RESUMO
Monogenic early onset osteoporosis (EOOP) is a rare disease defined by low bone mineral density (BMD) that results in increased risk of fracture in children and young adults. Although several causative genes have been identified, some of the EOOP causation remains unresolved. Whole-exome sequencing revealed a de novo heterozygous loss-of-function mutation in Wnt family member 11 (WNT11) (NM_004626.2:c.677_678dup p.Leu227Glyfs*22) in a 4-year-old boy with low BMD and fractures. We identified two heterozygous WNT11 missense variants (NM_004626.2:c.217G > A p.Ala73Thr) and (NM_004626.2:c.865G > A p.Val289Met) in a 51-year-old woman and in a 61-year-old woman, respectively, both with bone fragility. U2OS cells with heterozygous WNT11 mutation (NM_004626.2:c.690_721delfs*40) generated by CRISPR-Cas9 showed reduced cell proliferation (30%) and osteoblast differentiation (80%) as compared with wild-type U2OS cells. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells, but recombinant WNT11 treatment rescued the expression of Wnt pathway target genes. Furthermore, the expression of RSPO2, a WNT11 target involved in bone cell differentiation, and its receptor leucine-rich repeat containing G protein-coupled receptor 5 (LGR5), was decreased in WNT11 mutant cells. Treatment with WNT5A and WNT11 recombinant proteins reversed LGR5 expression, but Wnt family member 3A (WNT3A) recombinant protein treatment had no effect on LGR5 expression in mutant cells. Moreover, treatment with recombinant RSPO2 but not WNT11 or WNT3A activated the canonical pathway in mutant cells. In conclusion, we have identified WNT11 as a new gene responsible for EOOP, with loss-of-function variant inhibiting bone formation via Wnt canonical and non-canonical pathways. WNT11 may activate Wnt signaling by inducing the RSPO2-LGR5 complex via the non-canonical Wnt pathway.
Assuntos
Osteoporose , Via de Sinalização Wnt , Diferenciação Celular/fisiologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/genética , Receptores Acoplados a Proteínas G , Proteínas Wnt/genética , Via de Sinalização Wnt/genéticaRESUMO
Dysregulated transforming growth factor TGF-ß signaling underlies the pathogenesis of genetic disorders affecting the connective tissue such as Loeys-Dietz syndrome. Here, we report 12 individuals with bi-allelic loss-of-function variants in IPO8 who presented with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation; the individuals were from nine unrelated families. Importin 8 belongs to the karyopherin family of nuclear transport receptors and was previously shown to mediate TGF-ß-dependent SMADs trafficking to the nucleus in vitro. The important in vivo role of IPO8 in pSMAD nuclear translocation was demonstrated by CRISPR/Cas9-mediated inactivation in zebrafish. Consistent with IPO8's role in BMP/TGF-ß signaling, ipo8-/- zebrafish presented mild to severe dorso-ventral patterning defects during early embryonic development. Moreover, ipo8-/- zebrafish displayed severe cardiovascular and skeletal defects that mirrored the human phenotype. Our work thus provides evidence that IPO8 plays a critical and non-redundant role in TGF-ß signaling during development and reinforces the existing link between TGF-ß signaling and connective tissue defects.
Assuntos
Doenças Ósseas/etiologia , Doenças Cardiovasculares/etiologia , Doenças do Tecido Conjuntivo/etiologia , Imunidade Celular/imunologia , Mutação com Perda de Função , Perda de Heterozigosidade , beta Carioferinas/genética , Adolescente , Adulto , Animais , Doenças Ósseas/patologia , Doenças Cardiovasculares/patologia , Criança , Doenças do Tecido Conjuntivo/patologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Transdução de Sinais , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Adulto Jovem , Peixe-Zebra , beta Carioferinas/metabolismoRESUMO
Noonan syndrome belongs to the family of RASopathies, a group of multiple congenital anomaly disorders caused by pathogenic variants in genes encoding components or regulators of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway. Collectively, all these pathogenic variants lead to increased RAS/MAPK activation. The better understanding of the molecular mechanisms underlying the different manifestations of NS and RASopathies has led to the identification of molecular targets for specific pharmacological interventions. Many specific agents (e.g. SHP2 and MEK inhibitors) have already been developed for the treatment of RAS/MAPK-driven malignancies. In addition, other molecules with the property of modulating RAS/MAPK activation are indicated in non-malignant diseases (e.g. C-type natriuretic peptide analogues in achondroplasia or statins in hypercholesterolemia). Conclusion: Drug repositioning of these molecules represents a challenging approach to treat or prevent medical complications associated with RASopathies. What is Known: ⢠Noonan syndrome and related disorders are caused by pathogenic variants in genes encoding components or regulators of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway, resulting in increased activation of this pathway. ⢠This group of disorders is now known as RASopathies and represents one of the largest groups of multiple congenital anomaly diseases known. What is New: ⢠The identification of pathophysiological mechanisms provides new insights into the development of specific therapeutic strategies, in particular treatment aimed at reducing RAS/MAPK hyperactivation. ⢠Drug repositioning of specific agents already developed for the treatment of malignant (e.g. SHP2 and MEK inhibitors) or non-malignant diseases (e.g. C-type natriuretic peptide analogues in achondroplasia or statins in hypercholesterolaemia) represents a challenging approach to the treatment of RASopathies.
