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1.
PLoS One ; 11(12): e0167984, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27936167

RESUMO

The vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657del5; rs587776650) in the NBN gene on chromosome 8q21. This mutation is essentially confined to Slavic populations and may thus be considered a Slavic founder mutation. Notably, not a single parenthood of a homozygous c.657del5 carrier has been reported to date, while heterozygous carriers do reproduce but have an increased cancer risk. These observations seem to conflict with the considerable carrier frequency of c.657del5 of 0.5% to 1% as observed in different Slavic populations because deleterious mutations would be eliminated quite rapidly by purifying selection. Therefore, we propose that heterozygous c.657del5 carriers have increased reproductive success, i.e., that the mutation confers heterozygote advantage. In fact, in our cohort study of the reproductive history of 24 NBS pedigrees from the Czech Republic, we observed that female carriers gave birth to more children on average than female non-carriers, while no such reproductive differences were observed for males. We also estimate that c.657del5 likely occurred less than 300 generations ago, thus supporting the view that the original mutation predated the historic split and subsequent spread of the 'Slavic people'. We surmise that the higher fertility of female c.657del5 carriers reflects a lower miscarriage rate in these women, thereby reflecting the role of the NBN gene product, nibrin, in the repair of DNA double strand breaks and their processing in immune gene rearrangements, telomere maintenance, and meiotic recombination, akin to the previously described role of the DNA repair genes BRCA1 and BRCA2.


Assuntos
Proteínas de Ciclo Celular/genética , Efeito Fundador , Mutação , Síndrome de Quebra de Nijmegen/genética , Proteínas Nucleares/genética , Reprodução/genética , Adulto , Estudos de Coortes , República Tcheca , Dano ao DNA , Reparo do DNA , Feminino , Triagem de Portadores Genéticos , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Quebra de Nijmegen/etnologia , Eslováquia
2.
Sci Rep ; 5: 11649, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26130459

RESUMO

Skeletal ciliopathies are a heterogeneous group of autosomal recessive osteochondrodysplasias caused by defects in formation, maintenance and function of the primary cilium. Mutations in the underlying genes affect the molecular motors, intraflagellar transport complexes (IFT), or the basal body. The more severe phenotypes are caused by defects of genes of the dynein-2 complex, where mutations in DYNC2H1, WDR34 and WDR60 have been identified. In a patient with a Jeune-like phenotype we performed exome sequencing and identified compound heterozygous missense and nonsense mutations in DYNC2LI1 segregating with the phenotype. DYNC2LI1 is ubiquitously expressed and interacts with DYNC2H1 to form the dynein-2 complex important for retrograde IFT. Using DYNC2LI1 siRNA knockdown in fibroblasts we identified a significantly reduced cilia length proposed to affect cilia function. In addition, depletion of DYNC2LI1 induced altered cilia morphology with broadened ciliary tips and accumulation of IFT-B complex proteins in accordance with retrograde IFT defects. Our results expand the clinical spectrum of ciliopathies caused by defects of the dynein-2 complex.


Assuntos
Dineínas do Citoplasma/genética , Mutação/genética , Cílios/metabolismo , Códon sem Sentido/genética , Dineínas do Citoplasma/química , Exoma/genética , Fibroblastos/metabolismo , Imunofluorescência , Heterozigoto , Humanos , Estrutura Terciária de Proteína , Análise de Sequência de DNA
3.
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
4.
Am J Med Genet A ; 167A(4): 837-41, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25735987

RESUMO

We identified a de novo deletion of 14q11.2 in a Czech patient with developmental delay, mild autistic features, macrosomy, macrocephaly, orthognathic deformities, and dysmorphic facial features. The clinical follow-up of the patient lasting 14 years documented changes in the facial dysmorphism from infancy to adolescence. The deletion affects approximately 200 kb of DNA with five protein-coding genes and two snoRNA genes. Two of the protein-coding genes, SUPT16H and CHD8, have been proposed as candidate genes for a new microdeletion syndrome. Our patient further supports the existence of this syndrome and extends its phenotypic spectrum, especially points to the possibility that orthognathic deformities may be associated with microdeletions of 14q11.2. CHD8 mutations have been found in patients with neurodevelopmental disorders and macrocephaly. The HNRNPC gene, repeatedly deleted in patients with developmental delay, is another candidate as its 5́ end is adjacent to the deletion, and the expression of this gene may be affected by position effect.


