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ATP13A3 has emerged as a critical gene in the etiology of pulmonary arterial hypertension (PAH), particularly in severe, childhood‑onset cases. Recent clinical reports indicate that biallelic ATP13A3 variants are associated with a markedly aggressive form of PAH, where early identification of these variants directly influenced therapeutic decision‑making in affected pediatric patients (PMID:35506084).
Multiple independent case studies have documented the occurrence of deleterious ATP13A3 mutations in a recessive inheritance pattern, with at least three unrelated families demonstrating segregation of the variant with the disease phenotype (PMID:34493544). In these studies, affected individuals carried compound heterozygous or homozygous mutations, underscoring a dose‑dependent effect and revealing a clear genetic underpinning for early‑onset PAH.
The genetic evidence is compelling, with a spectrum of variant types observed in ATP13A3. These include frameshift, nonsense, and missense variants. For instance, the variant selected for discussion, c.3079dup (p.Trp1027fs), was identified in multiple independent cases and is representative of the loss‑of‑function alterations seen in these patients (PMID:34493544). This broad variant spectrum, combined with the segregation data within families, reinforces the gene‑disease link.
Segregation analyses in reported families provide further support for the clinical validity of this association. In the biallelic cases, affected siblings and additional relatives have been shown to carry pathogenic ATP13A3 variants, collectively documenting segregation in at least three affected relatives across the families (PMID:34493544).
Functional studies have bolstered the genetic findings by elucidating the pathogenic mechanism of ATP13A3 in PAH. Experimental assessments demonstrate that ATP13A3 encodes a P5B‑type transport ATPase involved in polyamine transport. Disruption of this function results in endothelial cell dysfunction, increased permeability, and reduced proliferation, which are known contributors to PAH pathogenesis. Notably, in vitro and in vivo models recapitulated the human phenotype, lending strong support to the hypothesis that loss‑of‑function mutations in ATP13A3 directly drive disease development (PMID:38626311).
In summary, the integration of robust genetic data and compelling functional evidence supports a strong association between ATP13A3 and pulmonary arterial hypertension. The identification of biallelic, loss‑of‑function variants, along with clear segregation of the mutations in affected families, provides a solid foundation for the clinical application of genetic testing in PAH. This strong gene‑disease association not only aids in precise diagnostic decision‑making but also opens potential avenues for targeted therapies.
Key Take‑home message: Recognizing ATP13A3 as a critical genetic determinant in pediatric PAH enables tailored management strategies and guides both clinical practice and therapeutic development.
Gene–Disease AssociationStrongBiallelic ATP13A3 variants identified in three unrelated families with childhood‑onset PAH with clear segregation and multiple lines of experimental support (PMID:34493544). Genetic EvidenceStrongA diverse spectrum of variants, including frameshift and missense mutations such as c.3079dup (p.Trp1027fs), has been documented across multiple probands and segregated within families (PMID:34493544). Functional EvidenceStrongFunctional assays reveal that ATP13A3 loss impairs polyamine transport and disrupts endothelial cell function, which is consistent with PAH pathogenesis as validated in both in vitro and mouse models (PMID:38626311). |