Assuntos
Anormalidades Múltiplas , Acondroplasia , Inibidores de Hidroximetilglutaril-CoA Redutases , Síndrome de Noonan , Humanos , Síndrome de Noonan/tratamento farmacológico , Síndrome de Noonan/genética , Peptídeo Natriurético Tipo C , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Quinases de Proteína Quinase Ativadas por MitógenoRESUMO
The NADSYN1 gene [MIM*608285] encodes the NAD synthetase 1 enzyme involved in the final step of NAD biosynthesis, crucial for cell metabolism and organ embryogenesis. Perturbating the role of NAD biosynthesis results in the association of vertebral, cardiac, renal, and limb anomalies (VCRL). This condition was initially characterized as severe with perinatal lethality or developmental delay and complex malformations in alive cases. Sixteen NADSYN1-associated patients have been published so far. This study illustrates the wide phenotypic variability in NADSYN1-associated NAD deficiency disorder. We report the clinical and molecular findings in three novel cases, two of them being siblings with the same homozygous variant and presenting with either a very severe prenatal lethal or a mild phenotypic form. In addition to an exhaustive literature, we validate the expansion of the spectrum of NAD deficiency disorder. Our findings indicate that NAD deficiency disorder should be suspected not only in the presence of the full spectrum of VCRL, but even a single of the aforementioned organs is affected. Decreased plasmatic levels of NAD should then strongly encourage the screening for any of the genes responsible for a NAD deficiency disorder.
Assuntos
Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida , NAD , Feminino , Humanos , Gravidez , Homozigoto , Coluna Vertebral/anormalidades , SíndromeRESUMO
Assessing weight and height development is a key element of pediatric follow-up. Growth retardation, even in isolation, may be the first symptom of a chronic disease and should therefore always be investigated. Many chronic diseases can be responsible and in most cases, diagnosis and management of the disease will minimize the impact on statural growth. The reconstruction of growth curves on the health record is essential to obtain a vision of the growth kinetics of the child and to orient the diagnosis. The study of the evolution of the ratio between weight and height is an essential point in the diagnostic process.
Assuntos
Estatura , Criança , HumanosRESUMO
Src homology 2 domain-containing phosphatase 2 (SHP2), encoded by the PTPN11 gene, is a ubiquitous protein tyrosine phosphatase that is a critical regulator of signal transduction. Germ line mutations in the PTPN11 gene responsible for catalytic gain or loss of function of SHP2 cause 2 disorders with multiple organ defects: Noonan syndrome (NS) and NS with multiple lentigines (NSML), respectively. Bleeding anomalies have been frequently reported in NS, but causes remain unclear. This study investigates platelet activation in patients with NS and NSML and in 2 mouse models carrying PTPN11 mutations responsible for these 2 syndromes. Platelets from NS mice and patients displayed a significant reduction in aggregation induced by low concentrations of GPVI and CLEC-2 agonists and a decrease in thrombus growth on a collagen surface under arterial shear stress. This was associated with deficiencies in GPVI and αIIbß3 integrin signaling, platelet secretion, and thromboxane A2 generation. Similarly, arterial thrombus formation was significantly reduced in response to a local carotid injury in NS mice, associated with a significant increase in tail bleeding time. In contrast, NSML mouse platelets exhibited increased platelet activation after GPVI and CLEC-2 stimulation and enhanced platelet thrombotic phenotype on collagen matrix under shear stress. Blood samples from NSML patients also showed a shear stress-dependent elevation of platelet responses on collagen matrix. This study brings new insights into the understanding of SHP2 function in platelets, points to new thrombopathies linked to platelet signaling defects, and provides important information for the medical care of patients with NS in situations involving risk of bleeding.