Assuntos
Anormalidades Múltiplas/diagnóstico , Deleção Cromossômica , Cromossomos Humanos Par 14/genética , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Adolescente , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Seguimentos , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Megalencefalia/diagnóstico , Megalencefalia/genética
5.
Eur J Hum Genet ; 23(2): 256-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24781758

RESUMO

The recently proposed adaptor protein 4 (AP-4) deficiency syndrome comprises a group of congenital neurological disorders characterized by severe intellectual disability (ID), delayed or absent speech, hereditary spastic paraplegia, and growth retardation. AP-4 is a heterotetrameric protein complex with important functions in vesicle trafficking. Mutations in genes affecting different subunits of AP-4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been reported in patients with the AP-4 deficiency phenotype. We describe two siblings from a non-consanguineous couple who presented with severe ID, absent speech, microcephaly, growth retardation, and progressive spastic tetraplegia. Whole-exome sequencing in the two patients identified the novel homozygous 2-bp deletion c.1160_1161delCA (p.(Thr387Argfs*30)) in AP4B1. Sanger sequencing confirmed the mutation in the siblings and revealed it in the heterozygous state in both parents. The AP4B1-associated phenotype has previously been assigned to spastic paraplegia-47. Identification of a novel AP4B1 alteration in two patients with clinical manifestations highly similar to other individuals with mutations affecting one of the four AP-4 subunits further supports the observation that loss of AP-4 assembly or functionality underlies the common clinical features in these patients and underscores the existence of the clinically recognizable AP-4 deficiency syndrome.


Assuntos
Complexo 4 de Proteínas Adaptadoras/genética , Mutação da Fase de Leitura , Deficiência Intelectual/genética , Quadriplegia/genética , Adolescente , Criança , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Quadriplegia/diagnóstico , Irmãos , Síndrome
6.
Cas Lek Cesk ; 153(5): 242-5, 2014.
Artigo em Tcheco | MEDLINE | ID: mdl-25370770

RESUMO

BACKGROUND: Increased frequency of chromosomal aberration in children of mothers aged 35 years and older is very well known and since 1973 it is an indication to investigate the foetal karyotype in cells obtained by invasive method (amniocentesis), because the genetic risk of severe affection is higher than the risk of necessary invasive method. Mutagenic effect of advanced paternal age is known only among geneticists (1-4). The reason is not only low absolute risk of new mutation but particularly a high number of involved genes and last not least the limited spectrum of autosomal dominant disorders without abiotrofic character. Therefore the preventive methods for elimination of this risk are very limited. Only a few of them could be recognized prenatally by noninvasive methods of prenatal diagnostics. METHODS: Genealogical, anamnestic and clinical data of 83 patients were studied with clinical suspection on neurocardiofaciocutaneous syndrome (NCFCs) (5-7). The diagnosis has not been confirmed in 29 patients, no mutation was detected in 8 investigated genes (PTPN11, SOS1, HRAS, BRAF, RAF1, MEK1, KRAS, NRAS). In 54 patients with autosomal dominant inherited Noonan syndrome, Costello syndrome and cardiofaciocutaneous syndrome the diagnosis was confirmed on DNA level and the biological fitness was estimated for each disorder. Paternal age at conception was compared in the group of patients with familial and sporadic occurrence of Noonan and NCFC syndromes. The clinical prognosis of this disorder is represented by biological fitness of patients. Coefficient of selection is 0,6 in Noonan and LEOPARD syndromes (29 from 48). All 6 patients with Costello and cardiofaciocutaneous syndromes developed due to a new mutation. CONCLUSION: Paternal age at birth was studied in 83 children patients with autosomal dominant Neurocardiofaciocutaneous syndrome (Noonan, LEOPARD, Costello, CFC) with a high population incidence and decreased biological fitness. Due to severe congenital heart defects, failure to thrive in infancy, increased risk for malignancy and further health problems the clinical prognosis of patients in the past was not good. Therefore high mutation rate is expected until now. Identification of genes responsible for manifestation of this disorder, enables to confirm the diagnosis and to recognize inherited and de novo mutations. Genealogy and DNA analysis of PTPN11, SOS1, HRAS, BRAF, RAF1, MEK1, KRAS and NRAS were obtained in cohort of 54 patients with NCFC syndromes and their parents. There were 48 patients with Noonan and LEOPARD syndromes, in 29 cases due to mutation de novo, 19 patients inherited the mutation from one of parents. All 6 patients with Costello syndrome and CFC syndrome were affected due to new mutation. DNA analysis revealed 32 mutations in PTPN11 gene, mutation in SOS1 gene was found in 10 patients, RAF1 mutation was present in 3 patients; mutation in MEK1, KRAS and NRAS genes was present in one patient each. In Costello syndrome and CFC syndrome mutations in HRAS (4 patients) and BRAF (2 patients) genes were detected. Genealogic data allow analysing parental age in the group of patients with new mutation and inherited mutation. Paternal age at conception of patients with Noonan syndrome due to new mutation was significantly increased in comparison to the group of fathers of Noonan patients with inherited mutation - 38,4 years and 29,6 years, resp., range 28 to 55 years and 25 to 35 years, resp. Maternal age was slightly increased too, -30,9 and 27,7, resp. and range 24 to 42 years and 21 to 36 years, resp. but not significantly. The results support the mutagenic effect of paternal age, espec. autosomal dominant mutations.


