ATP6V0A4 – autosomal recessive distal renal tubular acidosis

The ATP6V0A4 gene encodes the a4 subunit of the vacuolar H⁺-ATPase involved in distal nephron acidification. Pathogenic variants lead to autosomal recessive distal renal tubular acidosis (MONDO:0018440), characterized by impaired urinary acidification and systemic acidemia.

Multiple case reports describe novel ATP6V0A4 mutations in infants and children with dRTA. A Japanese infant with compound heterozygous Ile549fsX580 and Ile557Leu558del presented with failure to thrive, vomiting, metabolic acidosis, hyperammonemia, and nephrocalcinosis (PMID:20221774). Two siblings with compound heterozygous c.2419C>T (p.Arg807Ter) and c.2420G>A (p.Arg807Gln) exhibited failure to thrive and late-onset sensorineural hearing loss, underscoring the need for early audiologic assessment (PMID:23754897).

In a cohort of 26 rdRTA kindreds, linkage and mutation analysis identified ATP6V0A4 defects in 12 unrelated families. Variants included c.1187dup (p.Tyr396Ter), splice site mutations, and missense changes, confirming genetic heterogeneity and autosomal recessive segregation (PMID:12414817).

A Mexican study of nine families found three homozygous ATP6V0A4 variants (p.Arg194Ter, p.Asp411Tyr, p.Arg743Trp) and one frameshift (p.Val52MetfsTer25), with p.Asp411Tyr occurring in four families due to a founder effect. All ATP6V0A4 patients showed dRTA without early hearing loss (PMID:27247958).

Functional assays support pathogenicity of intronic and missense variants. A minigene splicing study demonstrated that c.1029+5G>A causes a 104-bp insertion after exon 11, abolishing normal transcript (PMID:29202719). Cellular expression of p.Ser544Leu showed impaired V-ATPase assembly and reduced proton transport in HEK293T cells (PMID:32123165).

Clinically, ATP6V0A4-related dRTA presents in infancy with failure to thrive (HP:0001508), hyperchloremic metabolic acidosis (HP:0001942), hypokalemia (HP:0002900), nephrocalcinosis (HP:0000121), hypercalciuria (HP:0002150), and variable sensorineural hearing impairment (HP:0000407). Early genetic testing and audiologic evaluation are recommended regardless of initial hearing status (PMID:23754897).

The autosomal recessive inheritance, identification of multiple loss-of-function and missense variants in unrelated probands, segregation in families, and corroborating functional data support a Strong gene–disease relationship. Sequencing of ATP6V0A4 is clinically useful for confirming dRTA diagnosis and guiding metabolic and audiologic management.

References

• European journal of pediatrics • 2010 • Novel compound heterozygous ATP6V0A4 mutations in an infant with distal renal tubular acidosis. PMID:20221774
• International medical case reports journal • 2011 • Importance of early audiologic assessment in distal renal tubular acidosis. PMID:23754897
• Journal of medical genetics • 2002 • Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss. PMID:12414817
• Molecular genetics & genomic medicine • 2016 • Mutations in ATP6V1B1 and ATP6V0A4 genes cause recessive distal renal tubular acidosis in Mexican families. PMID:27247958
• BMC nephrology • 2017 • An in vitro splicing assay reveals the pathogenicity of a novel intronic variant in ATP6V0A4 for autosomal recessive distal renal tubular acidosis. PMID:29202719
• Medicine • 2019 • A novel homozygous deletion in ATP6V0A4 causes distal renal tubular acidosis: A case report. PMID:31348261
• Cell death & disease • 2020 • Screening and function discussion of a hereditary renal tubular acidosis family pathogenic gene. PMID:32123165

Evidence Based Scoring (AI generated)