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Autosomal recessive cutis laxa type 2D (ARCL2D) is a rare connective tissue disorder characterized by generalized cutis laxa, muscular hypotonia, cardiac abnormalities, ptosis, and joint contractures. Biallelic pathogenic variants in ATP6V1A, encoding the A subunit of the vacuolar ATPase (v-ATPase), disrupt endomembrane acidification and glycosylation pathways, underpinning the ARCL2D phenotype.
In a confirmatory study, three affected individuals from two unrelated families were identified by whole-exome and Sanger sequencing, bringing the total number of reported ARCL2D cases to six across both reports ([PMID:33320377]). All six probands exhibited severe cutis laxa at birth, muscular weakness, elevated muscle enzymes, and variable survival; two died in infancy, three survive into adolescence with mild or absent intellectual disability.
Genetically, affected individuals harbor biallelic ATP6V1A variants, including missense changes and the first in-frame deletion, c.1513_1514del (p.Asp505_Phe534del), which abolishes subunit A expression. Segregation in two families confirmed autosomal recessive inheritance with affected siblings and carrier parents.
Functional studies in patient fibroblasts demonstrated fragmented Golgi morphology, delayed Brefeldin A-induced retrograde transport, and abnormal N-glycosylation, consistent with loss-of-function of v-ATPase. These cellular phenotypes mirror biochemical hallmarks of metabolic cutis laxa and support a haploinsufficiency mechanism.
No conflicting reports have challenged the association of ATP6V1A with ARCL2D. The combination of multiple unrelated families, robust segregation data, and concordant functional assays meets criteria for a Strong clinical validity classification.
Key Take-Home: Biallelic ATP6V1A variants cause ARCL2D via defective v-ATPase function, and genetic testing for ATP6V1A should be included in diagnostic panels for cutis laxa.
Gene–Disease AssociationStrongSix affected individuals from two unrelated families ([PMID:33320377]), segregation in families, concordant functional data Genetic EvidenceStrongBiallelic ATP6V1A variants in six probands, confirmed segregation in two families Functional EvidenceModeratePatient fibroblast assays demonstrate Golgi fragmentation, delayed retrograde transport, and glycosylation abnormalities |