ATP6V1E1 was first reported in relation to ATP6V1E1-CDG (also known as autosomal recessive cutis laxa 2C), an autosomal recessive congenital disorder of glycosylation, in 2016 (Alazami et al, PMID: 27023906). ATP6V1E1-CDG is characterized by the features of cutis laxa (wrinkly, inelastic, droopy skin), redundant skin, typical mask-like facial appearance, muscular hypotonia, cardiac abnormalities, and glycosylation and Golgi defects.
Two variants, both missense, have been reported in 3 homozygous probands, each with an affected sibling with the same genotype (Alazami et al, 2016, PMID: 27023906; Van Damme et al, 2017, PMID: 28065471) (Genetic evidence, 1.2 points).
This gene-disease relationship is also supported by experimental evidence, including the biochemical function of the gene product. encodes a subunit of the V1 domain of V-ATPase, a multi-subunit proton pump that maintains organelle luminal pH in eukaryotic cells. Variants in genes encoding other subunits of V-ATPase (ATP6V0A2, ATP6V1A) have been implicated in causing similar clinical features. Specifically, the clinical validity classification for ATP6V0A2 with CDG has been classified as definitive by the ClinGen CDG GCEP. In addition, studies on skin biopsy samples and cultured fibroblasts from an affected individual show disruption of vesicular trafficking and abnormalities of elastic fibers and the extracellular matrix, consistent with the connective tissue features observed in patients (Van Damme et al, 2017, PMID: 28065471). Two zebrafish models with atp6v1e1b deficiency recapitulate features of the disorder, including dermis abnormalities, vascular defects, glycosylation defects, and Golgi abnormalities (Pottie et al, 2021, PMID: 34143769) (Experimental evidence: 4.5 points)
In summary, there is limited evidence supporting the relationship between ATP6V1E1 and ATP6V1E1-CDG (also known as autosomal recessive cutis laxa 2C). This classification was approved by the ClinGen Congenital Disorders of Glycosylation Gene Curation Expert Panel on May 1, 2024 (SOP version 10).