AKT1 gene mutation levels are correlated with the type of dermatologic lesions in patients with Proteus syndrome.
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ABSTRACT:
SUBMITTER: Lindhurst MJ
PROVIDER: S-EPMC3868633 | biostudies-literature | 2014 Feb
REPOSITORIES: biostudies-literature
Publications
AKT1 gene mutation levels are correlated with the type of dermatologic lesions in patients with Proteus syndrome.
Lindhurst Marjorie J MJ Wang Ji-An JA Bloomhardt Hadley M HM Witkowski Alison M AM Singh Larry N LN Bick David P DP Gambello Michael J MJ Powell Cynthia M CM Lee Chyi-Chia Richard CR Darling Thomas N TN Biesecker Leslie G LG
The Journal of investigative dermatology 20130724 2
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Project description:BackgroundThe Proteus syndrome is characterized by the overgrowth of skin, connective tissue, brain, and other tissues. It has been hypothesized that the syndrome is caused by somatic mosaicism for a mutation that is lethal in the nonmosaic state.MethodsWe performed exome sequencing of DNA from biopsy samples obtained from patients with the Proteus syndrome and compared the resultant DNA sequences with those of unaffected tissues obtained from the same patients. We confirmed and extended an observed association, using a custom restriction-enzyme assay to analyze the DNA in 158 samples from 29 patients with the Proteus syndrome. We then assayed activation of the AKT protein in affected tissues, using phosphorylation-specific antibodies on Western blots.ResultsOf 29 patients with the Proteus syndrome, 26 had a somatic activating mutation (c.49G→A, p.Glu17Lys) in the oncogene AKT1, encoding the AKT1 kinase, an enzyme known to mediate processes such as cell proliferation and apoptosis. Tissues and cell lines from patients with the Proteus syndrome harbored admixtures of mutant alleles that ranged from 1% to approximately 50%. Mutant cell lines showed greater AKT phosphorylation than did control cell lines. A pair of single-cell clones that were established from the same starting culture and differed with respect to their mutation status had different levels of AKT phosphorylation.ConclusionsThe Proteus syndrome is caused by a somatic activating mutation in AKT1, proving the hypothesis of somatic mosaicism and implicating activation of the PI3K-AKT pathway in the characteristic clinical findings of overgrowth and tumor susceptibility in this disorder. (Funded by the Intramural Research Program of the National Human Genome Research Institute.).
| S-EPMC3170413 | biostudies-literature
Project description:Vascular malformation, a key clinical phenotype of Proteus syndrome, lacks effective models for pathophysiological study and drug development due to limited patient sample access. To bridge this gap, we built a human vascular organoid model replicating Proteus syndrome's vasculature. Using CRISPR/Cas9 genome editing and gene overexpression, we created induced pluripotent stem cells (iPSCs) embodying the Proteus syndrome-specific AKTE17K point mutation for organoid generation. Our findings revealed that AKT overactivation in these organoids resulted in smaller sizes yet increased vascular connectivity, although with less stable connections. This could be due to the significant vasculogenesis induced by AKT overactivation. This phenomenon likely stems from boosted vasculogenesis triggered by AKT overactivation, leading to increased vascular sprouting. Additionally, a notable increase in dysfunctional PDGFRβ+ mural cells, impaired in matrix secretion, was observed in these AKT-overactivated organoids. The application of AKT inhibitors (ARQ092, AZD5363, or GDC0068) reversed the vascular malformations; the inhibitors' effectiveness was directly linked to reduced connectivity in the organoids. In summary, our study introduces an innovative in vitro model combining organoid technology and gene editing to explore vascular pathophysiology in Proteus syndrome. This model not only simulates Proteus syndrome vasculature but also holds potential for mimicking vasculatures of other genetically driven diseases. It represents an advance in drug development for rare diseases, historically plagued by slow progress.
