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1.
Am J Hum Genet ; 97(6): 914-21, 2015 Dec 03.
Artículo en Inglés | MEDLINE | ID: mdl-26637981

RESUMEN

Somatic mutations in TEK, the gene encoding endothelial cell tyrosine kinase receptor TIE2, cause more than half of sporadically occurring unifocal venous malformations (VMs). Here, we report that somatic mutations in PIK3CA, the gene encoding the catalytic p110α subunit of PI3K, cause 54% (27 out of 50) of VMs with no detected TEK mutation. The hotspot mutations c.1624G>A, c.1633G>A, and c.3140A>G (p.Glu542Lys, p.Glu545Lys, and p.His1047Arg), frequent in PIK3CA-associated cancers, overgrowth syndromes, and lymphatic malformation (LM), account for >92% of individuals who carry mutations. Like VM-causative mutations in TEK, the PIK3CA mutations cause chronic activation of AKT, dysregulation of certain important angiogenic factors, and abnormal endothelial cell morphology when expressed in human umbilical vein endothelial cells (HUVECs). The p110α-specific inhibitor BYL719 restores all abnormal phenotypes tested, in PIK3CA- as well as TEK-mutant HUVECs, demonstrating that they operate via the same pathogenic pathways. Nevertheless, significant genotype-phenotype correlations in lesion localization and histology are observed between individuals with mutations in PIK3CA versus TEK, pointing to gene-specific effects.


Asunto(s)
Mutación , Neovascularización Patológica/genética , Fosfatidilinositol 3-Quinasas/genética , Malformaciones Vasculares/genética , Alelos , Fosfatidilinositol 3-Quinasa Clase I , Regulación de la Expresión Génica , Frecuencia de los Genes , Estudios de Asociación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/enzimología , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Neovascularización Patológica/enzimología , Neovascularización Patológica/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Receptor TIE-2/antagonistas & inhibidores , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Transducción de Señal , Tiazoles/farmacología , Transfección , Malformaciones Vasculares/enzimología , Malformaciones Vasculares/patología , Venas/enzimología , Venas/patología
2.
Am J Med Genet A ; 170A(2): 523-530, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26544544

RESUMEN

Congenital limb anomalies occur in Europe with a prevalence of 3.81/1,000 births and can have a major impact on patients and their families. The present study concerned a female fetus aborted at 23 weeks of gestation because she was affected by non-syndromic bilateral absence of the zeugopod (leg) and autopod (foot). Autopsy of the aborted fetus, X-ray imaging, MRI, and histochemical analysis showed that the distal extremity of both femurs was continued by a cartilage-like mass, without joint cavitation. Karyotype was normal. Moreover, no damaging variant was detected by exome sequencing. The limb characteristics of the fetus, which to our knowledge have not yet been reported in humans, suggest a developmental arrest similar to anomalies described in chicks following surgical experiments on the apical ectodermal ridge of the lower limbs.


Asunto(s)
Feto/anomalías , Feto/patología , Articulación de la Rodilla/anomalías , Deformidades Congénitas de las Extremidades/patología , Extremidad Inferior/patología , Adulto , Femenino , Humanos , Articulación de la Rodilla/patología , Extremidad Inferior/crecimiento & desarrollo , Masculino , Pronóstico
3.
Hum Mol Genet ; 22(17): 3438-48, 2013 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-23633549

RESUMEN

Mutations in the endothelial cell (EC) tyrosine kinase receptor TIE2 cause inherited and sporadic forms of venous malformation. The recurrent somatic mutation L914F and common germline mutation R849W differ in terms of phosphorylation level, as well as sub-cellular localization and trafficking of the receptor. Previous studies have shed light on certain pathogenic properties of R849W, but the mechanisms of action of L914F are unknown. We used global gene expression profiling to study the effects of L914F on ECs. We found that L914F strongly dysregulates genes involved in vascular development, cell migration and extracellular matrix processing, while R849W has weak effects. We also demonstrate, for the first time, that TIE2-mutant ECs are deficient in the production of PDGFB, both in vitro and ex vivo in patient tissues. This defect is mediated by the chronic, ligand-independent activation of AKT by the mutant receptors. Inadequate secretion of the major mural cell attractant likely plays an important role in the development of abnormal vascular channels, contributing to the characteristic paucity of surrounding vascular smooth muscle cells.


