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Clinical Heterogeneity in two patients with Noonan-like Syndrome associated with the same SHOC2 mutation.

ABSTRACT: Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM #607721) has been recently related to the invariant c.4A?>?G missense change in SHOC2. It is characterized by features reminiscent of Noonan syndrome. Ectodermal involvement, short stature associated to growth hormone (GH) deficiency (GHD), and cognitive deficits are common features. We compare in two patients with molecularly confirmed NS/LAH diagnosis, the clinical phenotype and pathogenetic mechanism underlying short stature. In particular, while both the patients exhibited a severe short stature, GH/IGFI axis functional evaluation revealed a different pathogenetic alteration, suggesting in one patient an upstream alteration (typical GHD) and in the other one a peripheral GH insensitivity.

SUBMITTER: Capalbo D

PROVIDER: S-EPMC4231415 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Clinical Heterogeneity in two patients with Noonan-like Syndrome associated with the same SHOC2 mutation.

Capalbo Donatella D Scala Maria Giuseppa MG Melis Daniela D Minopoli Giorgia G Improda Nicola N Palamaro Loredana L Pignata Claudio C Salerno Mariacarolina M

Italian journal of pediatrics 20120920

Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM #607721) has been recently related to the invariant c.4A > G missense change in SHOC2. It is characterized by features reminiscent of Noonan syndrome. Ectodermal involvement, short stature associated to growth hormone (GH) deficiency (GHD), and cognitive deficits are common features. We compare in two patients with molecularly confirmed NS/LAH diagnosis, the clinical phenotype and pathogenetic mechanism underlying short stature. In partic ...[more]

PMID: 22995099

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Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair.

Project description:N-myristoylation is a common form of co-translational protein fatty acylation resulting from the attachment of myristate to a required N-terminal glycine residue. We show that aberrantly acquired N-myristoylation of SHOC2, a leucine-rich repeat-containing protein that positively modulates RAS-MAPK signal flow, underlies a clinically distinctive condition of the neuro-cardio-facial-cutaneous disorders family. Twenty-five subjects with a relatively consistent phenotype previously termed Noonan-like syndrome with loose anagen hair (MIM607721) shared the 4A>G missense change in SHOC2 (producing an S2G amino acid substitution) that introduces an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. Expression of SHOC2(S2G) in vitro enhanced MAPK activation in a cell type-specific fashion. Induction of SHOC2(S2G) in Caenorhabditis elegans engendered protruding vulva, a neomorphic phenotype previously associated with aberrant signaling. These results document the first example of an acquired N-terminal lipid modification of a protein causing human disease.

| S-EPMC2765465 | biostudies-literature

SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis.

Project description:Dephosphorylation of the inhibitory "S259" site on RAF kinases (S259 on CRAF, S365 on BRAF) plays a key role in RAF activation. The MRAS GTPase, a close relative of RAS oncoproteins, interacts with SHOC2 and protein phosphatase 1 (PP1) to form a heterotrimeric holoenzyme that dephosphorylates this S259 RAF site. MRAS and SHOC2 function as PP1 regulatory subunits providing the complex with striking specificity against RAF. MRAS also functions as a targeting subunit as membrane localization is required for efficient RAF dephosphorylation and ERK pathway regulation in cells. SHOC2's predicted structure shows remarkable similarities to the A subunit of PP2A, suggesting a case of convergent structural evolution with the PP2A heterotrimer. We have identified multiple regions in SHOC2 involved in complex formation as well as residues in MRAS switch I and the interswitch region that help account for MRAS's unique effector specificity for SHOC2-PP1. MRAS, SHOC2, and PPP1CB are mutated in Noonan syndrome, and we show that syndromic mutations invariably promote complex formation with each other, but not necessarily with other interactors. Thus, Noonan syndrome in individuals with SHOC2, MRAS, or PPPC1B mutations is likely driven at the biochemical level by enhanced ternary complex formation and highlights the crucial role of this phosphatase holoenzyme in RAF S259 dephosphorylation, ERK pathway dynamics, and normal human development.

| S-EPMC6233131 | biostudies-literature

Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation.

Project description:Noonan syndrome (NS) is characterized by short stature, facial dysmorphisms and congenital heart defects. PTPN11 mutations are the most common cause of NS. Patients with NS have a predisposition for leukemia and certain solid tumors. Data on the incidence of malignancies in NS are lacking. Our objective was to estimate the cancer risk and spectrum in patients with NS carrying a PTPN11 mutation. In addition, we have investigated whether specific PTPN11 mutations result in an increased malignancy risk. We have performed a cohort study among 297 Dutch NS patients with a PTPN11 mutation (mean age 18 years). The cancer histories were collected from the referral forms for DNA diagnostics, and by consulting the Dutch national registry of pathology and the Netherlands Cancer Registry. The reported frequencies of cancer among NS patients were compared with the expected frequencies using population-based incidence rates. In total, 12 patients with NS developed a malignancy, providing a cumulative risk for developing cancer of 23% (95% confidence interval (CI), 8-38%) up to age 55 years, which represents a 3.5-fold (95% CI, 2.0-5.9) increased risk compared with that in the general population. Hematological malignancies occurred most frequently. Two malignancies, not previously observed in NS, were found: a malignant mastocytosis and malignant epithelioid angiosarcoma. No correlation was found between specific PTPN11 mutations and cancer occurrence. In conclusion, this study provides first evidence of an increased risk of cancer in patients with NS and a PTPN11 mutation, compared with that in the general population. Our data do not warrant specific cancer surveillance.