Assuntos
Plaquetas/enzimologia , Mutação em Linhagem Germinativa , Síndrome de Noonan/enzimologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Transdução de Sinais , Animais , Plaquetas/patologia , Humanos , Camundongos , Camundongos Mutantes , Síndrome de Noonan/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/genéticaRESUMO
Growth retardation is a constant feature of Noonan syndrome (NS) but its physiopathology remains poorly understood. We previously reported that hyperactive NS-causing SHP2 mutants impair the systemic production of insulin-like growth factor 1 (IGF1) through hyperactivation of the RAS/extracellular signal-regulated kinases (ERK) signalling pathway. Besides endocrine defects, a direct effect of these mutants on growth plate has not been explored, although recent studies have revealed an important physiological role for SHP2 in endochondral bone growth. We demonstrated that growth plate length was reduced in NS mice, mostly due to a shortening of the hypertrophic zone and to a lesser extent of the proliferating zone. These histological features were correlated with decreased expression of early chondrocyte differentiation markers, and with reduced alkaline phosphatase staining and activity, in NS murine primary chondrocytes. Although IGF1 treatment improved growth of NS mice, it did not fully reverse growth plate abnormalities, notably the decreased hypertrophic zone. In contrast, we documented a role of RAS/ERK hyperactivation at the growth plate level since 1) NS-causing SHP2 mutants enhance RAS/ERK activation in chondrocytes in vivo (NS mice) and in vitro (ATDC5 cells) and 2) inhibition of RAS/ERK hyperactivation by U0126 treatment alleviated growth plate abnormalities and enhanced chondrocyte differentiation. Similar effects were obtained by chronic treatment of NS mice with statins. In conclusion, we demonstrated that hyperactive NS-causing SHP2 mutants impair chondrocyte differentiation during endochondral bone growth through a local hyperactivation of the RAS/ERK signalling pathway, and that statin treatment may be a possible therapeutic approach in NS.
Assuntos
Condrócitos/metabolismo , Fator de Crescimento Insulin-Like I/genética , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Animais , Butadienos/administração & dosagem , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Modelos Animais de Doenças , Lâmina de Crescimento/anormalidades , Lâmina de Crescimento/efeitos dos fármacos , Humanos , Fator de Crescimento Insulin-Like I/administração & dosagem , Sistema de Sinalização das MAP Quinases , Nitrilas/administração & dosagem , Síndrome de Noonan/tratamento farmacológico , Síndrome de Noonan/patologiaRESUMO
PURPOSE: Heritable thoracic aortic aneurysms and dissections (hTAAD) are life-threatening complications of well-known syndromic diseases or underdiagnosed nonsyndromic heritable forms (nshTAAD). Both have an autosomal dominant transmission and are genetically heterogeneous. Our objective was to describe the relevance of molecular diagnosis in these patients and the contribution of each gene in nshTAAD. METHODS: Two hundred twenty-six consecutive nshTAAD probands, either young (<45 years) sporadic or familial cases were included. A next-generation sequencing capture panel comprising 23 known disease-causing genes was performed. RESULTS: Class 4 or 5 variants were identified in 18% of the nshTAAD probands, while class 3 variants were found in 10% of them. The yield in familial cases was greater than in sporadic cases. SMAD3 and FBN1 genes were the major disease-causing genes. Unexpectedly, no premature termination codon variant was identified in the FBN1 gene. Furthermore, we report for the first time that aortic dissection or surgery occurred significantly more often and earlier in probands with a class 4 or 5 pathogenic variant. CONCLUSION: This study indicates that genetic screening using NGS is efficient in young and familial nshTAAD. The presence of a pathogenic variant has a possible predictive value, which needs to be further investigated because it may influence care.