Asunto(s)
Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-sis/metabolismo , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Malformaciones Vasculares/genética , Malformaciones Vasculares/metabolismo , Movimiento Celular/genética , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/metabolismo , Perfilación de la Expresión Génica , Mutación de Línea Germinal , Humanos , Músculo Liso Vascular/metabolismo , Fosforilación , Transducción de Señal/genética , Transducción de Señal/fisiología
4.
Am J Hum Genet ; 90(2): 356-62, 2012 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-22284827

RESUMEN

We have identified KIF11 mutations in individuals with syndromic autosomal-dominant microcephaly associated with lymphedema and/or chorioretinopathy. Initial whole-exome sequencing revealed heterozygous KIF11 mutations in three individuals with a combination of microcephaly and lymphedema from a microcephaly-lymphedema-chorioretinal-dysplasia cohort. Subsequent Sanger sequencing of KIF11 in a further 15 unrelated microcephalic probands with lymphedema and/or chorioretinopathy identified additional heterozygous mutations in 12 of them. KIF11 encodes EG5, a homotetramer kinesin motor. The variety of mutations we have found (two nonsense, two splice site, four missense, and six indels causing frameshifts) are all predicted to have an impact on protein function. EG5 has previously been shown to play a role in spindle assembly and function, and these findings highlight the critical role of proteins necessary for spindle formation in CNS development. Moreover, identification of KIF11 mutations in patients with chorioretinopathy and lymphedema suggests that EG5 is involved in the development and maintenance of retinal and lymphatic structures.


Asunto(s)
Colestasis/genética , Anomalías Congénitas/genética , Cinesinas/genética , Linfedema/congénito , Microcefalia/genética , Mutación , Anomalías Múltiples/genética , Estudios de Cohortes , Exoma , Facies , Femenino , Heterocigoto , Humanos , Linfedema/genética , Masculino , Linaje , Fenotipo , Displasia Retiniana/genética
5.
Hum Mutat ; 34(12): 1632-41, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24038909

RESUMEN

Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal-dominant disorder, caused by heterozygous RASA1 mutations, and manifesting multifocal CMs and high risk for fast-flow lesions. A limited number of patients have been reported, raising the question of the phenotypic borders. We identified new patients with a clinical diagnosis of CM-AVM, and patients with overlapping phenotypes. RASA1 was screened in 261 index patients with: CM-AVM (n = 100), common CM(s) (port-wine stain; n = 100), Sturge-Weber syndrome (n = 37), or isolated AVM(s) (n = 24). Fifty-eight distinct RASA1 mutations (43 novel) were identified in 68 index patients with CM-AVM and none in patients with other phenotypes. A novel clinical feature was identified: cutaneous zones of numerous small white pale halos with a central red spot. An additional question addressed in this study was the "second-hit" hypothesis as a pathophysiological mechanism for CM-AVM. One tissue from a patient with a germline RASA1 mutation was available. The analysis of the tissue showed loss of the wild-type RASA1 allele. In conclusion, mutations in RASA1 underscore the specific CM-AVM phenotype and the clinical diagnosis is based on identifying the characteristic CMs. The high incidence of fast-flow lesions warrants careful clinical and radiologic examination, and regular follow-up.


Asunto(s)
Malformaciones Arteriovenosas/diagnóstico , Malformaciones Arteriovenosas/genética , Capilares/anomalías , Mutación , Fenotipo , Mancha Vino de Oporto/diagnóstico , Mancha Vino de Oporto/genética , Proteína Activadora de GTPasa p120/genética , Sustitución de Aminoácidos , Análisis Mutacional de ADN , Femenino , Orden Génico , Estudios de Asociación Genética , Humanos , Masculino , Estudios Prospectivos , Estudios Retrospectivos
6.
Clin Cancer Res ; 29(20): 4076-4087, 2023 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-37531234

