LOSS-OF-FUNCTION MUTATIONS IN ATP6V0A2 IMPAIR VESICULAR ‫عنوان الوثيقة‬
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TRAFFICKING, ELASTIN DEPOSITION, AND CELL SURVIVAL
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.
Online ISSN 1460-2083 - Print ISSN 0964-6906
Human Molecular Genetics
2010 Oxford University Press
Oxford Journals
18
12
15 June 2009.
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