Assuntos
Aneurisma da Aorta Torácica/genética , Dissecção Aórtica/genética , Fibrilina-1/genética , Proteína Smad3/genética , Adolescente , Adulto , Idoso , Dissecção Aórtica/diagnóstico , Dissecção Aórtica/fisiopatologia , Aneurisma da Aorta Torácica/diagnóstico , Criança , Códon sem Sentido/genética , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Patologia Molecular/métodos , Linhagem , Adulto JovemRESUMO
PurposeFetal growth is a complex process involving maternal, placental and fetal factors. The etiology of fetal growth retardation remains unknown in many cases. The aim of this study is to identify novel human mutations and genes related to Silver-Russell syndrome (SRS), a syndromic form of fetal growth retardation, usually caused by epigenetic downregulation of the potent fetal growth factor IGF2.MethodsWhole-exome sequencing was carried out on members of an SRS familial case. The candidate gene from the familial case and two other genes were screened by targeted high-throughput sequencing in a large cohort of suspected SRS patients. Functional experiments were then used to link these genes into a regulatory pathway.ResultsWe report the first mutations of the PLAG1 gene in humans, as well as new mutations in HMGA2 and IGF2 in six sporadic and/or familial cases of SRS. We demonstrate that HMGA2 regulates IGF2 expression through PLAG1 and in a PLAG1-independent manner.ConclusionGenetic defects of the HMGA2-PLAG1-IGF2 pathway can lead to fetal and postnatal growth restriction, highlighting the role of this oncogenic pathway in the fine regulation of physiological fetal/postnatal growth. This work defines new genetic causes of SRS, important for genetic counseling.
Assuntos
Proteínas de Ligação a DNA/genética , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/metabolismo , Predisposição Genética para Doença , Variação Genética , Proteína HMGA2/genética , Fator de Crescimento Insulin-Like II/genética , Linhagem Celular , Proteínas de Ligação a DNA/metabolismo , Epigênese Genética , Fácies , Feminino , Retardo do Crescimento Fetal/diagnóstico , Regulação da Expressão Gênica no Desenvolvimento , Estudos de Associação Genética , Genótipo , Gráficos de Crescimento , Proteína HMGA2/metabolismo , Humanos , Fator de Crescimento Insulin-Like II/metabolismo , Modelos Biológicos , Mutação , Linhagem , Transdução de Sinais , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/metabolismo , Sequenciamento Completo do GenomaRESUMO
BACKGROUND: Marfan syndrome (MFS) is an autosomal-dominant connective tissue disorder usually associated with heterozygous mutations in the gene encoding fibrillin-1 (FBN1). Homozygous and compound heterozygous cases are rare events and have been associated with a clinical severe presentation. OBJECTIVES: Report unexpected findings of homozygosity and compound heterozygosity in the course of molecular diagnosis of heterozygous MFS and compare the findings with published cases. METHODS AND RESULTS: In the context of molecular diagnosis of heterozygous MFS, systematic sequencing of the FBN1 gene was performed in 2500 probands referred nationwide. 1400 probands carried a heterozygous mutation in this gene. Unexpectedly, among them four homozygous cases (0.29%) and five compound heterozygous cases (0.36%) were identified (total: 0.64%). Interestingly, none of these cases carried two premature termination codon mutations in the FBN1 gene. Clinical features for these carriers and their families were gathered and compared. There was a large spectrum of severity of the disease in probands carrying two mutated FBN1 alleles, but none of them presented extremely severe manifestations of MFS in any system compared with carriers of only one mutated FBN1 allele. This observation is not in line with the severe clinical features reported in the literature for four homozygous and three compound heterozygous probands. CONCLUSION: Homozygotes and compound heterozygotes were unexpectedly identified in the course of molecular diagnosis of MFS. Contrary to previous reports, the presence of two mutated alleles was not associated with severe forms of MFS. Although homozygosity and compound heterozygosity are rarely found in molecular diagnosis, they should not be overlooked, especially among consanguineous families. However, no predictive evaluation of severity should be provided.
Assuntos
Fibrilina-1/genética , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Patologia Molecular , Alelos , Códon sem Sentido , Feminino , Predisposição Genética para Doença , Testes Genéticos , Heterozigoto , Homozigoto , Humanos , Masculino , Síndrome de Marfan/patologia , Mutação de Sentido Incorreto/genética , LinhagemRESUMO
Thoracic aortic aneurysm and dissection (TAAD) is an autosomal-dominant disorder with major life-threatening complications. The disease displays great genetic heterogeneity with some forms allelic to Marfan and Loeys-Dietz syndrome, and an important number of cases still remain unexplained at the molecular level. Through whole-exome sequencing of affected members in a large TAAD-affected family, we identified the c.472C>T (p.Arg158(∗)) nonsense mutation in MFAP5 encoding the extracellular matrix component MAGP-2. This protein interacts with elastin fibers and the microfibrillar network. Mutation screening of 403 additional probands identified an additional missense mutation of MFAP5 (c.62G>T [p.Trp21Leu]) segregating with the disease in a second family. Functional analyses performed on both affected individual's cells and in vitro models showed that these two mutations caused pure or partial haploinsufficiency. Thus, alteration of MAGP-2, a component of microfibrils and elastic fibers, appears as an initiating mechanism of inherited TAAD.