RESUMEN

PURPOSE: The EORTC-90111-24111 phase II window study evaluated afatinib versus no preoperative treatment in patients with primary squamous cell carcinoma of the head and neck (HNSCC). We investigated afatinib-induced tumor and microenvironment modifications by comparing pre- and posttreatment tumor biopsies. PATIENTS AND METHODS: Thirty treatment-naïve patients with primary HNSCC were randomized. Twenty-five patients received afatinib for 14 days before surgery (40 mg 1×/day) and 5 patients were attributed to the control arm. Biopsies were taken at work-up and during surgery. Good quality RNA samples were used for omics analyses. The control arm was enlarged by samples coming from our previous similar window study. RESULTS: IHC analyses of afatinib-treated tumor biopsies showed a decrease in pEGFR (P ≤ 0.05) and pERK (P ≤ 0.05); and an increase in CD3+ (P ≤ 0.01) and CD8+ (P ≤ 0.01) T-cell infiltration, and in CD3+ (P ≤ 0.05) T-cell density. RNA sequencing analyses of afatinib-treated tumor samples showed upregulation of inflammatory genes and increased expression scores of signatures predictive of response to programmed cell death protein 1 blockade (P ≤ 0.05). In posttreatment biopsies of afatinib-treated patients, two clusters were observed. Cluster 1 showed a higher expression of markers and gene sets implicated in epithelial-to-mesenchymal transition (EMT) and activation of cancer-associated fibroblasts (CAF) compared with cluster 2 and controls. CONCLUSIONS: Short-term treatment with afatinib in primary HNSCC induces CD3+ and CD8+ tumor infiltration and, in some patients, EMT and CAF activation. These results open perspectives to overcome resistance mechanisms to anti-HER therapy and to potentiate the activity of immune checkpoint inhibitors.

7.
Eur J Cancer ; 195: 113372, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37913682

RESUMEN

BACKGROUND: Only 15-20% of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) patients derive long-term benefit from nivolumab or pembrolizumab. We developed a circulating tumour DNA (ctDNA) tumour-agnostic assay aimed at the early prediction of single agent programmed cell death 1 (PD1) inhibitor efficacy in R/M SCCHN. PATIENTS AND METHODS: Our tumour-agnostic assay included 37 genes frequently mutated in R/M SCCHN and two HPV16 genes. Primary endpoint was the concordance between ctDNA kinetics (ΔctDNA) and the best overall response according to Response Evaluation Criteria in Solid Tumors version 1.1. ΔctDNA was defined as the difference in mean variant allele frequency (VAF) between the on-treatment sample harvested 6-10 weeks (FU1) after PD1 inhibitor initiation and the pre-treatment plasma sample (ΔctDNA = mean FU1 VAF - mean pre-treatment VAF). RESULTS: ctDNA was detected in 35/44 (80%) of the pre-treatment plasma samples. The concordance between ΔctDNA and imaging response was observed in 74%. Median progression-free survival was 8.6 months in the favourable ΔctDNA group and 2.5 months in the unfavourable ΔctDNA group (p = 0.057). Median overall survival (OS) was 18.1 and 8.2 months in the favourable and unfavourable ΔctDNA groups, respectively (p = 0.13). In patients with PD-L1 expressing SCCHN (Combined Positive Score ≥1), OS was significantly better in patients with favourable ΔctDNA compared with patients with unfavourable ΔctDNA: median OS was 41.5 and 8.4 months (p = 0.033), respectively. CONCLUSIONS: Tumour-agnostic ctDNA analysis for human papillomavirus (HPV)-negative and HPV-positive R/M SCCHN is feasible. ctDNA kinetics show promising results in predicting the efficacy of PD1 inhibitors in R/M SCCHN.


Asunto(s)
Carcinoma de Células Escamosas , ADN Tumoral Circulante , Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , ADN Tumoral Circulante/genética , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/secundario
8.
Cancers (Basel) ; 13(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809148

RESUMEN

Epidermal growth factor receptor (EGFR) overexpression is observed in 90% of human papillomavirus (HPV)-negative squamous cell carcinomas of the head and neck (SCCHN). Cell cycle pathway impairments resulting in cyclin-dependent kinase (CDK) 4 and 6 activation, are frequently observed in SCCHN. We investigated the efficacy of ribociclib, a CDK4/6 inhibitor, in combination with cetuximab, a monoclonal antibody targeting the EGFR, in HPV-negative SCCHN patient-derived tumor xenograft (PDTX) models. The combination of cetuximab and ribociclib was not significantly more active than cetuximab monotherapy in all models investigated. In addition, the combination of cetuximab and ribociclib was less active than ribociclib monotherapy in the cetuximab-resistant PDTX models. In these models, a significant downregulation of the retinoblastoma (Rb) protein was observed in cetuximab-treated mice. We also observed Rb downregulation in the SCCHN cell lines chronically exposed and resistant to cetuximab. In addition, Rb downregulation induced interleukin 6 (Il-6) secretion and the Janus kinase family member/signal transducer and activator of transcription (JAK/STAT) pathway activation that might be implicated in the cetuximab resistance of these cell lines. To conclude, cetuximab is not an appropriate partner for ribociclib in cetuximab-resistant SCCHN models. Our work has significant clinical implications since the combination of anti-EGFR therapy with CDK4/6 inhibitors is currently being investigated in clinical trials.

