Skeletal Muscle Pathology in Costello and Cardio-Facio-Cutaneous Syndromes: Developmental Consequences of Germline Ras/MAPK Activation on Myogenesis
ABSTRACT Cardio-facio-cutaneous syndrome (CFC) and Costello syndrome (CS) are two of the more rare RASopathies caused by altered signal transduction of the Ras/mitogen-activated protein kinase (MAPK) pathway. All of the RASopathies exhibit some degree of hypotonia, but CS and CFC are more severe. To determine if individuals with CS and CFC have an underlying skeletal myopathy, we systematically evaluated skeletal muscle pathology in both conditions. We reviewed pathology reports from six individuals who had undergone a skeletal muscle biopsy, and we reviewed histology slides on two cases with CS and one case with CFC. All patients in the cohort had histopathologic findings, and two consistent abnormalities were identified. The first was the presence of abnormal muscle fiber size and variability, and the second was the presence of type 2 fiber predominance. Given the degree of hypotonia typically present in these patients, the overall architecture of the muscle was relatively normal, without showing indications of severe structural histopathology or metabolic abnormalities. Because the Ras/MAPK pathway is vital for skeletal myogenesis, we evaluated the effects of CS and CFC mutations on myogenesis using C2C12 myoblasts. All CS/CFC mutations inhibited myoblast differentiation as indicated by fewer myosin heavy chain expressing cells and a decrease in the number of myotubes as compared to controls. These findings indicate that CS and CFC may have a true myopathy related to an inherent dysregulation of skeletal myogenesis, which further expands our understanding of the consequences of germline Ras/MAPK mutations.
- SourceAvailable from: Carmen Gloria Morovic
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- "In particular, RARRES3, a retinoid-inducible growth regulator, was shown to reduce the level of activated Ras . HRAS activation was reported to inhibit skeletal myogenesis by favoring proliferation of myoblasts and by blocking their differentiation into muscle cells [29-32]. For these reasons, one may speculate that, in our patients, the heterozygous deletion of RARRES3 suppressor gene could have induced an enhancement of HRAS expression and activity interfering with correct skeletal muscle differentiation. "
ABSTRACT: Background Poland Syndrome (PS) is a rare disorder characterized by hypoplasia/aplasia of the pectoralis major muscle, variably associated with thoracic and upper limb anomalies. Familial recurrence has been reported indicating that PS could have a genetic basis, though the genetic mechanisms underlying PS development are still unknown. Case presentation Here we describe a couple of monozygotic (MZ) twin girls, both presenting with Poland Syndrome. They carry a de novo heterozygous 126 Kbp deletion at chromosome 11q12.3 involving 5 genes, four of which, namely HRASLS5, RARRES3, HRASLS2, and PLA2G16, encode proteins that regulate cellular growth, differentiation, and apoptosis, mainly through Ras-mediated signaling pathways. Conclusions Phenotype concordance between the monozygotic twin probands provides evidence supporting the genetic control of PS. As genes controlling cell growth and differentiation may be related to morphological defects originating during development, we postulate that the observed chromosome deletion could be causative of the phenotype observed in the twin girls and the deleted genes could play a role in PS development.BMC Medical Genetics 05/2014; 15(1):63. DOI:10.1186/1471-2350-15-63 · 2.08 Impact Factor
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ABSTRACT: Costello syndrome (OMIM# 218040) is a distinctive rare multisystem disorder comprising a characteristic coarse facial appearance, intellectual disabilities, and tumor predisposition. Although the diagnosis can be suspected clinically, confirmation requires identification of a heterozygous mutation in the proto-oncogene HRAS. In contrast to somatic oncogenic mutations in neoplasia, the Costello syndrome changes are typically introduced in the paternal germline. The predicted amino acid substitutions allow for constitutive or prolonged activation of the HRAS protein, resulting in dysregulation of the Ras/mitogen activated protein kinase pathway. Dysregulation of this signaling pathway is the disease mechanism shared among Costello syndrome and other rasopathies, including neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, and Legius syndrome. The Ras/mitogen activated protein kinase pathway governs cell proliferation and differentiation, and its dysregulation affects cardiac and brain development, accounting for the significant overlap in physical and developmental differences and common medical problems among rasopathies. Unlike the genetically heterogeneous Noonan syndrome and cardio-facio-cutaneous syndrome, Costello syndrome is caused by HRAS mutations only. Patients, clinicians, and researchers may benefit from a multidisciplinary "rasopathy clinic," which serves patients with more common conditions such as Noonan syndrome and neurofibromatosis and those affected by rare conditions such as Costello syndrome.Genetics in medicine: official journal of the American College of Medical Genetics 03/2012; 14(3):285-92. DOI:10.1038/gim.0b013e31822dd91f · 7.33 Impact Factor
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ABSTRACT: RASopathies are a group of genetic conditions due to alterations of the Ras/MAPK pathway. Neurocutaneous findings are hallmark features of the RASopathies, but musculoskeletal abnormalities are also frequent. The objective was to evaluate handgrip strength in the RASopathies. Individuals with RASopathies (e.g., Noonan syndrome, Costello syndrome, cardio-facio-cutaneous [CFC] syndrome, and neurofibromatosis type 1 [NF1]) and healthy controls were evaluated. Two methods of handgrip strength were tested: GRIP-D Takei Hand Grip Dynamometer and the Martin vigorimeter. A general linear model was fitted to compare average strength among the groups, controlling for confounders such as age, gender, height, and weight. Takei dynamometer: handgrip strength was decreased in each of the syndromes compared with controls. Decreased handgrip strength compared with sibling controls was also seen with the Martin vigorimeter (P < 0.0001). Handgrip strength is decreased in the RASopathies. The etiology of the reduced muscle force is unknown, but likely multifactorial.Muscle & Nerve 09/2012; 46(3):394-9. DOI:10.1002/mus.23324 · 2.28 Impact Factor