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1.
Parkinsonism Relat Disord ; 72: 75-79, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32120303

RESUMO

OBJECTIVE: To investigate the molecular cause(s) underlying a severe form of infantile-onset parkinsonism and characterize functionally the identified variants. METHODS: A trio-based whole exome sequencing (WES) approach was used to identify the candidate variants underlying the disorder. In silico modeling, and in vitro and in vivo studies were performed to explore the impact of these variants on protein function and relevant cellular processes. RESULTS: WES analysis identified biallelic variants in WARS2, encoding the mitochondrial tryptophanyl tRNA synthetase (mtTrpRS), a gene whose mutations have recently been associated with multiple neurological phenotypes, including childhood-onset, levodopa-responsive or unresponsive parkinsonism in a few patients. A substantial reduction of mtTrpRS levels in mitochondria and reduced OXPHOS function was demonstrated, supporting their pathogenicity. Based on the infantile-onset and severity of the phenotype, additional variants were considered as possible genetic modifiers. Functional assessment of a selected panel of candidates pointed to a de novo missense mutation in CHRNA6, encoding the α6 subunit of neuronal nicotinic receptors, which are involved in the cholinergic modulation of dopamine release in the striatum, as a second event likely contributing to the phenotype. In silico, in vitro (Xenopus oocytes and GH4C1 cells) and in vivo (C. elegans) analyses demonstrated the disruptive effects of the mutation on acetylcholine receptor structure and function. CONCLUSION: Our findings consolidate the association between biallelic WARS2 mutations and movement disorders, and suggest CHRNA6 as a genetic modifier of the phenotype.

2.
Int J Mol Sci ; 20(22)2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31739639

RESUMO

Inherited retinal dystrophies (IRDs) are a group of clinically and genetically heterogeneous degenerative disorders. To date, mutations have been associated with IRDs in over 270 disease genes, but molecular diagnosis still remains elusive in about a third of cases. The methodologic developments in genome sequencing techniques that we have witnessed in this last decade have represented a turning point not only in diagnosis and prognosis but, above all, in the identification of new therapeutic perspectives. The discovery of new disease genes and pathogenetic mechanisms underlying IRDs has laid the groundwork for gene therapy approaches. Several clinical trials are ongoing, and the recent approval of Luxturna, the first gene therapy product for Leber congenital amaurosis, marks the beginning of a new era. Due to its anatomical and functional characteristics, the retina is the organ of choice for gene therapy, although there are quite a few difficulties in the translational approaches from preclinical models to humans. In the first part of this review, an overview of the current knowledge on methodological issues and future perspectives of gene therapy applied to IRDs is discussed; in the second part, the state of the art of clinical trials on the gene therapy approach in IRDs is illustrated.

3.
Artigo em Inglês | MEDLINE | ID: mdl-30797015

RESUMO

In recent years, there has been an explosive increase in genetic studies related to autism spectrum disorder (ASD). This implicated the accumulation of a large amount of molecular data that may be used to verify various hypotheses and models developed to explore the complex genetic component of ASD. Several lines of evidence support the view that structural genomic variation contributes to the pathogenesis of ASD. The introduction of more sophisticated techniques for whole-genome screening, including array comparative genome hybridization and high-resolution single nucleotide polymorphism analysis, has allowed to identify an increasing number of ASD susceptibility loci. Copy number variants (CNVs) are the most common type of structural variation in the human genome and are considered important contributors to the pathogenesis of neurodevelopmental disorders, including ASD. In this review, we describe the accumulated evidence concerning the genetic events associated with ASD, and summarize current knowledge about the clinical relevance of CNVs in these disorders.


Assuntos
Transtorno do Espectro Autista/genética , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença/genética , Humanos
4.
Hum Mol Genet ; 25(17): 3824-3835, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27466182