9.
JAMA ; 304(23): 2611-9, 2010 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-21156949

RESUMEN

CONTEXT: Pheochromocytomas and paragangliomas are genetically heterogeneous neural crest-derived neoplasms. We recently identified germline mutations of the novel transmembrane-encoding gene FP/TMEM127 in familial and sporadic pheochromocytomas consistent with a tumor suppressor effect. OBJECTIVES: To examine the prevalence and spectrum of FP/TMEM127 mutations in pheochromocytomas and paragangliomas and to test the effect of mutations in vitro. DESIGN, SETTING, AND PARTICIPANTS: We sequenced the FP/TMEM127 gene in 990 individuals with pheochromocytomas and/or paragangliomas, including 898 previously unreported cases without mutations in other susceptibility genes from 8 independent worldwide referral centers between January 2009 and June 2010. A multiplex polymerase chain reaction-based method was developed to screen for large gene deletions in 545 of these samples. Confocal microscopy of 5 transfected mutant proteins was used to determine their subcellular localization. MAIN OUTCOME MEASURES: The frequency and type of FP/TMEM127 mutation or deletion was assessed and correlated with clinical variables; the subcellular localization of 5 overexpressed mutants was compared with wild-type FP/TMEM127 protein. RESULTS: We identified 19 potentially pathogenic FP/TMEM127 germline mutations in 20 independent families, but no large deletions were detected. All mutation carriers had adrenal tumors, including 7 bilateral (P = 2.7 × 10(-4)) and/or with familial disease (5 of 20 samples; P = .005). The median age at disease onset in the FP/TMEM127 mutation group was similar to that of patients without a mutation (41.5 vs 45 years, respectively; P = .54). The most common presentation was that of a single benign adrenal tumor in patients older than 40 years. Malignancy was seen in 1 mutation carrier (5%). Expression of 5 novel FP/TMEM127 mutations in cell lines revealed diffuse localization of the mutant proteins in contrast with the discrete multiorganelle distribution of wild-type TMEM127. CONCLUSIONS: Germline mutations of FP/TMEM127 were associated with pheochromocytoma but not paraganglioma and occurred in an age group frequently excluded from genetic screening algorithms. Disease-associated mutations disrupt intracellular distribution of the FP/TMEM127 protein.


Asunto(s)
Neoplasias de las Glándulas Suprarrenales/genética , Mutación de Línea Germinal , Proteínas de la Membrana/genética , Paraganglioma/genética , Feocromocitoma/genética , Adolescente , Neoplasias de las Glándulas Suprarrenales/metabolismo , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Proteínas de la Membrana/metabolismo , Microscopía Confocal , Persona de Mediana Edad , Paraganglioma/metabolismo , Feocromocitoma/metabolismo , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN
10.
Oral Oncol ; 104: 104631, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32169746

RESUMEN

OBJECTIVES: The molecular landscape of head and neck squamous cell carcinoma (HNSCC) harbors potentially actionable genomic alterations. We aimed to study the utility of liquid biopsy to (i) characterize the mutational landscape of recurrent/metastatic HNSCC using a comprehensive gene panel and (ii) estimate the concordance between DNA mutations identified from circulating tumor DNA (ctDNA) and matched tumor tissues. MATERIALS AND METHODS: Targeted next-generation sequencing (NGS) was performed on cell-free DNA (cfDNA) of 39 patients with locoregional recurrent (n = 19) and/or metastatic (n = 20) HNSCC. Tumor biopsy (n = 18) was sequenced using the same technique. RESULTS: ctDNA was detected in 51% of patients (20/39) with a higher probability of detection in metastatic than locoregional recurrent disease (70% versus 30%, p = 0.025). 81% and 58% of the tissue tumor variants were not detected in plasma when considering all patients and only metastatic patients with detectable ctDNA, respectively. In a multivariate analysis, the likelihood of detecting the tissue tumor variant in plasma was related to metastatic status (p = 0.012), tumor variant allele frequency (p < 0.001) and ctDNA quantity (p < 0.001). 26% of the variants were detected only in liquid and not in the solid biopsy. Three patients without an available tumor sample had plasma containing three different potentially actionable PIK3CA mutations. CONCLUSION: CtDNA detection and characterization using targeted NGS is feasible in metastatic HNSCC. Liquid biopsies do not reflect the complete mutation profile of the tumor but have the potential to identify actionable mutations when tumor biopsies are not available as well as variants not found in matched tumor tissue.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Biopsia Líquida/métodos , Carcinoma de Células Escamosas de Cabeza y Cuello/cirugía , Femenino , Humanos , Masculino , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia
12.
J Invest Dermatol ; 137(1): 207-216, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27519652