Assuntos
Análise Mutacional de DNA , Displasia Ectodérmica/genética , Insuficiência de Crescimento/genética , Cardiopatias Congênitas/genética , Idade Paterna , Adolescente , Fatores Etários , Criança , Pré-Escolar , Aberrações Cromossômicas , Displasia Ectodérmica/diagnóstico , Facies , Insuficiência de Crescimento/diagnóstico , Feminino , Genes Dominantes/genética , Predisposição Genética para Doença/genética , Cardiopatias Congênitas/diagnóstico , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Diagnóstico Pré-Natal
7.
Hum Mutat ; 35(9): 1092-100, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24924640

RESUMO

Marshall-Smith syndrome (MSS) is a very rare malformation syndrome characterized by typical craniofacial anomalies, abnormal osseous maturation, developmental delay, failure to thrive, and respiratory difficulties. Mutations in the nuclear factor 1/X gene (NFIX) were recently identified as the cause of MSS. In our study cohort of 17 patients with a clinical diagnosis of MSS, conventional sequencing of NFIX revealed frameshift and splice-site mutations in 10 individuals. Using multiplex ligation-dependent probe amplification analysis, we identified a recurrent deletion of NFIX exon 6 and 7 in five individuals. We demonstrate this recurrent deletion is the product of a recombination between AluY elements located in intron 5 and 7. Two other patients had smaller deletions affecting exon 6. These findings show that MSS is a genetically homogeneous Mendelian disorder. RT-PCR experiments with newly identified NFIX mutations including the recurrent exon 6 and 7 deletion confirmed previous findings indicating that MSS-associated mutant mRNAs are not cleared by nonsense-mediated mRNA decay. Predicted MSS-associated mutant NFIX proteins consistently have a preserved DNA binding and dimerization domain, whereas they grossly vary in their C-terminal portion. This is in line with the hypothesis that MSS-associated mutations encode dysfunctional proteins that act in a dominant negative manner.


Assuntos
Anormalidades Múltiplas/genética , Elementos Alu , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Craniofaciais/genética , Éxons , Fatores de Transcrição NFI/genética , Displasia Septo-Óptica/genética , Deleção de Sequência , Anormalidades Múltiplas/diagnóstico , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/diagnóstico , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Anormalidades Craniofaciais/diagnóstico , Análise Mutacional de DNA , Facies , Feminino , Expressão Gênica , Loci Gênicos , Humanos , Lactente , Masculino , Mutação , Fenótipo , RNA Mensageiro/genética , Displasia Septo-Óptica/diagnóstico , Adulto Jovem
8.
Orphanet J Rare Dis ; 8: 119, 2013 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-23919306