RESUMO

SHOC2 is a scaffold protein composed almost entirely by leucine-rich repeats (LRRs) and having an N-terminal region enriched in alternating lysine and glutamate/aspartate residues (KEKE motifs). SHOC2 acts as a positive modulator of the RAS-RAF-MEK-ERK signalling cascade by favouring stable RAF1 interaction with RAS. We previously reported that the p.Ser2Gly substitution in SHOC2 underlies Mazzanti syndrome, a RASopathy clinically overlapping Noonan syndrome, promoting N-myristoylation and constitutive targeting of the mutant to the plasma membrane. We also documented transient nuclear translocation of wild-type SHOC2 upon EGF stimulation, suggesting a more complex function in signal transduction.Here, we characterized the domains controlling SHOC2 shuttling between the nucleus and cytoplasm, and those contributing to SHOC2S2G mistargeting to the plasma membrane, analysed the structural organization of SHOC2's LRR motifs, and determined the impact of SHOC2 mislocalization on ERK signalling. We show that LRRs 1 to 13 constitute a structurally recognizable domain required for SHOC2 import into the nucleus and constitutive targeting of SHOC2S2G to the plasma membrane, while the KEKE motif-rich region is necessary to achieve efficient SHOC2 export from the nucleus. We also document that SHOC2S2G localizes both in raft and non-raft domains, and that it translocates to the non-raft domains following stimulation. Finally, we demonstrate that SHOC2 trapping at different subcellular sites has a diverse impact on ERK signalling strength and dynamics, suggesting a dual counteracting modulatory role of SHOC2 in the control of ERK signalling exerted at different intracellular compartments.


Assuntos
Núcleo Celular/metabolismo , Citoplasma/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Síndrome dos Cabelos Anágenos Frouxos/genética , Síndrome de Noonan/genética , Motivos de Aminoácidos , Animais , Células COS , Linhagem Celular , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/genética , Sistema de Sinalização das MAP Quinases , Camundongos , Células NIH 3T3 , Transporte Proteico
5.
Hum Mutat ; 36(11): 1080-7, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26173643

RESUMO

The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domain.


Assuntos
Estudos de Associação Genética , Mutação , Síndrome de Noonan/genética , Domínios e Motivos de Interação entre Proteínas/genética , Proteínas Son Of Sevenless/genética , Adolescente , Adulto , Alelos , Substituição de Aminoácidos , Criança , Análise Mutacional de DNA , Exoma , Facies , Feminino , Genótipo , Humanos , Masculino , Modelos Moleculares , Síndrome de Noonan/diagnóstico , Fenótipo , Conformação Proteica , Proteínas Son Of Sevenless/química , Adulto Jovem
6.
Am J Med Genet A ; 167A(8): 1902-7, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25846317

RESUMO

Noonan-like syndrome with loose anagen hair (NSLH), also known as Mazzanti syndrome, is a RASopathy characterized by craniofacial features resembling Noonan syndrome, cardiac defects, cognitive deficits and behavioral issues, reduced growth generally associated with GH deficit, darkly pigmented skin, and an unique combination of ectodermal anomalies. Virtually all cases of NSLH are caused by an invariant and functionally unique mutation in SHOC2 (c.4A>G, p.Ser2Gly). Here, we report on a child with molecularly confirmed NSLH who developed a neuroblastoma, first suspected at the age 3 months by abdominal ultrasound examination. Based on this finding, scanning of the SHOC2 coding sequence encompassing the c.4A>G change was performed on selected pediatric cohorts of malignancies documented to occur in RASopathies (i.e., neuroblastoma, brain tumors, rhabdomyosarcoma, acute lymphoblastic, and myeloid leukemia), but failed to identify a functionally relevant cancer-associated variant. While these results do not support a major role of somatic SHOC2 mutations in these pediatric cancers, this second instance of neuroblastoma in NSLAH suggests a possible predisposition to this malignancy in subjects heterozygous for the c.4A>G SHOC2 mutation.


Assuntos
Neuroblastoma/complicações , Síndrome de Noonan/fisiopatologia , Humanos , Recém-Nascido , Masculino , Síndrome de Noonan/complicações
7.
Nat Genet ; 46(8): 815-7, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25017102

RESUMO

Primrose syndrome and 3q13.31 microdeletion syndrome are clinically related disorders characterized by tall stature, macrocephaly, intellectual disability, disturbed behavior and unusual facial features, with diabetes, deafness, progressive muscle wasting and ectopic calcifications specifically occurring in the former. We report that missense mutations in ZBTB20, residing within the 3q13.31 microdeletion syndrome critical region, underlie Primrose syndrome. This finding establishes a genetic link between these disorders and delineates the impact of ZBTB20 dysregulation on development, growth and metabolism.