Assuntos
Aneurisma da Aorta Torácica/genética , Dissecção Aórtica/genética , Proteínas Contráteis/genética , Glicoproteínas/genética , Haploinsuficiência/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Dissecção Aórtica/fisiopatologia , Aneurisma da Aorta Torácica/fisiopatologia , Criança , Códon sem Sentido , Proteínas Contráteis/metabolismo , Exoma/genética , Feminino , Fibroblastos , Glicoproteínas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Pessoa de Meia-Idade , Linhagem , Análise de Sequência de DNARESUMO
LEOPARD syndrome (multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, sensorineural Deafness; LS), also called Noonan syndrome with multiple lentigines (NSML), is a rare autosomal dominant disorder associating various developmental defects, notably cardiopathies, dysmorphism, and short stature. It is mainly caused by mutations of the PTPN11 gene that catalytically inactivate the tyrosine phosphatase SHP2 (Src-homology 2 domain-containing phosphatase 2). Besides its pleiotropic roles during development, SHP2 plays key functions in energetic metabolism regulation. However, the metabolic outcomes of LS mutations have never been examined. Therefore, we performed an extensive metabolic exploration of an original LS mouse model, expressing the T468M mutation of SHP2, frequently borne by LS patients. Our results reveal that, besides expected symptoms, LS animals display a strong reduction of adiposity and resistance to diet-induced obesity, associated with overall better metabolic profile. We provide evidence that LS mutant expression impairs adipogenesis, triggers energy expenditure, and enhances insulin signaling, three features that can contribute to the lean phenotype of LS mice. Interestingly, chronic treatment of LS mice with low doses of MEK inhibitor, but not rapamycin, resulted in weight and adiposity gains. Importantly, preliminary data in a French cohort of LS patients suggests that most of them have lower-than-average body mass index, associated, for tested patients, with reduced adiposity. Altogether, these findings unravel previously unidentified characteristics for LS, which could represent a metabolic benefit for patients, but may also participate to the development or worsening of some traits of the disease. Beyond LS, they also highlight a protective role of SHP2 global LS-mimicking modulation toward the development of obesity and associated disorders.
Assuntos
Dieta , Síndrome LEOPARD/genética , Obesidade/prevenção & controle , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Magreza/genética , Adipócitos/citologia , Tecido Adiposo/metabolismo , Adiposidade , Animais , Composição Corporal , Diferenciação Celular , Modelos Animais de Doenças , Metabolismo Energético , Insulina/metabolismo , Lentivirus/metabolismo , Lipólise , MAP Quinase Quinase Quinase 1/antagonistas & inibidores , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Fenótipo , Recombinação GenéticaRESUMO
AIMS: To evaluate the benefit of adding Losartan to baseline therapy in patients with Marfan syndrome (MFS). METHODS AND RESULTS: A double-blind, randomized, multi-centre, placebo-controlled, add on trial comparing Losartan (50 mg when <50 kg, 100 mg otherwise) vs. placebo in patients with MFS according to Ghent criteria, age >10 years old, and receiving standard therapy. 303 patients, mean age 29.9 years old, were randomized. The two groups were similar at baseline, 86% receiving ß-blocker therapy. The median follow-up was 3.5 years. The evolution of aortic diameter at the level of the sinuses of Valsalva was not modified by the adjunction of Losartan, with a mean increase in aortic diameter at the level of the sinuses of Valsalva of 0.44 mm/year (s.e. = 0.07) (-0.043 z/year, s.e. = 0.04) in patients receiving Losartan and 0.51 mm/year (s.e. = 0.06) (-0.01 z/year, s.e. = 0.03) in those receiving placebo (P = 0.36 for the comparison on slopes in millimeter per year and P = 0.69 for the comparison on slopes on z-scores). Patients receiving Losartan had a slight but significant decrease in systolic and diastolic blood pressure throughout the study (5 mmHg). During the study period, aortic surgery was performed in 28 patients (15 Losartan, 13 placebo), death occurred in 3 patients [0 Losartan, 3 placebo, sudden death (1) suicide (1) oesophagus cancer (1)]. CONCLUSION: Losartan was able to decrease blood pressure in patients with MFS but not to limit aortic dilatation during a 3-year period in patients >10 years old. ß-Blocker therapy alone should therefore remain the standard first line therapy in these patients.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Doenças da Aorta/tratamento farmacológico , Losartan/administração & dosagem , Síndrome de Marfan/complicações , Adolescente , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Doenças da Aorta/complicações , Doenças da Aorta/mortalidade , Pressão Sanguínea/efeitos dos fármacos , Dilatação Patológica/complicações , Dilatação Patológica/tratamento farmacológico , Dilatação Patológica/mortalidade , Método Duplo-Cego , Esquema de Medicação , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/prevenção & controle , Masculino , Síndrome de Marfan/mortalidade , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