RESUMO

BACKGROUND: Congenital generalized lipodystrophy (CGL) or Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare genetic syndrome characterized by the absence of adipose tissue. As CGL is thought to be related to malfunctions in adipocyte development, genes involved in the mechanisms of adipocyte biology and maintenance or differentiation of adipocytes, especially transcription factors are candidates. Several genes (BSCL1-4) were found to be associated to the syndrome but not all CGL patients carry mutations in these genes. METHODS AND RESULTS: In a patient with CGL and insulin resistance we investigated the known candidate genes but the patient did not carry a relevant mutation. Analyses of the insulin activated signal transduction pathways in isolated fibroblasts of the patient revealed a postreceptor defect altering expression of the immediate early gene c-fos. Sequence analyses revealed a novel homozygous point mutation (c.-439, T→A) in the patients' c-fos promoter. The point mutation was located upstream of the well characterized promoter elements in a region with no homology to any known cis-elements. The identified mutation was not detected in a total of n=319 non lipodystrophic probands. In vitro analyses revealed that the mutation facilitates the formation of a novel and specific protein/DNA complex. Using mass spectrometry we identified the proteins of this novel complex. Cellular investigations demonstrate that the wild type c-fos promoter can reconstitute the signaling defect in the patient, excluding further upstream signaling alterations, and vice versa the investigations with the c-fos promoter containing the identified mutation generally reduce basal and inducible c-fos transcription activity. As a consequence of the identified point mutation gene expression including c-Fos targeted genes is significantly altered, shown exemplified in cells of the patient. CONCLUSION: The immediate-early gene c-fos is one essential transcription factor to initiate adipocyte differentiation. According to the role of c-fos in adipocyte differentiation our findings of a mutation that initiates a repression mechanism at c-fos promoter features the hypothesis that diminished c-fos expression might play a role in CGL by interfering with adipocyte development.


Assuntos
Genes fos/genética , Lipodistrofia Generalizada Congênita/genética , Mutação Puntual , Adipócitos/citologia , Adipócitos/fisiologia , Adulto , Diferenciação Celular , Feminino , Expressão Gênica , Genes Precoces , Genes fos/fisiologia , Humanos
9.
Hum Mutat ; 34(5): 686-96, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23420520

RESUMO

Warburg Micro syndrome and Martsolf syndrome (MS) are heterogeneous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Causative biallelic germline mutations have been identified in RAB3GAP1, RAB3GAP2, or RAB18, each of which encode proteins involved in membrane trafficking. This report provides an up to date overview of all known disease variants identified in 29 previously published families and 52 new families. One-hundred and forty-four Micro and nine Martsolf families were investigated, identifying mutations in RAB3GAP1 in 41% of cases, mutations in RAB3GAP2 in 7% of cases, and mutations in RAB18 in 5% of cases. These are listed in Leiden Open source Variation Databases, which was created by us for all three genes. Genotype-phenotype correlations for these genes have now established that the clinical phenotypes in Micro syndrome and MS represent a phenotypic continuum related to the nature and severity of the mutations present in the disease genes, with more deleterious mutations causing Micro syndrome and milder mutations causing MS. RAB18 has not yet been linked to the RAB3 pathways, but mutations in all three genes cause an indistinguishable phenotype, making it likely that there is some overlap. There is considerable genetic heterogeneity for these disorders and further gene identification will help delineate these pathways.


Assuntos
Catarata/genética , Genótipo , Hipogonadismo/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto , Fenótipo , Proteínas rab de Ligação ao GTP/genética , Proteínas rab3 de Ligação ao GTP/genética , Sequência de Aminoácidos , Animais , Catarata/patologia , Criança , Pré-Escolar , Humanos , Hipogonadismo/patologia , Lactente , Deficiência Intelectual/patologia , Imagem por Ressonância Magnética , Masculino , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos , Proteínas rab de Ligação ao GTP/química , Proteínas rab3 de Ligação ao GTP/química
10.
Neuromolecular Med ; 13(3): 204-11, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21833744