Assuntos
Anormalidades Múltiplas/genética , Calcinose/genética , Otopatias/genética , Deficiência Intelectual/genética , Atrofia Muscular/genética , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Sequência de Aminoácidos , Sequência de Bases , Linhagem Celular , Deleção Cromossômica , Cromossomos Humanos Par 3 , Deficiências do Desenvolvimento/genética , Feminino , Predisposição Genética para Doença , Células HEK293 , Humanos , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos
8.
Am J Med Genet A ; 164A(4): 1015-20, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24458587

RESUMO

Fetal hydrops is a condition resulting from interstitial fluid accumulation in fetal compartments secondary to increased capillary permeability and characterized by high rates of perinatal mortality and morbidity. Clinical features include skin edema, hydrothorax, pericardial effusion, ascites with or without polyhydramnios, and placental edema. While it may occur as associated feature in multiple disorders, it has been documented to recur in Noonan syndrome, the most common disorder among RASopathies, but also in cardiofaciocutaneous and Costello syndromes. Here, we report on the occurrence of severe hydrops in a newborn heterozygous for the invariant c.4A>G missense change in SHOC2 which underlies Noonan-like syndrome with loose anagen hair, documenting that it represents a clinically relevant complication in this condition, shared by RASopathies.


Assuntos
Hidropisia Fetal/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Heterozigoto , Humanos , Recém-Nascido , Síndrome dos Cabelos Anágenos Frouxos/genética , Síndrome de Noonan/genética
9.
Circ Cardiovasc Genet ; 5(3): 317-26, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22589294

RESUMO

BACKGROUND: Most cases of apparently idiopathic hypertrophic cardiomyopathy (HCM) in children are caused by mutations in cardiac sarcomere protein genes. HCM also commonly occurs as an associated feature in some patients with disorders caused by mutations in genes encoding components of the RAS-mitogen activated protein kinase (MAPK) signaling pathway. Although diagnosis of these disorders is based on typical phenotypic features, the dysmorphic manifestations can be subtle and therefore overlooked. The aim of this study was to determine the prevalence of mutations in RAS-MAPK genes in preadolescent children with idiopathic HCM. METHODS AND RESULTS: Seventy-eight patients diagnosed with apparently nonsyndromic HCM aged ≤13 years underwent clinical and genetic evaluation. The entire protein coding sequence of 9 genes implicated in Noonan syndrome and related conditions (PTPN11, SOS1, HRAS, KRAS, NRAS, BRAF, RAF1, MAP2K1, and MAP2K2), together with CBL (exons 8 and 9) and SHOC2 (4A>G), were screened for mutations. Five probands (6.4%) carried novel sequence variants in SOS1 (2 individuals), BRAF, MAP2K1, and MAP2K2. Structural and molecular data suggest that these variants may have functional significance. Nine cardiac sarcomere protein genes were screened also; 2 individuals also had mutations in MYBPC. CONCLUSIONS: This study reports novel and potentially pathogenic sequence variants in genes of the RAS-MAPK pathway, suggesting that genetic lesions promoting signaling dysregulation through RAS contribute to disease pathogenesis or progression in children with HCM.


Assuntos
Cardiomiopatia Hipertrófica/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Transdução de Sinais/genética , Proteínas ras/metabolismo , Criança , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Proteínas Quinases Ativadas por Mitógeno/genética , Linhagem , Fenótipo , Proteínas ras/genética
10.
Hum Mutat ; 32(7): 760-72, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21387466

RESUMO

Noonan syndrome (NS) is among the most common nonchromosomal disorders affecting development and growth. NS is caused by aberrant RAS-MAPK signaling and is genetically heterogeneous, which explains, in part, the marked clinical variability documented for this Mendelian trait. Recently, we and others identified SOS1 as a major gene underlying NS. Here, we explored further the spectrum of SOS1 mutations and their associated phenotypic features. Mutation scanning of the entire SOS1 coding sequence allowed the identification of 33 different variants deemed to be of pathological significance, including 16 novel missense changes and in-frame indels. Various mutation clusters destabilizing or altering orientation of regions of the protein predicted to contribute structurally to the maintenance of autoinhibition were identified. Two previously unappreciated clusters predicted to enhance SOS1's recruitment to the plasma membrane, thus promoting a spatial reorientation of domains contributing to inhibition, were also recognized. Genotype-phenotype analysis confirmed our previous observations, establishing a high frequency of ectodermal anomalies and a low prevalence of cognitive impairment and reduced growth. Finally, mutation analysis performed on cohorts of individuals with nonsyndromic pulmonic stenosis, atrial septal defects, and ventricular septal defects excluded a major contribution of germline SOS1 lesions to the isolated occurrence of these cardiac anomalies.