| S-EPMC10849631 | biostudies-literature
Project description:Proteus syndrome (PS) is characterized by progressive, disproportionate, segmental overgrowth, and tumor susceptibility caused by a somatic mosaic AKT1 activating mutation. Each individual has unique manifestations making this disorder extremely heterogeneous. We correlated three variables in 38 tissue samples from a patient who died with PS: the gross affection status, the microscopic affection status, and the mutation level. The AKT1 mutation was measured using a PCR-based RFLP assay. Thirteen samples were grossly normal; six had detectable mutation (2-29%) although four of these six were histopathologically normal. Of the seven grossly normal samples that had no mutation, only four were histologically normal. The mutation level in the grossly abnormal samples was 3-35% and all but the right and left kidneys, skull, and left knee bone, with mutation levels of 19%, 15%, 26%, and 17%, respectively, had abnormal histopathology. The highest mutation level was in a toe bone sample whereas the lowest levels were in the soft tissue surrounding that toe, and an omental fat nodule. We also show here that PS overgrowth can be caused by cellular proliferation or by extracellular matrix expansion. Additionally, papillary thyroid carcinoma was identified, a tumor not previously associated with PS. We conclude that gross pathology and histopathology correlate poorly with mutation levels in PS, that overgrowth can be mediated by cellular proliferation or extracellular matrix expansion, and that papillary thyroid carcinoma is part of the tumor susceptibility of PS. New methods need to be developed to facilitate genotype-phenotype correlation in mosaic disorders. © 2016 Wiley Periodicals, Inc.
| S-EPMC5042707 | biostudies-literature
Project description:Proteus syndrome is a rare syndrome characterized by disproportionate overgrowth of limbs, multiple hamartomas, and vascular malformations. The cerebriform connective tissue nevi, also called cerebriform plantar hyperplasia, are present in most patients, and is the main characteristic of the syndrome. If present, even alone, they can be considered as a pathognomonic sign. This article reports a classic case of Proteus syndrome in a 2-year-old male patient who began to show a discrete asymmetry of the right hemibody in relation to the left one after birth, which increased over the months. He also showed cerebriform plantar hyperplasia and Port-wine stains, among other alterations.
| S-EPMC5674710 | biostudies-other
Project description: Not available
| S-EPMC7784982 | biostudies-literature
Project description:Proteus syndrome is a mosaic disorder that can cause progressive postnatal overgrowth of nearly any organ or tissue. To date, Proteus syndrome has been exclusively associated with the mosaic c.49G > A p.(Glu17Lys) pathogenic variant in AKT1, a variant that is also present in many cancers. Here we describe an individual with severe Proteus syndrome who died at 7.5 yr of age from combined parenchymal and restrictive pulmonary disease. Remarkably, this individual was found to harbor a mosaic c.49_50delinsAG p.(Glu17Arg) variant in AKT1 at a variant allele fraction that ranged from <0.01 to 0.46 in fibroblasts established from an overgrown digit. This variant was demonstrated to be constitutively activating by phosphorylation of AKT(S473). These data document allelic heterogeneity for Proteus syndrome. We recommend that individuals with a potential clinical diagnosis of Proteus syndrome who are negative for the p.(Glu17Lys) variant be tested for other variants in AKT1.
| S-EPMC7304363 | biostudies-literature
Project description:ObjectiveTo explore the molecular etiology of Waardenburg syndrome type II (WS2) in a family from Yunnan province, China.MethodsA total of 406 genes related to hereditary hearing loss were sequenced using next-generation sequencing. DNA samples were isolated from the peripheral blood DNA of probands. Those pathogenic mutations detected by next-generation sequencing in probands and their parents were validated by Sanger sequencing. The conservatism of variation sites in genes was also analyzed. The protein expression was detected by flow cytometry.ResultsA heterozygous mutation c.178delG (p.D60fs*49) in the SOX10 gene was identified in the proband, which is a frameshift mutation and may cause protein loss of function and considered to be a pathogenic mutation. This was determined to be a de novo mutation because her family were demonstrated to be wild-type and symptom free. SOX10, FGFR3, SOX2, and PAX3 protein levels were reduced as determined by flow cytometry.ConclusionA novel frameshift mutation in SOX10 gene was identified in this study, which may be the cause of WS2 in proband. In addition, FGFR3, SOX2, and PAX3 might also participate in promoting the progression of WS2.
