PDGFRB – Penttinen Premature Aging Syndrome

Penttinen syndrome (MONDO:0011150) is an autosomal-dominant progeroid disorder characterized by lipoatrophy, dermal atrophy, fine hair, proptosis, prematurely aged appearance and acro-osteolysis. Causative heterozygous PDGFRB variants confer gain-of-function effects on the receptor tyrosine kinase β, leading to tissue-specific dysregulation of PDGF signaling.

Genetic evidence supports a strong gene-disease association. Four simplex cases of Penttinen syndrome were initially reported with a de novo PDGFRB c.1994T>C (p.Val665Ala) variant (PMID:26279204). A fifth unrelated individual with identical de novo c.1994T>C (p.Val665Ala) was subsequently described (PMID:40248971). These five probands define an autosomal-dominant inheritance pattern with recurrent missense variation and no other variant classes reported.

The recurrent c.1994T>C (p.Val665Ala) variant has been observed in five unrelated individuals, all simplex de novo cases, indicating a mutational hotspot in the kinase domain. No loss-of-function or splice variants have been associated with Penttinen syndrome, and no familial segregation beyond de novo occurrence has been documented.

Functional assays demonstrate constitutive receptor activation. Transfection of PDGFRB p.Val665Ala into HeLa cells elicited ligand-independent phosphorylation of STAT3 and PLCγ, confirming gain-of-function signaling (PMID:26279204). Subsequent studies revealed that the p.Val665Ala mutant activates STAT1 in the absence of ligand, eliciting an interferon-like transcriptional program (PMID:35689379).

Importantly, the aberrant signaling by PDGFRB p.Val665Ala is targetable: imatinib, dasatinib, nilotinib and ponatinib inhibited receptor autophosphorylation and downstream pathways at therapeutic concentrations (PMID:35689379). This provides a mechanistic rationale for tyrosine kinase inhibitor therapy in Penttinen syndrome.

No studies have refuted the pathogenicity of p.Val665Ala in Penttinen syndrome, and the absence of alternative genetic causes in reported probands strengthens the association. Further work may explore long-term outcomes of TKI treatment and the full phenotypic spectrum.

Key Take-home: PDGFRB c.1994T>C (p.Val665Ala) is a recurrent gain-of-function variant causing autosomal-dominant Penttinen syndrome with a progeroid phenotype that is amenable to targeted kinase inhibition.

References

• American journal of human genetics • 2015 • A Point Mutation in PDGFRB Causes Autosomal-Dominant Penttinen Syndrome PMID:26279204
• American journal of medical genetics. Part A • 2025 • A Case of Penttinen Syndrome With Radiographic Acroosteolysis From Age 3 Year PMID:40248971
• Journal of cellular and molecular medicine • 2022 • Penttinen syndrome-associated PDGFRB Val665Ala variant causes aberrant constitutive STAT1 signalling PMID:35689379

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