Assuntos
Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Proteína SOS1/genética , Adolescente , Adulto , Criança , Éxons , Feminino , Estudos de Associação Genética , Comunicação Interatrial/genética , Comunicação Interventricular/genética , Humanos , Mutação INDEL/genética , Íntrons , Masculino , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Mutação , Mutação de Sentido Incorreto/genética , Conformação Proteica , Estenose da Valva Pulmonar/genética , Proteína SOS1/química
11.
Nat Genet ; 41(9): 1022-6, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19684605

RESUMO

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.


Assuntos
Cabelo/crescimento & desenvolvimento , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Ácido Mirístico/metabolismo , Síndrome de Noonan/metabolismo , Actinas/metabolismo , Núcleo Celular/metabolismo , Citoesqueleto/metabolismo , Técnica Indireta de Fluorescência para Anticorpo , Corantes Fluorescentes/metabolismo , Mutação em Linhagem Germinativa , Humanos , Indóis/metabolismo , Mutação de Sentido Incorreto , Síndrome de Noonan/genética
12.
Hum Mutat ; 30(4): 695-702, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19206169

RESUMO

Noonan, LEOPARD, and cardiofaciocutaneous syndromes (NS, LS, and CFCS) are developmental disorders with overlapping features including distinctive facial dysmorphia, reduced growth, cardiac defects, skeletal and ectodermal anomalies, and variable cognitive deficits. Dysregulated RAS-mitogen-activated protein kinase (MAPK) signal traffic has been established to represent the molecular pathogenic cause underlying these conditions. To investigate the phenotypic spectrum and molecular diversity of germline mutations affecting BRAF, which encodes a serine/threonine kinase functioning as a RAS effector frequently mutated in CFCS, subjects with a diagnosis of NS (N=270), LS (N=6), and CFCS (N=33), and no mutation in PTPN11, SOS1, KRAS, RAF1, MEK1, or MEK2, were screened for the entire coding sequence of the gene. Besides the expected high prevalence of mutations observed among CFCS patients (52%), a de novo heterozygous missense change was identified in one subject with LS (17%) and five individuals with NS (1.9%). Mutations mapped to multiple protein domains and largely did not overlap with cancer-associated defects. NS-causing mutations had not been documented in CFCS, suggesting that the phenotypes arising from germline BRAF defects might be allele specific. Selected mutant BRAF proteins promoted variable gain of function of the kinase, but appeared less activating compared to the recurrent cancer-associated p.Val600Glu mutant. Our findings provide evidence for a wide phenotypic diversity associated with mutations affecting BRAF, and occurrence of a clinical continuum associated with these molecular lesions.


Assuntos
Anormalidades Múltiplas/genética , Mutação em Linhagem Germinativa , Síndrome LEOPARD/genética , Síndrome de Noonan/genética , Proteínas Proto-Oncogênicas B-raf/genética , Anormalidades Múltiplas/patologia , Estudos de Coortes , Face/anormalidades , Feminino , Frequência do Gene , Variação Genética , Genótipo , Cardiopatias Congênitas/patologia , Humanos , Síndrome LEOPARD/patologia , Masculino , Mutação de Sentido Incorreto , Síndrome de Noonan/patologia , Fenótipo , Anormalidades da Pele
13.
Eur J Hum Genet ; 17(6): 733-40, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19156172

RESUMO

Cardio-facio-cutaneous syndrome (CFCS) is a rare disease characterized by mental retardation, facial dysmorphisms, ectodermal abnormalities, heart defects and developmental delay. CFCS is genetically heterogeneous and mutations in the KRAS, BRAF, MAP2K1 (MEK1) and MAP2K2 (MEK2) genes, encoding for components of the RAS-mitogen activated protein kinase (MAPK) signaling pathway, have been identified in up to 90% of cases. Here we screened a cohort of 33 individuals with CFCS for MEK1 and MEK2 gene mutations to further explore their molecular spectrum in this disorder, and to analyze genotype-phenotype correlations. Three MEK1 and two MEK2 mutations were detected in six patients. Two missense MEK1 (L42F and Y130H) changes and one in-frame MEK2 (K63_E66del) deletion had not been reported earlier. All mutations were localized within exon 2 or 3. Together with the available records, the present data document that MEK1 mutations are relatively more frequent than those in MEK2, with exons 2 and 3 being mutational hot spots in both genes. Mutational analysis of the affected MEK1 and MEK2 exons did not reveal occurrence of mutations among 75 patients with Noonan syndrome, confirming the low prevalence of MEK gene defects in this disorder. Clinical review of known individuals with MEK1/MEK2 mutations suggests that these patients show dysmorphic features, ectodermal abnormalities and cognitive deficit similar to what was observed in BRAF-mutated patients and in the general CFCS population. Conversely, congenital heart defects, particularly mitral valve and septal defects, and ocular anomalies seem to be less frequent among MEK1/MEK2 mutation-positive patients.


