Noonan syndrome with loose anagen hair with variants in the <scp><i>PPP1CB</i></scp> gene: First familial case reported

Huckstadt, Victoria; Chinton, Josefina; Gomez, Abel; Obregón, María Gabriela; Gravina, Luis Pablo

doi:10.1002/ajmg.a.62089

Cited by 12 publications

(6 citation statements)

References 13 publications

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“…Human de novo mutations in PP1β cause intellectual disability (Gripp et al ., 2016; Hamdan et al ., 2014; Huckstadt et al ., 2021; Lin et al ., 2018; Ma et al ., 2016; Umeki et al ., 2019; Zambrano et al ., 2017; Zhou et al ., 2020). The clinical profile of patients with these mutations resembles a Rasopathy, specifically Noonan syndrome with loose anagen hair.…”

Section: Discussionmentioning

confidence: 99%

PP1β opposes classic PP1 function, inhibiting spine maturation and promoting LTP

Foley

McKee

Ganguly

et al. 2023

Preprint

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Protein phosphatase 1 (PP1) regulates synaptic plasticity and has been described as a molecular constraint on learning and memory. There are three neuronal isoforms, PP1α, PP1β, and PP1γ, but little is known about their individual functions. PP1α and PP1γ are assumed to mediate the effects of PP1 on learning and memory based on their enrichment at dendritic spines and their preferential binding to neurabin and spinophilin, major PP1 synaptic scaffolding proteins. However, it was recently discovered that human de novo PP1β mutations cause intellectual disability, suggesting an important but ill-defined role for PP1β. In this study, we investigated the functions of each PP1 isoform in hippocampal synaptic physiology using conditional CA1-specific knockout mice. In stark contrast to classic PP1 function, we found that PP1β promotes synaptic plasticity as well as spatial memory. These changes in synaptic plasticity and memory are accompanied by changes in GluA1 phosphorylation, GluN2A levels, and dendritic spine density and morphology, including silent synapse number. These functions of PP1β reveal a previously unidentified signaling pathway regulating spine maturation and plasticity, broadening our understanding of the complex role of PP1 in synaptic physiology.

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Section: Discussionmentioning

confidence: 99%

PP1β opposes classic PP1 function, inhibiting spine maturation and promoting LTP

Foley

McKee

Ganguly

et al. 2023

Preprint

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“…PP1C is a class of serine/threonine phosphatases with three highly conserved isoforms (PP1CA, PP1CB, and PP1CC with >90% sequence identity) that are ubiquitously expressed and catalyze the dephosphorylation of a substantial fraction of phosphoserine/threonine in all eukaryotic cells [29][30][31] . Mutations in the PP1CB isoform have been found in NS, and these residues are conserved in other PP1C isoforms [32][33][34][35] .To understand how SHOC2, MRAS, and PP1C proteins assemble to form a ternary complex that regulates dephosphorylation of the RAF CR2-pS and how RASopathy mutations…”

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confidence: 99%

Structure of the SHOC2–MRAS–PP1C complex provides insights into RAF activation and Noonan syndrome

