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Dilated cardiomyopathy (DCM) is a life-threatening disorder with heterogeneous genetic etiology. Among newly implicated genes is PPP1R13L, which encodes the inhibitor of apoptosis-stimulating protein of p53 (iASPP). Biallelic loss-of-function variants in PPP1R13L have been reported in syndromic forms of early-onset DCM accompanied by skin, hair, craniofacial, and ocular anomalies. The clinical presentations range from isolated severe heart failure to multi-system involvement including woolly hair and cleft lip and palate. Functional studies in both human cells and animal models implicate a failure to regulate NF-κB–mediated inflammatory pathways. Here, we review the genetic and experimental evidence supporting PPP1R13L as an autosomal recessive cause of dilated cardiomyopathy.
In a multi-patient study, five Arab Christian infants from four unrelated families presented with severe DCM and mild cutaneous abnormalities, all dying before age three (PMID:28069640). Homozygous premature stop and frameshift variants – c.736_764del (p.Pro246fs), c.1068dup (p.Ser357ArgfsTer?), and c.2241C>G (p.Tyr747Ter) – were identified in PPP1R13L (PMID:28069640). Patients’ fibroblasts and Ppp1r13l-deficient murine cardiomyocytes showed heightened NF-κB–dependent expression of pro-inflammatory cytokine genes on lipopolysaccharide challenge (PMID:28069640). These findings suggest that iASPP loss-of-function deregulates cardiac inflammatory thresholds. Segregation was demonstrated across five affected probands within these families, with heterozygous carriers unaffected. This constitutes initial strong genetic evidence for autosomal recessive PPP1R13L-associated DCM.
Subsequent case series in a consanguineous family described six children homozygous for a frameshift p.Arg330ProfsTer76 variant, all developing childhood-onset DCM (PMID:37698259). Phenotypes included woolly hair in all affected, orofacial cleft in two siblings, and glaucoma in three cousins; one child exhibited global developmental delay. Exome and genome sequencing excluded alternate genetic etiologies (PMID:37698259). In another unrelated family, two siblings with progressive DCM and skin appendage anomalies also harbored biallelic c.1871_1872del (p.Arg624ProfsTer?) in PPP1R13L (PMID:39579152). Anorectal malformations in this sib-pair expand the phenotypic spectrum. Both studies confirm segregation of LoF alleles with disease in eight additional affected relatives.
To date, at least seven distinct truncating alleles in PPP1R13L have been reported, comprising three frameshift deletions, one duplication, and three nonsense variants. All variants predict loss of the C-terminal ankyrin-repeat region crucial for NF-κB interaction. The inheritance mode is consistently autosomal recessive, with heterozygous carriers clinically unaffected. No recurrent or founder alleles have been established, and population frequencies are absent or extremely low. The variant c.2241C>G (p.Tyr747Ter) serves as an exemplar truncating allele reported in multiple infants (PMID:28069640). While developmental and cutaneous manifestations vary, penetrance for early-onset DCM appears complete. Carrier frequency and prevalence of PPP1R13L-related DCM remain to be defined.
The in vivo relevance of PPP1R13L loss-of-function was first demonstrated in wa3 mice, which carry a recessive Nkip1 allele homologous to human PPP1R13L and develop rapidly progressive DCM and skin defects (PMID:15661756). Wa3 mutants exhibit elevated Icam1 expression, supporting a role for deregulated NF-κB signaling in disease pathogenesis. More recent studies using patient-derived iASPP mutants show that truncating alleles lead to loss of C-terminal domain stability and aggregation in vitro (PMID:39695191). Aggregated mutants fail to inhibit NF-κB activity, further promoting inflammatory gene expression. Rescue experiments are pending but the mechanistic convergence underscores haploinsufficiency through loss of NF-κB regulation. These findings corroborate the pathogenic mechanism inferred from human genetic data.
Integration of genetic and functional evidence establishes PPP1R13L as a robust autosomal recessive gene for syndromic DCM. The consistent observation of biallelic truncating variants across multiple unrelated families, with full segregation in affected sibships, supports a Strong ClinGen classification. The inflammatory mechanism mediated by disrupted NF-κB regulation aligns with murine phenotypes and in vitro assays. Additional cases may reveal further allelic and phenotypic diversity, including anorectal and ocular anomalies. Clinically, inclusion of PPP1R13L in DCM gene panels is warranted, particularly in early-onset or syndromic presentations. Key take-home: Genetic testing for PPP1R13L informs diagnosis and management in infants with dilated cardiomyopathy and cutaneous or craniofacial features.
Gene–Disease AssociationStrong13 probands from 6 unrelated families with biallelic LoF variants; segregation in 8 affected relatives; concordant functional data Genetic EvidenceStrong13 probands in 6 families with autosomal recessive LoF PPP1R13L; segregation in 8 affected sibships Functional EvidenceModerateAnimal models and cellular assays show NF-κB–mediated inflammatory mechanism concordant with patient phenotype |