Assuntos
Anormalidades Múltiplas/genética , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 2/genética , Mutação/genética , Fenótipo , Criança , Pré-Escolar , Estudos de Coortes , Displasia Ectodérmica/genética , Feminino , Cardiopatias Congênitas/genética , Humanos , Deficiência Intelectual/genética , Masculino , Síndrome
14.
Eur J Hum Genet ; 17(4): 420-5, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18854871

RESUMO

Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFCS) are related developmental disorders caused by mutations in genes encoding various components of the RAS-MAPK signaling cascade. NS is associated with mutations in the genes PTPN11, SOS1, RAF1, or KRAS, whereas CFCS can be caused by mutations in BRAF, MEK1, MEK2, or KRAS. The NS phenotype is rarely accompanied by multiple giant cell lesions (MGCL) of the jaw (Noonan-like/MGCL syndrome (NL/MGCLS)). PTPN11 mutations are the only genetic abnormalities reported so far in some patients with NL/MGCLS and in one individual with LEOPARD syndrome and MGCL. In a cohort of 75 NS patients previously tested negative for mutations in PTPN11 and KRAS, we detected SOS1 mutations in 11 individuals, four of whom had MGCL. To explore further the relevance of aberrant RAS-MAPK signaling in syndromic MGCL, we analyzed the established genes causing CFCS in three subjects with MGCL associated with a phenotype fitting CFCS. Mutations in BRAF or MEK1 were identified in these patients. All mutations detected in these seven patients with syndromic MGCL had previously been described in NS or CFCS without apparent MGCL. This study demonstrates that MGCL may occur in NS and CFCS with various underlying genetic alterations and no obvious genotype-phenotype correlation. This suggests that dysregulation of the RAS-MAPK pathway represents the common and basic molecular event predisposing to giant cell lesion formation in patients with NS and CFCS rather than specific mutation effects.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Células Gigantes/patologia , Síndrome de Noonan/genética , Síndrome de Noonan/patologia , Anormalidades Múltiplas/diagnóstico , Adolescente , Adulto , Criança , Estudos de Coortes , Feminino , Cardiopatias/congênito , Cardiopatias/patologia , Humanos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Mutação , Síndrome de Noonan/diagnóstico , Fenótipo , Dermatopatias/patologia , Síndrome , Proteínas ras/genética , Proteínas ras/metabolismo
15.
J Clin Endocrinol Metab ; 92(8): 3141-7, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17488789

RESUMO

CONTEXT: In Italy, the surveillance of congenital hypothyroidism (CH) is performed by the Italian National Registry of Infants with CH (INRICH). Up to now, about 3600 infants with CH are recorded in the INRICH, and a high number of twins are included. OBJECTIVE: Our objective was to estimate the risk of CH in multiple and single deliveries and to compare neonatal features of CH twins with twins from the general population. DESIGN: The Italian population of CH infants recorded in the INRICH from 1989-2000 was investigated. RESULTS: A more than 3-fold higher frequency of twins was found in the CH population than in the general population, and for the first time, it was possible to estimate the CH incidence in multiple (10.1 in 10,000) and single deliveries (3.2 in 10,000 live births). Significantly higher frequencies of in situ gland as well as lower TSH mean level at screening were found in twin than in singleton CH babies. The concordance rate for permanent CH was very low (4.3%) and due to only three concordant couples. However, a high recurrence risk for CH was estimated in siblings of affected babies recorded in the INRICH, including twins considered as siblings. CONCLUSIONS: The high CH incidence observed in twins is worthy of interest for the high number of induced pregnancies in Italy as well as in other Western countries. Moreover, the low concordance rate for CH among twins together with a high recurrence risk for the disease among siblings indicates that environmental risk factors may act as a trigger on a susceptible genetic background in the etiology of the disease.