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A First Case Report of Subependymoma in PTPN11 Mutation-Associated Noonan Syndrome.

Project description:Noonan syndrome (NS) is an autosomal dominant disorder in some cases caused by PTPN11 mutations. Since somatic mutations in PTPN11 are seen in several tumor types, NS which causes germline PTPN11 mutations are also increase the risk of hematologic malignancies and brain solid tumors. However, the report of brain tumors in Noonan syndrome remains rather rare. Here, we report the first case of an 11-year-old Thai boy with Noonan syndrome who presented with symptoms related to hydrocephalus secondary to subependymoma in the fourth ventricle, and PTPN11 mutation was identified in this patient.

| S-EPMC6766114 | biostudies-literature

Noonan syndrome: rhGH treatment and PTPN11 mutation.

Project description:ObjectiveTo analyze the clinical data and genetic characteristics of Noonan syndrome, both the effect and side effects of recombinant human growth hormone (rhGH) treatment.MethodsWe collected clinical data from 8 children with Noonan syndrome diagnosed from November 2017 to June 2021. The diagnosis was clarified by exome second-generation sequencing and parental PCR-NGS validation and interpretation of the preceding evidence, and growth hormone therapy was administered. Of the cases, four males and four females were seen for slow height growth and the median age at diagnosis was 8 years 7 months (1 year 7 months to 12 years 6 months).ResultsHere, 7 children were treated with rhGH. Compared to the pre-treatment period, the growth rate increased after rhGH treatment [3.7 ± 0.5 cm/year before treatment and 8.0 ± 1.0 cm/year after treatment, p < 0.01], with the maximum growth rate between 3 and 6 months of treatment and decreasing with the duration of treatment thereafter. The growth hormone treatment was discontinued and the orthopedic consultation was ordered with regular follow-up, which was considered to be related to the PTPN11 mutation.ConclusionNoonan syndrome is characterized by slow growth, short stature, mental retardation, peculiar facial features, structural heart abnormalities and abnormal bone metabolism. and osteochondroma was found after case 2 rhGH treatment. Genetic examination is mostly caused by PTPN11 mutation. It is recommended to pay attention to bone metabolism abnormalities before growth hormone treatment, especially in children with PTPN11 mutations.

| S-EPMC10655517 | biostudies-literature

Hematopoietic and neural crest defects in zebrafish shoc2 mutants: a novel vertebrate model for Noonan-like syndrome.

Project description:The extracellular signal-related kinase 1 and 2 (ERK1/2) pathway is a highly conserved signaling cascade with numerous essential functions in development. The scaffold protein Shoc2 amplifies the activity of the ERK1/2 pathway and is an essential modulator of a variety of signaling inputs. Germline mutations in Shoc2 are associated with the human developmental disease known as the Noonan-like syndrome with loose anagen hair. Clinical manifestations of this disease include congenital heart defects, developmental delays, distinctive facial abnormalities, reduced growth and cognitive deficits along with hair anomalies. The many molecular details of pathogenesis of the Noonan-like syndrome and related developmental disorders, cumulatively called RASopathies, remain poorly understood. Mouse knockouts for Shoc2 are embryonic lethal, emphasizing the need for additional animal models to study the role of Shoc2 in embryonic development. Here, we characterize a zebrafish shoc2 mutant, and show that Shoc2 is essential for development, and that its loss is detrimental for the development of the neural crest and for hematopoiesis. The zebrafish model of the Noonan-like syndrome described here provides a novel system for the study of structure-function analyses and for genetic screens in a tractable vertebrate system.

| S-EPMC6337701 | biostudies-literature

The role of USP7 in the Shoc2-ERK1/2 signaling axis and Noonan-like syndrome with loose anagen hair.