RESUMO

Ataxia telangiectasia (AT) is a genomic instability syndrome characterised, among others, by progressive cerebellar degeneration, oculocutaneous telangiectases, immunodeficiency, elevated serum alpha-phetoprotein level, chromosomal breakage, hypersensitivity to ionising radiation and increased cancer risk. This autosomal recessive disorder is caused by mutations in the ataxia telangiectasia mutated (ATM) gene coding for serine/threonine protein kinase with a crucial role in response to DNA double-strand breaks. We characterised genotype and phenotype of 12 Slavic AT patients from 11 families. Mutation analysis included sequencing of the entire coding sequence, adjacent intron regions, 3'UTR and 5'UTR of the ATM gene and multiplex ligation-dependent probe amplification (MLPA) for the detection of large deletions/duplications at the ATM locus. The high incidence of new and individual mutations demonstrates a marked mutational heterogeneity of AT in the Czech Republic. Our data indicate that sequence analysis of the entire coding region of ATM is sufficient for a high detection rate of mutations in ATM and that MLPA analysis for the detection of deletions/duplications seems to be redundant in the Slavic population.


Assuntos
Ataxia Telangiectasia/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Proteínas Mutadas de Ataxia Telangiectasia , Criança , Pré-Escolar , República Tcheca , Análise Mutacional de DNA , Feminino , Humanos , Masculino
11.
Cas Lek Cesk ; 150(2): 97-9, 2011.
Artigo em Tcheco | MEDLINE | ID: mdl-21560448

RESUMO

BACKGROUND: Nijmegen breakage syndrome (NBS) is one of the chromosomal instability syndromes due to DNA repair disorder. The syndrome is autosomal recessive determined, in homozygotes is characterized by many disorders including high predisposition to lymphoreticular malignancy in childhood and adolescence. METHODS: Laboratory findings represent low level of immunoglobulins, B and T lymphocytes, increased sensitivity to the mutagens, especially hyperradiosensitivity and increased chromosomal instability. Heterozygotes show also elevated radiosensitivity and have an increased cancer risk in adult age. There is no predilection of the malignancy. Colorectal cancer was found often among the relatives of patients with NBS. Majority of the NBS patients are of the Central and Eastern European origin and carry the common founder mutation 657del5 in the NBN gene. The formation of second malignancy both in homozygotes and heterozygotes can be prevented by excluding any radiation. The aim of study is estimation of frequency of 657del5 heterozygotes among patients with colorectal cancer. RESULTS AND CONCLUSIONS: Within a group of 161 patients with colorectal cancer 5 heterozygotes with 657del5 mutation were registered, e.g. 5-times higher incidence than expected. The elemental prevention in patients with proved positivity of Slavic mutation in NBN gene is to exclude any radiation.


Assuntos
Proteínas de Ciclo Celular/genética , Neoplasias Colorretais/genética , Heterozigoto , Mutação , Proteínas Nucleares/genética , Adulto , Idoso , Neoplasias Colorretais/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Quebra de Nijmegen/complicações , Síndrome de Quebra de Nijmegen/genética , Eslováquia
13.
Nat Genet ; 42(1): 27-9, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19966803

RESUMO

Noonan syndrome, a developmental disorder characterized by congenital heart defects, reduced growth, facial dysmorphism and variable cognitive deficits, is caused by constitutional dysregulation of the RAS-MAPK signaling pathway. Here we report that germline NRAS mutations conferring enhanced stimulus-dependent MAPK activation account for some cases of this disorder. These findings provide evidence for an obligate dependency on proper NRAS function in human development and growth.