Bonsor

Alexander

Snead

et al. 2022

Nat Struct Mol Biol

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SHOC2 acts as a strong synthetic lethal interactor with MEK inhibitors in multiple KRAS cancer cell lines. SHOC2 forms a heterotrimeric complex with MRAS and PP1C that is essential for regulating RAF and MAPK-pathway activation by dephosphorylating a specific phosphoserine on RAF kinases. Here we present the high-resolution crystal structure of SHOC2-MRAS-PP1C (SMP) complex and apo-SHOC2. Our structures reveal that SHOC2, MRAS and PP1C form a stable ternary complex where all three proteins synergistically interact with each other. Our results show that dephosphorylation of RAF substrates by PP1C is enhanced upon interacting with SHOC2 and MRAS. The SMP complex only forms when MRAS is in an active state and is dependent on SHOC2 functioning as a scaffolding protein in the complex by bringing PP1C and MRAS together. Our results provide structural insights into the role of the SMP complex in RAF activation, how mutations found in Noonan syndrome enhance the complex formation and reveal new avenues for therapeutic interventions.C. elegans as a positive modulator of the MAPK pathway 12,13 . It is a ubiquitously expressed protein composed primarily of predicted leucine-rich repeats (LRRs). N-terminal to the LRR domains, SHOC2 contains a ~90-residue long sequence that is predicted to be intrinsically disordered and has been suggested to be necessary for complex formation with MRAS and PP1C 11,14 . Germline mutations in SHOC2 (S2G, M173I, and Q269H/H270Y) have been detected in NS 11,[15][16][17] . SHOC2 plays a vital role in transformation, metastasis, epithelial-tomesenchymal transition, and MAPK pathway inhibitor resistance [18][19][20][21] . Multiple genome-scale, single-gene CRISPR/Cas9 fitness screens in human cancer cells have suggested selective dependency of RAS mutant cells on SHOC2 20,[22][23][24] . SHOC2 was also identified as the strongest synthetic lethal target in the presence of MEK inhibitors in KRAS mutant lung and pancreatic cancer cell lines 19 . Thus, SHOC2 may provide a unique therapeutic opportunity within the RTK-RAS-MAPK pathway in oncogenic RAS cells.The SMP complex formation is initiated following MRAS activation as SHOC2 and PP1C bind only to MRAS-GTP 25 . The canonical RAS family members HRAS, KRAS, and NRAS, also bind SHOC2, although with considerably lower affinity than MRAS 26 . The nature of the selectivity for MRAS is not known. MRAS shares ~50% sequence identity with the canonical RAS proteins and contains an extra ten amino acids at the N-terminus. Activating mutations in MRAS are very rare in cancer; however, gain-of-function mutations (G23V, T68I, Q71R) in MRAS have been identified in NS patients 27,28 . In the SMP complex, PP1C provides the enzymatic activity for dephosphorylation. PP1C is a class of serine/threonine phosphatases with three highly conserved isoforms (PP1CA, PP1CB, and PP1CC with >90% sequence identity) that are ubiquitously expressed and catalyze the dephosphorylation of a substantial fraction of phosphoserine/threonine in all eukaryotic cells [29][30][31] . Mutation...

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“…Most familial cases that have been reported have shown an overrepresentation of affected mothers. Although males appear to have reduced fertility, male transmission is well described and not uncommon ( 16 , 17 , 25 – 29 ).…”

Section: Vertical Transmission In Noonan Syndrome and Role Of Ras Pat...mentioning

confidence: 99%

Abnormalities of pubertal development and gonadal function in Noonan syndrome

et al. 2023

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BackgroundNoonan syndrome (NS) is a genetic multisystem disorder characterised by variable clinical manifestations including dysmorphic facial features, short stature, congenital heart disease, renal anomalies, lymphatic malformations, chest deformities, cryptorchidism in males.MethodsIn this narrative review, we summarized the available data on puberty and gonadal function in NS subjects and the role of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway in fertility. In addition, we have reported our personal experience on pubertal development and vertical transmission in NS.ConclusionsAccording to the literature and to our experience, NS patients seem to have a delay in puberty onset compared to the physiological timing reported in healthy children. Males with NS seem to be at risk of gonadal dysfunction secondary not only to cryptorchidism but also to other underlying developmental factors including the MAP/MAPK pathway and genetics. Long-term data on a large cohort of males and females with NS are needed to better understand the impact of delayed puberty on adult height, metabolic profile and well-being. The role of genetic counselling and fertility related-issues is crucial.

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Noonan syndrome with loose anagen hair with variants in the PPP1CB gene: First familial case reported

Cited by 12 publications

References 13 publications

PP1β opposes classic PP1 function, inhibiting spine maturation and promoting LTP

PP1β opposes classic PP1 function, inhibiting spine maturation and promoting LTP

Structure of the SHOC2–MRAS–PP1C complex provides insights into RAF activation and Noonan syndrome

Abnormalities of pubertal development and gonadal function in Noonan syndrome

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