PPP1CB – Noonan syndrome-like disorder with loose anagen hair 2

The protein phosphatase 1 catalytic subunit beta (PPP1CB) has been definitively implicated in Noonan syndrome-like disorder with loose anagen hair 2 (MONDO:0054588). ClinGen assigns a Strong gene-disease association based on 19 unrelated probands (17 previously reported + 2 newly described) harboring de novo missense variants c.146C>G (p.Pro49Arg) (PMID:32476286; PMID:40586991).

Inheritance is autosomal dominant with all affected individuals carrying a heterozygous de novo missense change at codon 49 of PPP1CB. No familial segregation beyond de novo occurrence has been observed. The variant spectrum is currently limited to this single recurrent missense allele c.146C>G (p.Pro49Arg), identified in multiple unrelated patients.

Clinically, patients present with global developmental delay (HP:0001263), short stature (HP:0004322), congenital heart defects including abnormal heart morphology (HP:0001627) and the pathognomonic loose anagen hair phenotype (HP:0040169), consistent across all reports.

Functional studies support a gain-of-function mechanism in RAS/MAPK signaling. Co-immunoprecipitation demonstrates that PPP1CB binds to LZTR1 and RAF1, forming a holophosphatase complex that regulates RAF1 Ser259 phosphorylation; LZTR1 knockdown alters RAF1 pSer259 levels, implicating PPP1CB in pathway activation (PMID:30368668).

Isoform-specific localization studies further show that PP1β localizes distinctly to neuronal cytoskeletal elements, aligning with neurodevelopmental and structural brain phenotypes observed in patients (PMID:10502246). These data converge on a model whereby p.Pro49Arg perturbs PPP1CB regulatory interactions, driving aberrant MAPK pathway activation and the NSLAH2 phenotype.

No conflicting evidence has been reported. While additional in vivo modeling and rescue assays would strengthen mechanistic insight, current genetic and biochemical data robustly support clinical testing of PPP1CB in patients with Noonan-like features and loose anagen hair.

Key Take-home: De novo recurrent PPP1CB p.Pro49Arg is a pathogenic gain-of-function variant responsible for NSLAH2, guiding molecular diagnosis and potential targeted pathway modulation.

References

• American Journal of Medical Genetics. Part A • 2020 • A case report of Noonan syndrome-like disorder with loose anagen hair 2 treated with recombinant human growth hormone. PMID:32476286
• Neurogenetics • 2025 • Complete commissural agenesis in a child with Noonan-like syndrome with loose anagen hair 2. PMID:40586991
• Human Genetics • 2019 • Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes. PMID:30368668
• The Journal of Comparative Neurology • 1999 • Differential cellular and subcellular localization of protein phosphatase 1 isoforms in brain. PMID:10502246

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