RESUMEN

Blue rubber bleb nevus syndrome (Bean syndrome) is a rare, severe disorder of unknown cause, characterized by numerous cutaneous and internal venous malformations; gastrointestinal lesions are pathognomonic. We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with blue rubber bleb nevus syndrome. Somatic mutations were also identified in five of six individuals with sporadically occurring multifocal venous malformations. In contrast to common unifocal venous malformation, which is most often caused by the somatic L914F TIE2 mutation, multifocal forms are predominantly caused by double (cis) mutations, that is, two somatic mutations on the same allele of the gene. Mutations are identical in all lesions from a given individual. T1105N-T1106P is recurrent in blue rubber bleb nevus, whereas Y897C-R915C is recurrent in sporadically occurring multifocal venous malformation: both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells.


Asunto(s)
Neoplasias Gastrointestinales/genética , Predisposición Genética a la Enfermedad/epidemiología , Mutación , Nevo Azul/genética , Receptor TIE-2/genética , Neoplasias Cutáneas/genética , Malformaciones Vasculares/genética , Bélgica , Estudios de Cohortes , Femenino , Neoplasias Gastrointestinales/diagnóstico , Humanos , Incidencia , Masculino , Nevo Azul/diagnóstico , Enfermedades Raras , Neoplasias Cutáneas/diagnóstico , Malformaciones Vasculares/diagnóstico
13.
Medicine (Baltimore) ; 95(15): e2968, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27082544

RESUMEN

The serine/threonine kinase With-No-Lysine (K) Kinase 1 (WNK1) activates the thiazide-sensitive Na(+)/Cl(-) cotransporter through phosphorylation of STE20/SPS1-related proline/alanine-rich kinase, another serine/threonine kinase encoded by STK39. The aim of this study was to look for association between WNK1 and STK39 gene variants, and blood pressure (BP) and hypertension. Seven hundred seventy-nine Caucasian hypertensive patients (HYP) recruited in 6 academic centers from Belgium, and 906 normotensive (NT) controls were genotyped for 5 single nucleotide polymorphisms-rs3754777, rs6749447, rs35929607 (STK39), rs1468326, and rs765250 (WNK1)-using the Snapshot method. The rare TT genotype at the rs3754777 locus (STK39) was overrepresented in HYP versus NT (7.3% vs 3.0%, P = 0.0002). In the whole study population, the multivariable-adjusted odds ratio (OR) for having hypertension associated with the TT genotype was 5.9 (95% confidence interval: 2.2-15.6), and systolic BP was 10 mm Hg higher in TT compared with wild-type subjects (140.1 vs 130.4 mm Hg, P = 0.002). Similarly, the AA genotype at the rs1468326 locus (WNK1) was twice as frequent in HYP versus NT (5.5% vs 2.3%, P < 0.0001), and associated with an increased adjusted OR of hypertension (4.1; 1.5-11.7) and a higher systolic BP (139.8 vs 130.1 mm Hg, P = 0.003). In the whole cohort, a dose-dependent increase in systolic BP was observed according to the number of at-risk genotypes (0: 129.8 mm Hg; 1: 133.0 mm Hg; 2: 149.3 mm Hg, P = 0.02). Single nucleotide polymorphisms rs3754777 (STK39) and rs1468326 (WNK1) were associated with hypertension and BP in our multicenter Belgian case-control study, which supports the role of STK39 and WNK1 as potential hypertension susceptibility genes. Replication in different clinical settings and study of other candidate loci belonging to the same molecular pathway is warranted.