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Project description:In this work, we sought to delineate the prevalence of cardiothoracic imaging findings of Proteus syndrome in a large cohort at our institution. Of 53 individuals with a confirmed diagnosis of Proteus syndrome at our institution from 10/2001 to 10/2019, 38 individuals (men, n = 23; average age = 24 years) underwent cardiothoracic imaging (routine chest CT, CT pulmonary angiography and/or cardiac MRI). All studies were retrospectively and independently reviewed by two fellowship-trained cardiothoracic readers. Disagreements were resolved by consensus. Differences between variables were analyzed via parametric and nonparametric tests based on the normality of the distribution. The cardiothoracic findings of Proteus syndrome were diverse, but several were much more common and included: scoliosis from bony overgrowth (94%), pulmonary venous dilation (62%), band-like areas of lung scarring (56%), and hyperlucent lung parenchyma (50%). In addition, of 20 individuals who underwent cardiac MRI, 9/20 (45%) had intramyocardial fat, mostly involving the endocardial surface of the left ventricular septal wall. There was no statistically significant difference among the functional cardiac parameters between individuals with and without intramyocardial fat. Only one individual with intramyocardial fat had mildly decreased function (LVEF = 53%), while all others had normal ejection fraction.
| S-EPMC7985501 | biostudies-literature
Project description:Proteus syndrome is a mosaic, progressive overgrowth disorder caused by a somatic activating variant c.49G > A p.(E17K) in AKT1. The presentation in affected individuals is variable, with a diversity of tissues demonstrating abnormalities. Common manifestations include skin and bony overgrowth, vascular malformations (VMs), cysts and benign tumors. We used two methods to create mouse models that had endogenously-regulated mosaic expression of the Proteus syndrome variant. Variant allele fractions (VAFs) ranged from 0% to 50% across numerous tissues in 44 Proteus syndrome mice. Mice were phenotypically heterogeneous with lesions rarely observed before 12 months of age. VMs were the most frequent finding with a total of 69 found in 29 of 44 Proteus syndrome mice. Twenty-eight cysts and ectasia, frequently biliary, were seen in 22 of 44 Proteus syndrome mice. Varying levels of mammary hyperplasia were seen in 10 of 16 female Proteus syndrome mice with other localized regions of hyperplasia and stromal expansion noted in several additional animals. Interestingly, 27 of 31 Proteus syndrome animals had non-zero blood VAF that is in contrast to the human disorder where it is rarely seen in peripheral blood. Identification of variant-positive cells by green fluorescent protein (GFP) staining in chimeric Proteus syndrome mice showed that in some lesions, hyperplastic cells were predominantly GFP/Akt1E17K-positive and showed increased pAKT signal compared to GFP-negative cells. However, hyperplastic mammary epithelium was a mixture of GFP/Akt1E17K-positive and negative cells with some GFP/Akt1E17K-negative cells also having increased pAKT signal suggesting that the variant-positive cells can induce lesion formation in a non-cell autonomous manner.
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Project description:Musculocontractural type of Ehlers-Danlos syndrome (MC-EDS) is a recently recognised connective tissue disorder. MC-EDS is caused by homozygous or compound heterozygous mutation in the carbohydrate sulfotransferase 14 (CHST14) gene on chromosome 15q15. Herein, we report a case of a 3-year-old boy with MC-EDS in whom a novel mutation in the CHST14 gene was discovered. Besides being the second report of this rare disorder from India, the child till 3 years has not had any bleeding tendency as described in the earlier reports of this disorder.
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