Assuntos
Hipotireoidismo Congênito/epidemiologia , Gravidez Múltipla/fisiologia , Adulto , Peso ao Nascer , Hipotireoidismo Congênito/diagnóstico , Hipotireoidismo Congênito/patologia , Feminino , Heterozigoto , Homozigoto , Humanos , Recém-Nascido , Itália/epidemiologia , Modelos Lineares , Masculino , Triagem Neonatal , Gravidez , Risco , Razão de Masculinidade , Glândula Tireoide/crescimento & desenvolvimento , Glândula Tireoide/patologia , Tireotropina/sangue , Tiroxina/sangue , Gêmeos
16.
J Clin Endocrinol Metab ; 91(4): 1428-33, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16418214

RESUMO

CONTEXT: Congenital hypothyroidism (CH) is a common endocrine disorder with an incidence of 1:3000-4000 at birth. In 80-85% of cases, CH is caused by defects in thyroid organogenesis, resulting in absent, ectopically located, and/or severely reduced gland [thyroid dysgenesis (TD)]. Mutations in genes controlling thyroid development have demonstrated that in a few cases, TD is a Mendelian trait. However, accumulating evidence supports the view that the genetics of TD are complex, possibly with a polygenic/multifactorial basis. A higher prevalence of congenital heart disease has been documented in children with CH than in the general population. Such an association suggests a possible pathogenic role of genes involved in both heart and thyroid development. NKX2-5 encodes a homeodomain-containing transcription factor with a major role in heart development, and mutations affecting this gene have been reported in individuals with congenital heart disease. OBJECTIVE: In the present work we investigated the possible involvement of NKX2-5 mutations in TD. RESULTS: Our results indicate that Nkx2-5(-/-) embryos exhibit thyroid bud hypoplasia, providing evidence that NKX2-5 plays a role in thyroid organogenesis and that NKX2-5 mutations contribute to TD. NKX2-5 mutational screening in 241 patients with TD allowed the identification of three heterozygous missense changes (R25C, A119S, and R161P) in four patients with TD. Functional characterization of the three mutations demonstrated reduced DNA binding and/or transactivation properties, with a dominant-negative effect on wild-type NKX2-5. CONCLUSION: Our results suggest a previously unknown role of NKX2-5 in the pathogenesis of TD.


Assuntos
Hipotireoidismo Congênito/genética , Proteínas de Homeodomínio/genética , Mutação de Sentido Incorreto/fisiologia , Fatores de Transcrição/genética , DNA/biossíntese , DNA/genética , Proteína Homeobox Nkx-2.5 , Humanos , Imuno-Histoquímica , Hibridização In Situ , Iodeto Peroxidase/metabolismo , Fenótipo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Tireoglobulina/metabolismo , Glândula Tireoide/fisiologia
17.
Am J Hum Genet ; 78(2): 279-90, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16358218

RESUMO

Germline mutations in PTPN11, the gene encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome (NS) and the clinically related LEOPARD syndrome (LS), whereas somatic mutations in the same gene contribute to leukemogenesis. On the basis of our previously gathered genetic and biochemical data, we proposed a model that splits NS- and leukemia-associated PTPN11 mutations into two major classes of activating lesions with differential perturbing effects on development and hematopoiesis. To test this model, we investigated further the diversity of germline and somatic PTPN11 mutations, delineated the association of those mutations with disease, characterized biochemically a panel of mutant SHP-2 proteins recurring in NS, LS, and leukemia, and performed molecular dynamics simulations to determine the structural effects of selected mutations. Our results document a strict correlation between the identity of the lesion and disease and demonstrate that NS-causative mutations have less potency for promoting SHP-2 gain of function than do leukemia-associated ones. Furthermore, we show that the recurrent LS-causing Y279C and T468M amino acid substitutions engender loss of SHP-2 catalytic activity, identifying a previously unrecognized behavior for this class of missense PTPN11 mutations.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Síndrome LEOPARD/genética , Leucemia/genética , Síndrome de Noonan/genética , Proteínas Tirosina Fosfatases/genética , Adulto , Sequência de Aminoácidos , Estudos de Coortes , Feminino , Mutação em Linhagem Germinativa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Masculino , Mutação , Conformação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Proteínas Tirosina Fosfatases/química
18.
Leuk Res ; 29(4): 459-62, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15725481