Assuntos
Genes ras , Mutação , Síndrome de Noonan/genética , Proteínas ras/genética , Adolescente , Sequência de Aminoácidos , Animais , Sequência de Bases , Células COS , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Síndrome de Noonan/metabolismo , Síndrome de Noonan/patologia , Fosforilação , Estrutura Terciária de Proteína , Homologia de Sequência de Aminoácidos , Transfecção , Adulto Jovem , Proteínas ras/química
14.
Gene ; 447(1): 12-7, 2009 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-19635536

RESUMO

Patients affected by the autosomal recessive Nijmegen Breakage Syndrome (NBS [MIM 251260]) have possibly the highest risk for developing a malignancy of all the chromosomal instability syndromes. This reflects the profound disturbance to genomic integrity and cellular homeostasis that is caused by the mutation of the essential mammalian gene, NBN. Whilst null-mutation of Nbn is lethal in the mouse, NBS patients survive due to the fact that the common human founder mutation, found in over 90% of patients, is in fact hypomorphic and leads, by alternative translation, to varying amounts of a partially functional carboxy-terminal protein fragment, p70-nibrin. The expression level of p70-nibrin correlates with cancer incidence amongst patients. Using real-time PCR we have now found that the variation in p70-nibrin expression cannot be attributed to differences in mRNA quantity and that nonsense-mediated mRNA decay is not responsible for the observed variation. We discuss an alternative explanation for p70-nibrin expression variation.


Assuntos
Alelos , Proteínas de Ciclo Celular/genética , Síndrome de Quebra de Nijmegen/genética , Proteínas Nucleares/genética , Proteínas de Ciclo Celular/metabolismo , Reparo do DNA , Predisposição Genética para Doença , Heterozigoto , Homozigoto , Humanos , Proteínas Nucleares/metabolismo , RNA Mensageiro/metabolismo , Transcrição Genética , Células Tumorais Cultivadas
15.
Eur J Med Genet ; 52(5): 337-40, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19416762

RESUMO

Noonan syndrome (NS) and related disorders are caused by mutations in various genes encoding molecules involved in the RAS-MAPK signalling cascade. There are strong genotype-phenotype correlations. BRAF is the major gene for cardio-facio-cutaneous syndrome (CFCS), and usually patients with a BRAF mutation have significant cognitive impairment. We report on a patient with LEOPARD syndrome and normal intelligence who was found to carry a novel sequence change in BRAF. The mutation p.L245F was demonstrated to be de novo with no evidence of somatic mosaicism. This observation illustrates that the phenotypic spectrum caused by BRAF mutations is broader than previously assumed and that mental retardation is not necessarily associated. We speculate that the impact of p.L245F on BRAF protein function differs either qualitatively or quantitatively from those mutations associated with CFCS.


Assuntos
Anormalidades Múltiplas/genética , Cardiopatias Congênitas/genética , Síndrome LEOPARD/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Sequência de Aminoácidos , Substituição de Aminoácidos , Sequência Conservada , DNA/genética , DNA/isolamento & purificação , Análise Mutacional de DNA , Facies , Humanos , Leucina/metabolismo , Masculino , Dados de Sequência Molecular , Síndrome de Noonan/genética , Homologia de Sequência de Aminoácidos
16.
Eur J Hum Genet ; 17(10): 1207-15, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19277062

RESUMO

Focal dermal hypoplasia (FDH) is an X-linked developmental disorder with male lethality characterized by patchy dermal hypoplasia, skeletal and dental malformations, and microphthalmia or anophthalmia. Recently, heterozygous loss-of-function mutations in the PORCN gene have been described to cause FDH. FDH shows some clinical overlap with the microphthalmia with linear skin defects (MLS) syndrome, another X-linked male lethal condition, associated with mutations of HCCS in the majority of cases. We performed DNA sequencing of PORCN in 13 female patients with the clinical diagnosis of FDH as well as four female patients with MLS syndrome and no mutation in HCCS. We identified PORCN mutations in all female patients with FDH. Eleven patients seem to have constitutional PORCN alterations in the heterozygous state and two individuals are mosaic for the heterozygous sequence change in PORCN. No PORCN mutation was identified in the MLS-affected patients, providing further evidence that FDH and MLS do not overlap genetically. X chromosome inactivation (XCI) analysis revealed a random or slightly skewed XCI pattern in leukocytes of individuals with intragenic PORCN mutation suggesting that defective PORCN does not lead to selective growth disadvantage, at least in leukocytes. We conclude that the PORCN mutation detection rate is high in individuals with a clear-cut FDH phenotype and somatic mosaicism can be present in a significant proportion of patients with mild or classic FDH.


