Document Details

Document Type : Article In Journal 
Document Title :
LOSS-OF-FUNCTION MUTATIONS IN ATP6V0A2 IMPAIR VESICULAR TRAFFICKING, ELASTIN DEPOSITION, AND CELL SURVIVAL
المرض الوراثي المتصف بليونة الجلد
 
Subject : Genetic disorder 
Document Language : English 
Abstract : Autosomal recessive cutis laxa type 2 (ARCL2), a syndrome of growth and developmental delay and redundant, inelastic skin, is caused by mutations in the a2 subunit of the vesicular ATPase H+-pump (ATP6V0A2). The goal of this study was to define the disease mechanisms that lead to connective tissue lesions in ARCL2. In a new cohort of 17 CL patients, DNA sequencing of ATP6V0A2 detected either homozygous or compound heterozygous mutations. A great degree of allelic and phenotypic heterogeneity was observed, with a missense mutation of a moderately conserved residue p.P87L leading to unusually mild disease. Abnormal N- and/or mucin type O-glycosylation was observed in all patients tested. Premature stop codon mutations led to decreased ATP6V0A2 mRNA levels by destabilizing the mutant mRNA via the nonsense-mediated decay pathway. Loss of ATP6V0A2 either by siRNA knockdown or in ARCL2 cells resulted distended Golgi sacs, accumulation of abnormal secretory vesicles, and multivesicular bodies. Immunostaining of ARCL2 cells showed abundant staining for tropoelastin in the Golgi, and other intracellular compartments, often associated with apoptotic nuclear morphology. TUNEL staining confirmed increased rates of apoptosis in ARCL2 cell cultures, and insoluble elastin assays showed significantly reduced deposition of elastin. Fibrillin-1 micorfibrils and secreted lysyl oxidase activity were normal in ARCL2 cells. We conclude that loss of function mutations in ATP6V0A2 lead to secretory defects that specifically impair tropoelastin trafficking and cell survival leading to the observed skin and connective tissue abnormalities in ARCL2. 
ISSN : 0964-6906 
Journal Name : Human Molecular Genetics 
Volume : 15 
Issue Number : 12 
Publishing Year : 1430 AH
2009 AD 
Article Type : Article 
Added Date : Thursday, February 11, 2010 

Researchers

Researcher Name (Arabic)Researcher Name (English)Researcher TypeDr GradeEmail
فيشوناثن هكثاجاودرHucthagowder, Vishwanathan InvestigatorDoctorate 
إيفا مورافاMorava, Eva InvestigatorDoctorate 
يووي كورناكKornak, Uwe InvestigatorDoctorate 
ديرك لفبرLefeber, Dirk InvestigatorDoctorate 
باجورن فسشرFischer, Björn InvestigatorDoctorate 
إيكاترينا ديميولاوDimopoulou, Aikaterini InvestigatorDoctorate 
انيكا الدنجرAldinger, Annika InvestigatorDoctorate 
جيون شويChoi, Jiwon InvestigatorDoctorate 
، إيليني ديفيزDavis, Elaine InvestigatorDoctorate 
ديان أبيولوAbuelo, Dianne InvestigatorDoctorate 
ماسييج اداموويكزAdamowicz, Maciej InvestigatorDoctorate 
جمانة يوسف الأعمىAL- Aama, Jumana YInvestigatorDoctoratejalama@kau.edu.sa
آخرون آخرونal, et InvestigatorDoctorate 

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