ATP6V0A2 – autosomal recessive cutis laxa type 2A

Autosomal recessive cutis laxa type 2A (ARCL2A; MONDO:0018163) is a congenital connective tissue disorder characterized by redundant, inelastic skin, facial dysmorphism and glycosylation defects. ARCL2A results from biallelic loss-of-function variants in ATP6V0A2, encoding the a2 subunit of the vacuolar H+-ATPase complex (PMID:19321599). Clinically, patients present with cutis laxa, growth and developmental delay, variable neurological involvement and combined N- and O-glycosylation defects.

Genetic testing has identified pathogenic ATP6V0A2 variants in 69 individuals from 64 unrelated families (PMID:33369135) and in 17 additional patients in an initial cohort study (PMID:19321599). All reported variants segregate in an autosomal recessive manner with homozygous or compound heterozygous genotypes confirmed in affected sib-pairs. One sibling pair carried a canonical splice acceptor variant c.1605+1G>A, while another family harbored a start-loss variant c.3G>C (p.Met1Ile) (PMID:33369135).

The variant spectrum includes 54 predicted null alleles—nonsense, frameshift and essential splice site changes—and 11 missense substitutions without clear hypomorphic effects, with no recurrent founder variants reported to date (PMID:33369135). Case reports have expanded this spectrum: a 22-year-old female with long philtrum and reduced visual acuity harbored a homozygous splice acceptor change (c.1605+1G>A) (PMID:36728588), and a Han-Chinese newborn with skin laxity carried a noncanonical intronic splice variant c.117+5G>T (PMID:38598037).

Phenotypic variability is notable. Facial dysmorphism (HP:0000271), seizures (HP:0001250) and high palate correlate with earlier age at ascertainment (p=0.024 and p=0.005 respectively) (PMID:33369135). Ophthalmic findings, including ptosis and macular scar lesions with reduced visual acuity (HP:0007663), underscore the need for multidisciplinary surveillance (PMID:36728588).

Functional assays in two Mexican Mestizo patients confirmed combined N-linked transferrin and variable O-linked ApoC-III glycosylation defects, consistent with ATP6V0A2-CDG (PMID:27896089). Cellular studies demonstrate that loss of ATP6V0A2 by siRNA or in patient fibroblasts causes Golgi cisternal distension, tropoelastin retention, impaired elastin secretion and increased apoptosis, establishing a loss-of-function mechanism (PMID:19321599).

Together, these data define haploinsufficiency of ATP6V0A2 as the pathogenic mechanism in ARCL2A, with concordant genetic and experimental evidence supporting a definitive gene–disease relationship. Ongoing identification of rare splice and missense alleles will refine genotype–phenotype correlations and inform genetic counseling.

Key Take-home: Biallelic ATP6V0A2 loss-of-function variants cause definitive ARCL2A; genetic testing and functional glycosylation assays are essential for diagnosis and management.

References

• Retinal cases & brief reports • 2024 • NOVEL RETINAL FINDINGS IN A PATIENT WITH AUTOSOMAL RECESSIVE CUTIS LAXA TYPE 2A. PMID:36728588
• American journal of medical genetics. Part A • 2021 • Review of clinical and molecular variability in autosomal recessive cutis laxa 2A. PMID:33369135
• Molecular genetics and metabolism reports • 2014 • ATP6V0A2 mutations present in two Mexican Mestizo children with an autosomal recessive cutis laxa syndrome type IIA. PMID:27896089
• Human molecular genetics • 2009 • Loss-of-function mutations in ATP6V0A2 impair vesicular trafficking, tropoelastin secretion and cell survival. PMID:19321599
• Molecular biology reports • 2024 • Identification of a novel intronic variant of ATP6V0A2 in a Han-Chinese family with cutis laxa. PMID:38598037

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