Asunto(s)
Hipertensión/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas Serina-Treonina Quinasas/genética , Adulto , Anciano , Bélgica , Presión Sanguínea , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Antígenos de Histocompatibilidad Menor , Polimorfismo de Nucleótido Simple , Proteína Quinasa Deficiente en Lisina WNK 1 , Población Blanca
14.
J Clin Invest ; 125(9): 3491-504, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26258417

RESUMEN

Venous malformations (VMs) are composed of ectatic veins with scarce smooth muscle cell coverage. Activating mutations in the endothelial cell tyrosine kinase receptor TIE2 are a common cause of these lesions. VMs cause deformity, pain, and local intravascular coagulopathy, and they expand with time. Targeted pharmacological therapies are not available for this condition. Here, we generated a model of VMs by injecting HUVECs expressing the most frequent VM-causing TIE2 mutation, TIE2-L914F, into immune-deficient mice. TIE2-L914F-expressing HUVECs formed VMs with ectatic blood-filled channels that enlarged over time. We tested both rapamycin and a TIE2 tyrosine kinase inhibitor (TIE2-TKI) for their effects on murine VM expansion and for their ability to inhibit mutant TIE2 signaling. Rapamycin prevented VM growth, while TIE2-TKI had no effect. In cultured TIE2-L914F-expressing HUVECs, rapamycin effectively reduced mutant TIE2-induced AKT signaling and, though TIE2-TKI did target the WT receptor, it only weakly suppressed mutant-induced AKT signaling. In a prospective clinical pilot study, we analyzed the effects of rapamycin in 6 patients with difficult-to-treat venous anomalies. Rapamycin reduced pain, bleeding, lesion size, functional and esthetic impairment, and intravascular coagulopathy. This study provides a VM model that allows evaluation of potential therapeutic strategies and demonstrates that rapamycin provides clinical improvement in patients with venous malformation.


Asunto(s)
Inmunosupresores/administración & dosificación , Mutación Missense , Receptor TIE-2 , Transducción de Señal , Sirolimus/administración & dosificación , Malformaciones Vasculares , Adolescente , Adulto , Animales , Modelos Animales de Enfermedad , Femenino , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Proyectos Piloto , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Malformaciones Vasculares/tratamiento farmacológico , Malformaciones Vasculares/genética , Malformaciones Vasculares/metabolismo , Malformaciones Vasculares/patología , Venas
15.
Orphanet J Rare Dis ; 10: 52, 2015 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-25934493

RESUMEN

BACKGROUND: Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome (MCLMR) is a rare autosomal dominant disorder with variable expressivity. It is characterized by mild-to-severe microcephaly, often associated with intellectual disability, ocular defects and lymphedema. It can be sporadic or inherited. Eighty-seven patients have been described to carry a mutation in KIF11, which encodes a homotetrameric motor kinesin, EG5. METHODS: We tested 23 unreported MCLMR index patients for KIF11. We also reviewed the clinical phenotypes of all our patients as well as of those described in previously published studies. RESULTS: We identified 14 mutations, 12 of which are novel. We detected mutations in 12 affected individuals, from 6 out of 6 familial cases, and in 8 out of 17 sporadic patients. Phenotypic evaluation of patients (our 26 + 61 earlier published = 87) revealed microcephaly in 91%, eye anomalies in 72%, intellectual disability in 67% and lymphedema in 47% of the patients. Unaffected carriers were rare (4 out of 87: 5%). Family history is not a requisite for diagnosis; 31% (16 out of 52) were de novo cases. CONCLUSIONS: All inherited cases, and 50% of sporadic cases of MCLMR are due to germline KIF11 mutations. It is possible that mosaic KIF11 mutations cause the remainder of sporadic cases, which the methods employed here were not designed to detect. On the other hand, some of them might have another mimicking disorder and genetic defect, as microcephaly is highly heterogeneous. In aggregate, KIF11 mutations likely cause the majority, if not all, of MCLMR.


Asunto(s)
Microcefalia/genética , Adulto , Facies , Femenino , Heterocigoto , Humanos , Discapacidad Intelectual/genética , Cinesinas/genética , Linfedema/genética , Masculino , Mutación , Fenotipo , Displasia Retiniana/genética , Adulto Joven
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