Noonan syndrome (NS), a genetic disease caused in half of cases by activating mutations of the tyrosine phosphatase SHP2 (PTPN11), is characterized by congenital cardiopathies, facial dysmorphic features, and short stature. How mutated SHP2 induces growth retardation remains poorly understood. We report here that early postnatal growth delay is associated with low levels of insulin-like growth factor 1 (IGF-1) in a mouse model of NS expressing the D61G mutant of SHP2. Conversely, inhibition of SHP2 expression in growth hormone (GH)-responsive cell lines results in increased IGF-1 release upon GH stimulation. SHP2-deficient cells display decreased ERK1/2 phosphorylation and rat sarcoma (RAS) activation in response to GH, whereas expression of NS-associated SHP2 mutants results in ERK1/2 hyperactivation in vitro and in vivo. RAS/ERK1/2 inhibition in SHP2-deficient cells correlates with impaired dephosphorylation of the adaptor Grb2-associated binder-1 (GAB1) on its RAS GTPase-activating protein (RASGAP) binding sites and is rescued by interfering with RASGAP recruitment or function. We demonstrate that inhibition of ERK1/2 activation results in an increase of IGF-1 levels in vitro and in vivo, which is associated with significant growth improvement in NS mice. In conclusion, NS-causing SHP2 mutants inhibit GH-induced IGF-1 release through RAS/ERK1/2 hyperactivation, a mechanism that could contribute to growth retardation. This finding suggests that, in addition to its previously shown beneficial effect on NS-linked cardiac and craniofacial defects, RAS/ERK1/2 modulation could also alleviate the short stature phenotype in NS caused by PTPN11 mutations.
Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hormônio do Crescimento/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , Mutação/genética , Síndrome de Noonan/enzimologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Adaptadoras de Transdução de Sinal , Animais , Animais Recém-Nascidos , Sítios de Ligação , Biometria , Ativação Enzimática/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/biossíntese , Janus Quinase 2/metabolismo , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Síndrome de Noonan/sangue , Síndrome de Noonan/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosfoproteínas/metabolismo , Fosforilação/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Fator de Transcrição STAT5/metabolismo , Proteínas ras/metabolismoRESUMO
BACKGROUND: This cross-sectional controlled study aims to assess health-related quality of life (HRQoL) of children and adolescents with a molecular diagnosis of Marfan syndrome (MFS) or related disorders and to evaluate the factors associated with HRQoL in this population. Sixty-three children with MFS and 124 age- and sex-matched healthy children were recruited. HRQoL was assessed using the Pediatric Quality of Life Inventory (PedsQL™) generic questionnaire. The correlation between HRQoL scores and the different continuous parameters (age, body mass index, disease severity, systemic score, aortic sinus diameter, and aerobic physical capacity) was evaluated using Pearson's or Spearman's coefficient. A multiple linear regression analysis was performed on the two health summary self-reported PedsQL™ scores (physical and psychosocial) to identify the factors associated with HRQoL in the MFS group. RESULTS: Except for emotional functioning, all other domains of HRQoL (psychosocial and physical health, social and school functions) were significantly lower in children with MFS compared to matched healthy children. In the MFS group, the physical health summary score was significantly lower in female than in male patients (self-report: absolute difference [95%CI] = -8.7 [-17.0; -0.47], P = 0.04; proxy-report: absolute difference [95%CI] = -8.6 [-17.3; 0.02], P = 0.05) and also negatively correlated with the systemic score (self-report: R = -0.24, P = 0.06; proxy-report: R = -0.29, P = 0.03) and with the height Z-score (proxy-report: R = -0.29, P = 0.03). There was no significant difference in the physical health summary scores between the different genetic subgroups. In the subgroup of 27 patients who performed a cardiopulmonary exercise test, self- and proxy-reported physical health summary scores were highly correlated with their aerobic physical capacity assessed by peak oxygen consumption (VO2max) and ventilatory anaerobic threshold (VAT). In the multivariate analysis, the most important independent predictors of decreased physical health were increased height, decreased body mass index, decreased VAT and use of prophylactic therapy. CONCLUSIONS: This study reports an impaired HRQoL in children and adolescents with MFS or related conditions, in comparison with matched healthy children. Educational and rehabilitation programs must be developed and evaluated to improve exercise capacity and HRQoL in these patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03236571 . Registered 28 July 2017.