RESUMO

Myelodysplastic syndromes (MDS) are comprised of a heterogeneous group of stem cell disorders characterized by ineffective hematopoiesis and susceptibility to transform to acute myeloid leukemia. The molecular pathways underlying disease initiation and evolution are still largely unknown. We recently demonstrated that acquired mutations in PTPN11 are a major event in JMML and occur with variable prevalence in children with other hematologic malignancies, including MDS. Here, we investigated contribution of PTPN11 mutations to adult MDS and CMML pathogenesis. Our results indicate that PTPN11 lesions might play a role in adult MDS/CMML pathogenesis but do not represent a major molecular event.


Assuntos
Leucemia Mielomonocítica Crônica/genética , Mutação , Síndromes Mielodisplásicas/genética , Proteínas Tirosina Fosfatases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Pessoa de Meia-Idade , Proteína Tirosina Fosfatase não Receptora Tipo 11
19.
Am J Hum Genet ; 75(3): 492-7, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15248152

RESUMO

Germline mutations in PTPN11--the gene encoding the nonreceptor protein tyrosine phosphatase SHP-2--represent a major cause of Noonan syndrome (NS), a developmental disorder characterized by short stature and facial dysmorphism, as well as skeletal, hematologic, and congenital heart defects. Like many autosomal dominant disorders, a significant percentage of NS cases appear to arise from de novo mutations. Here, we investigated the parental origin of de novo PTPN11 lesions and explored the effect of paternal age in NS. By analyzing intronic portions that flank the exonic PTPN11 lesions in 49 sporadic NS cases, we traced the parental origin of mutations in 14 families. Our results showed that all mutations were inherited from the father, despite the fact that no substitution affected a CpG dinucleotide. We also report that advanced paternal age was observed among cohorts of sporadic NS cases with and without PTPN11 mutations and that a significant sex-ratio bias favoring transmission to males was present in subjects with sporadic NS caused by PTPN11 mutations, as well as in families inheriting the disorder.


Assuntos
Mutação em Linhagem Germinativa , Mutação , Síndrome de Noonan/genética , Proteínas Tirosina Fosfatases/genética , Ilhas de CpG , Análise Mutacional de DNA , Éxons , Facies , Pai , Feminino , Genes Dominantes , Genótipo , Haplótipos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Íntrons , Masculino , Fenótipo , Reação em Cadeia da Polimerase , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Fatores Sexuais , Razão de Masculinidade
20.
Blood ; 104(2): 307-13, 2004 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-14982869

RESUMO

SHP-2 is a protein tyrosine phosphatase functioning as signal transducer downstream to growth factor and cytokine receptors. SHP-2 is required during development, and germline mutations in PTPN11, the gene encoding SHP-2, cause Noonan syndrome. SHP-2 plays a crucial role in hematopoietic cell development. We recently demonstrated that somatic PTPN11 mutations are the most frequent lesion in juvenile myelomonocytic leukemia and are observed in a smaller percentage of children with other myeloid malignancies. Here, we report that PTPN11 lesions occur in childhood acute lymphoblastic leukemia (ALL). Mutations were observed in 23 of 317 B-cell precursor ALL cases, but not among 44 children with T-lineage ALL. In the former, lesions prevalently occurred in TEL-AML1(-) cases with CD19(+)/CD10(+)/cyIgM(-) immunophenotype. PTPN11, NRAS, and KRAS2 mutations were largely mutually exclusive and accounted for one third of common ALL cases. We also show that, among 69 children with acute myeloid leukemia, PTPN11 mutations occurred in 4 of 12 cases with acute monocytic leukemia (FAB-M5). Leukemia-associated PTPN11 mutations were missense and were predicted to result in SHP-2 gain-of-function. Our findings provide evidence for a wider role of PTPN11 lesions in leukemogenesis, but also suggest a lineage-related and differentiation stage-related contribution of these lesions to clonal expansion.


Assuntos
Mutação em Linhagem Germinativa , Leucemia Monocítica Aguda/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Tirosina Fosfatases/genética , Adolescente , Diferenciação Celular/genética , Linhagem da Célula/genética , Criança , Estudos de Coortes , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Leucemia Monocítica Aguda/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Prevalência , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Transdução de Sinais , Proteínas ras/metabolismo
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