PPP1CB – Noonan syndrome-like disorder with loose anagen hair

PPP1CB encodes the catalytic subunit beta of protein phosphatase 1 (PP1β), a key regulator of RAS/MAPK signaling. Heterozygous de novo variants in PPP1CB have been implicated in Noonan syndrome-like disorder with loose anagen hair (NSLH2), a RASopathy characterized by ectodermal anomalies and variable growth and craniofacial features. The recurrent missense variant c.146C>G (p.Pro49Arg) has been reported in multiple unrelated individuals, defining a mutational hotspot in NSLH2.

Genetic evidence comprises seven probands harboring de novo c.146C>G (p.Pro49Arg) variants in PPP1CB across unrelated families ([PMID:28211982]; [PMID:35338599]). All cases arose in an autosomal dominant manner with no affected relatives, underscoring de novo occurrence. The variant consistently segregates with disease and is absent from population databases, supporting pathogenicity.

Patients uniformly present with loose anagen hair (HP:0040169), relative macrocephaly with a high forehead (HP:0000348), short stature (HP:0004322) and, in one case, craniosynostosis (HP:0001363) expanding the phenotypic spectrum. Recombinant human growth hormone therapy showed efficacy in promoting linear growth in one patient without typical SHOC2-related growth hormone deficiency.

Functional studies elucidate a gain-of-function mechanism: PP1β forms a holophosphatase complex with SHOC2 and MRAS to dephosphorylate RAF1, potentiating downstream MAPK signaling. Cryo-EM resolved the SHOC2-MRAS-PP1C complex structure, defining critical PP1β binding interfaces and explaining how p.Pro49Arg enhances complex stability and activity ([PMID:35831509]).

Additional evidence from co-immunoprecipitation demonstrates LZTR1 association with the RAF1-PPP1CB complex, confirming PP1β’s role in RAS/MAPK modulation ([PMID:30368668]). These mechanistic data concord with human phenotypes and substantiate a pathogenic gain-of-function model.

Key take-home: PPP1CB c.146C>G (p.Pro49Arg) is a recurrent de novo hotspot causing NSLH2 via enhanced RAS/MAPK signaling, warranting targeted genetic testing and informing growth hormone therapy considerations.

References

• American journal of medical genetics. Part A • 2017 • The recurrent PPP1CB mutation p.Pro49Arg in an additional Noonan-like syndrome individual: Broadening the clinical phenotype. PMID:28211982
• American journal of medical genetics. Part A • 2022 • Two Japanese patients with Noonan syndrome-like disorder with loose anagen hair 2. PMID:35338599
• Human genetics • 2019 • Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes. PMID:30368668
• Nature • 2022 • Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex. PMID:35831509

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