Assuntos
Síndrome de Marfan , Qualidade de Vida , Humanos , Síndrome de Marfan/fisiopatologia , Masculino , Feminino , Estudos Transversais , Criança , Adolescente , Inquéritos e QuestionáriosRESUMO
CONTEXT: Pituitary stalk interruption syndrome (PSIS) is rare in the pediatric population. It combines ectopic posterior pituitary stalk interruption and anterior pituitary hypoplasia with hormonal deficiencies. The phenotype is highly heterogeneous and obesity/overweight seems to be underreported in the literature. OBJECTIVE: To identify patients with PSIS and obesity or overweight, describe their phenotype, and compare them with patients with PSIS without overweight/obesity. METHODS: Sixty-nine children and young adults with PSIS in a Toulouse cohort from 1984 to 2019 were studied. We identified 25 obese or overweight patients (OB-OW group), and 44 were nonobese/overweight (NO group). Then the groups were compared. RESULTS: All cases were sporadic. The sex ratio was 1.6. The main reason for consultation in both groups was growth retardation (61% in OB-OW group, 77% in NO group). History of neonatal hypoglycemia was more common in the OB-OW than in the NO group (57% vs 14%, P = .0008), along with extrapituitary malformations (64% vs 20%, P < 0001). The incidence of caesarean section was higher in the OB-OW group (52%) than in the NO group (23%), although not significant (P = .07). CONCLUSION: Patients with PSIS who are obese/overweight display interesting phenotypic differences that suggest hypothalamic defects. Studies are needed that include additional information on hormonal levels, particularly regarding oxytocin and ghrelin.
Assuntos
Doenças da Hipófise , Hipófise , Criança , Feminino , Humanos , Gravidez , Cesárea , Obesidade/complicações , Obesidade/epidemiologia , Sobrepeso/complicações , Sobrepeso/epidemiologia , Doenças da Hipófise/complicações , Doenças da Hipófise/epidemiologia , Doenças da Hipófise/genética , Hipófise/anormalidades , Adulto JovemRESUMO
OBJECTIVES: The aim of this study is to analyze height after cessation of growth (final height [FH]) and its evolution over the last decades in X-linked hypophosphatemia (XLH) patients in France, as the data on natural history of FH in XLH are lacking. DESIGN: We performed a retrospective observational study in a large cohort of French XLH patients with available data on FH measurements. MATERIALS AND METHODS: We divided patients into 3 groups according to their birth year: group 1 born between 1950 and 1974, group 2 born between 1975 and 2000, and group 3 born between 2001 and 2006, respectively, and compared their FHs. RESULTS: A total of 398 patients were included. Mean FHs were the following: for group 1, -2.31 ± 1.11 standard deviation score (SDS) (n = 127), 156.3 ± 9.7â cm in men and 148.6 ± 6.5â cm in women; for group 2, -1.63 ± 1.13 SDS (n = 193), 161.6 ± 8.5â cm in men and 153.1 ± 7.2â cm in women; and for group 3, -1.34 ± 0.87 SDS (n = 78), 165.1 ± 5.5â cm in men and 154.7 ± 6â cm in women. We report a significant increase in mean FH SDS over 3 generations of patients, for both men and women (P < .001). Final height SDS in male (-2.08 ± 1.18) was lower than in female (-1.70 ± 1.12) (P = .002). CONCLUSION: The FH of XLH patients in France increased significantly over the last decades. Even though men's FHs improved more than women's, men with XLH remain shorter reflecting a more severe disease phenotype. While the results are promising, most patients with XLH remain short leaving room for improvement.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Hipofosfatemia , Humanos , Masculino , Feminino , Adulto , Raquitismo Hipofosfatêmico Familiar/genética , Estudos de Coortes , Estatura , Estudos Retrospectivos , Endopeptidase Neutra Reguladora de Fosfato PHEX , Hipofosfatemia/genéticaRESUMO