Project description:The ERK1/2 (also known as MAPK3 and MAPK1, respectively) signaling pathway is critical in organismal development and tissue morphogenesis. Deregulation of this pathway leads to congenital abnormalities with severe developmental dysmorphisms. The core ERK1/2 cascade relies on scaffold proteins, such as Shoc2 to guide and fine-tune its signals. Mutations in SHOC2 lead to the development of the pathology termed Noonan-like Syndrome with Loose Anagen Hair (NSLAH). However, the mechanisms underlying the functions of Shoc2 and its contributions to disease progression remain unclear. Here, we show that ERK1/2 pathway activation triggers the interaction of Shoc2 with the ubiquitin-specific protease USP7. We reveal that, in the Shoc2 module, USP7 functions as a molecular 'switch' that controls the E3 ligase HUWE1 and the HUWE1-induced regulatory feedback loop. We also demonstrate that disruption of Shoc2-USP7 binding leads to aberrant activation of the Shoc2-ERK1/2 axis. Importantly, our studies reveal a possible role for USP7 in the pathogenic mechanisms underlying NSLAH, thereby extending our understanding of how ubiquitin-specific proteases regulate intracellular signaling.

| S-EPMC8627560 | biostudies-literature

Noonan syndrome: clinical aspects and molecular pathogenesis.

Project description:Noonan syndrome (NS) is a relatively common, clinically variable and genetically heterogeneous developmental disorder characterized by postnatally reduced growth, distinctive facial dysmorphism, cardiac defects and variable cognitive deficits. Other associated features include ectodermal and skeletal defects, cryptorchidism, lymphatic dysplasias, bleeding tendency, and, rarely, predisposition to hematologic malignancies during childhood. NS is caused by mutations in the PTPN11, SOS1, KRAS, RAF1, BRAF and MEK1 (MAP2K1) genes, accounting for approximately 70% of affected individuals. SHP2 (encoded by PTPN11), SOS1, BRAF, RAF1 and MEK1 positively contribute to RAS-MAPK signaling, and possess complex autoinhibitory mechanisms that are impaired by mutations. Similarly, reduced GTPase activity or increased guanine nucleotide release underlie the aberrant signal flow through the MAPK cascade promoted by most KRAS mutations. More recently, a single missense mutation in SHOC2, which encodes a cytoplasmic scaffold positively controlling RAF1 activation, has been discovered to cause a closely related phenotype previously termed Noonan-like syndrome with loose anagen hair. This mutation promotes aberrantly acquired N-myristoylation of the protein, resulting in its constitutive targeting to the plasma membrane and dysregulated function. PTPN11, BRAF and RAF1 mutations also account for approximately 95% of LEOPARD syndrome, a condition which resembles NS phenotypically but is characterized by multiple lentigines dispersed throughout the body, café-au-lait spots, and a higher prevalence of electrocardiographic conduction abnormalities, obstructive cardiomyopathy and sensorineural hearing deficits. These recent discoveries demonstrate that the substantial phenotypic variation characterizing NS and related conditions can be ascribed, in part, to the gene mutated and even the specific molecular lesion involved.

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Noonan syndrome-associated SHP2 mutation differentially modulates the expression of postsynaptic receptors according to developmental maturation.

Project description:Glutamate is the major excitatory neurotransmitter in the central nervous system, and related signaling involves both AMPA and NMDA subtype receptors. The expression of glutamate receptors is dynamically regulated during development. Recent studies showed that the dysregulation of glutamate receptor expression and function is associated with neurodevelopmental disorders including intellectual disability. Previously, a Noonan syndrome (NS)-associated SHP2 mutation (SHP2D61G) was shown to increase the synaptic delivery of AMPA receptor, subsequently impairing synaptic plasticity and learning in adult mice. However, how the mutant SHP2 affects glutamate receptor expression during development is not known. Here, we found that the SHP2D61G differentially regulates the expression of AMPA and NMDA receptors depending on the stage of neuronal maturation. In cultured neurons (immature stage; DIV 6), overexpression of SHP2D61G significantly increased the average size and the number of NMDA receptor-containing particles, but not those with AMPA receptors. In early matured neurons (DIV 12), SHP2D61G significantly increased only the average size of AMPA receptor particles, and subsequently increased their number in matured neurons (DIV 18). Importantly, all the changes described above for SHP2D61G neurons were reversed by inhibiting MAPK. These data demonstrate that the increased activation of MAPK signaling pathway by SHP2D61G could deregulate the surface expression of synaptic receptors during neuronal development, which likely contributes to cognitive impairments in NS patients.

| S-EPMC6844293 | biostudies-literature

Noonan syndrome.

Project description:Noonan syndrome is a genetic multisystem disorder characterised by distinctive facial features, developmental delay, learning difficulties, short stature, congenital heart disease, renal anomalies, lymphatic malformations, and bleeding difficulties. Mutations that cause Noonan syndrome alter genes encoding proteins with roles in the RAS-MAPK pathway, leading to pathway dysregulation. Management guidelines have been developed. Several clinically relevant genotype-phenotype correlations aid risk assessment and patient management. Increased understanding of the pathophysiology of the disease could help development of pharmacogenetic treatments.

| S-EPMC4267483 | biostudies-literature

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