description of multiple mutations across glycosylation pathways not only revealed tremendous diversity in functional impairments, but also pointed to phenotypic similarities, emphasizing the interconnected flow of substrates underlying glycan assembly. The current list of 100 known glycosylation disorders provides an overview of the significance of glycosylation in human development and physiology. Congenital disorders of glycosylation -a consice chart of glycocalyx dysfunctionThierry Hennet, Jürg Cabalzar Institute of Physiology, University of Zurich, CH-8057 Zurich, Switzerland AbstractGlycosylation is a ubiquitous modification of lipids and proteins. Despite the essential contribution of glycoconjugates to the viability of all living organisms, diseases of glycosylation in humans have only been identified over the past few decades. The recent development of next-generation DNA sequencing techniques has accelerated the pace of discovery of novel glycosylation defects. The description of multiple mutations across glycosylation pathways has revealed a tremendous diversity of functional impairments bus also pointed to phenotypic similarities emphasizing the interconnected flow of substrates underlying glycan assembly. The current list of 100 known glycosylation disorders provides an overview on the significance of glycosylation in human development and physiology. Highlights Congenital disorders underline the role of glycosylation in human development.  Next-gen sequencing techniques expanded the discovery of glycosylation gene defects.  The clinical variability of glycosylation disorders implies they are underdiagnosed. Glycosylation disordersGlycosylation is by far the most complex form of protein [1,2] and lipid modification [3,4] in all domains of life. The tremendous diversity of glycoconjugate structures resulting from intricate biosynthetic pathways is a major factor hampering the assignment of functions to glycans chains. Much has been learnt from the study of disrupted glycosylation genes in model organisms, thereby establishing numerous essential contributions of glycans in regulating cell and organ functions [5]. The study of human diseases of glycosylation brings additional insights by providing a more differentiated view on glycan functions. Indeed, most human mutations are hypomorphic, thus causing partial loss of glycosylation reactions that lead to variable clinical manifestations.Diseases of glycosylation are also referred to as congenital disorders of glycosylation (CDG). Given the heterogeneity of glycans, the clinical scope of CDG is considerable, ranging from nearly normal phenotypes to sever...

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Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2

Cited by 327 publications

References 13 publications

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type

Congenital disorders of glycosylation: a concise chart of glycocalyx dysfunction

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