Noonan syndrome (NS) is a relatively common developmental disorder characterised by the association of craniofacial abnormalities, congenital heart defects, short stature and skeletal abnormalities, variable developmental delay/learning disability, and predisposition to certain cancers. NS is caused by germline mutations in genes encoding components or regulators of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway. Although abnormalities in the hypothalamic-pituitary-gonadal axis have long been reported in NS patients, there is only scarce published data on this subject. Puberty is usually delayed of about two years for both boys and girls with NS. However, in the majority of patients, it starts spontaneously suggesting a normal hypothalamic - pituitary input. The lower fat mass usually observed in NS patients may influence the timing of puberty. Although there is almost no reliable data on this issue, it is usually considered that fertility is not affected in NS females. In contrast, primary testicular insufficiency, predominant on Sertoli cell function, is reported in NS males. However, the exact frequency of infertility in adult males is unknown. More generally, although the features of NS are well described during childhood, little is known about the progression of the disease in adulthood. Prospective long-term follow-up studies are required to further investigate gonadal function and fertility in NS adults and to clarify the long-term follow-up of these patients.
Assuntos
Síndrome de Noonan , Adulto , Feminino , Mutação em Linhagem Germinativa , Gônadas , Humanos , Masculino , Mutação , Síndrome de Noonan/genética , Estudos Prospectivos , PuberdadeRESUMO
Noonan syndrome (NS) is a mostly dominantly inherited disorder affecting 1:1000 to 1:2500 live births. The phenotype varies in severity and can involve multiple organ systems over a patient's lifetime. Diagnosis is based on a combination of features, including typical facial features, short stature, skeletal abnormalities, presence of cardiac defects, mild developmental delay, cryptorchidism, lymphatic dysplasia and a family history of NS. The phenotype varies from oligosymptomatic adults without significant medical issues to severely affected neonates with life-threatening heart disease. Early, accurate diagnosis is important for individualised management and to optimise developmental and long-term outcomes, but mildly affected patients often go undiagnosed for both healthcare provider (HCP)-related and patient-related reasons. Lack of awareness of NS among HCPs means that some do not recognise the condition, particularly in mildly affected patients and families. Some families do not want to receive a diagnosis that medicalises a condition that may account for family traits (eg, distinctive facial features and short stature), particularly when a child's physical and cognitive development may be satisfactory. As for any condition with lifelong effects on multiple organ systems, a multidisciplinary approach provides the best care. It is proposed that increasing awareness of NS among non-specialist HCPs and other professionals could help direct a parent/carer to seek specialist advice and increase the number of NS diagnoses, with the potential to optimise lifelong patient outcomes. Non-specialists do not need to become experts in either diagnosis or treatment; however, early recognition of NS and referral to an appropriate specialist is important.
Assuntos
Cardiopatias , Síndrome de Noonan , Masculino , Humanos , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Síndrome de Noonan/terapia , FenótipoRESUMO
The SH2 containing protein tyrosine phosphatase 2(SHP2) plays essential roles in fundamental signaling pathways, conferring on it versatile physiological functions during development and in homeostasis maintenance, and leading to major pathological outcomes when dysregulated. Many studies have documented that SHP2 modulation disrupted glucose homeostasis, pointing out a relationship between its dysfunction and insulin resistance, and the therapeutic potential of its targeting. While studies from cellular or tissue-specific models concluded on both pros-and-cons effects of SHP2 on insulin resistance, recent data from integrated systems argued for an insulin resistance promoting role for SHP2, and therefore a therapeutic benefit of its inhibition. In this review, we will summarize the general knowledge of SHP2's molecular, cellular, and physiological functions, explaining the pathophysiological impact of its dysfunctions, then discuss its protective or promoting roles in insulin resistance as well as the potency and limitations of its pharmacological modulation.