Assuntos
Hipoplasia Dérmica Focal/genética , Microftalmia/genética , Aciltransferases , Processamento Alternativo , Pré-Escolar , Cromossomos Humanos X , Análise Mutacional de DNA , Feminino , Hipoplasia Dérmica Focal/complicações , Genes Ligados ao Cromossomo X , Humanos , Masculino , Proteínas de Membrana/genética , Microftalmia/complicações , Modelos Genéticos , Mutação , Fenótipo , Polimorfismo de Nucleotídeo Único
17.
Pediatr Nephrol ; 24(7): 1409-12, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19011905

RESUMO

A family with three children affected with congenital polycystic kidneys, hepatic fibrosis, mental retardation, minor anomalies of the hands, and dysmorphic facial features is reported. All children progressed to chronic renal failure. Linkage to the locus for autosomal recessive polycystic kidney disease was excluded by haplotype analysis. The family is endogamic, and the affected siblings are of both sexes, which is in agreement with an autosomal recessive determination of this syndrome. A similar syndrome was reported in 1990 by Labrune et al. [J Pediatr Gastroenterol Nutr (1990) 10:540-543]. Our report provides further evidence for the etiological heterogeneity of polycystic kidney with hepatic fibrosis. The syndrome reported here should be considered in the differential diagnosis of the early manifestation of polycystic kidneys. Mental retardation and hand anomalies are the hallmarks for the differential diagnosis of this syndrome.


Assuntos
Anormalidades Múltiplas/fisiopatologia , Deformidades Congênitas da Mão/fisiopatologia , Deficiência Intelectual/fisiopatologia , Hepatopatias/fisiopatologia , Doenças Renais Policísticas/fisiopatologia , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Irmãos , Gêmeos
19.
Eur J Cell Biol ; 87(2): 111-21, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17977616

RESUMO

The human genetic disorder, Nijmegen breakage syndrome (NBS), is characterised by radiosensitivity, immunodeficiency and an increased risk for cancer, particularly lymphoma. The NBS1 gene codes for a protein, nibrin, involved in the processing/repair of DNA double strand breaks and in cell cycle checkpoints. The majority of patients (>90%) are homozygous for a founder mutation. Despite this genetic homogeneity, the syndrome shows considerable clinical variability, for example, in age at development of a malignancy. We hypothesised that one reason for such variation might be individual differences in the clearance of heavily damaged precancerous cells by apoptosis. To test this hypothesis we have examined a set of 30 lymphoblastoid B-cell lines from NBS patients for their capacity to enter into apoptosis after a DNA-damaging treatment. There was a substantial 40-fold variation in apoptosis between cell lines from different patients. NBS patient cell lines could be grouped into a large, apoptosis-deficient group and a smaller group with essentially normal apoptotic response to DNA damage. In both groups, cell lines were proficient in TP53 phosphorylation and stabilisation after the same DNA-damaging treatment. Thus the observed variation in apoptosis capacity is not due to failure to activate TP53. Despite the large variation in apoptosis, no statistically significant correlation between apoptotic capacity of patient cell lines and clinical course of the disease was apparent.


Assuntos
Apoptose , Linfócitos B/fisiologia , Síndrome de Quebra de Nijmegen/fisiopatologia , Adolescente , Adulto , Linfócitos B/citologia , Bleomicina/farmacologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Criança , Dano ao DNA , Feminino , Humanos , Masculino , Síndrome de Quebra de Nijmegen/metabolismo , Síndrome de Quebra de Nijmegen/patologia , Proteínas Nucleares/metabolismo , Fosforilação , Proteína Supressora de Tumor p53/metabolismo
20.
J Natl Cancer Inst ; 99(24): 1875-80, 2007 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-18073374

RESUMO

BACKGROUND: The autosomal recessive chromosomal instability disorder Nijmegen breakage syndrome (NBS) is associated with increased risk of lymphoid malignancies and other cancers. Cells from NBS patients contain many double-stranded DNA breaks. More than 90% of NBS patients are homozygous for a founder mutation, 657del5, in the NBN gene. We investigated the 657del5 carrier status of cancer patients among blood relatives (i.e., first-, through fourth-degree relatives) of NBS patients in the Czech Republic and Slovakia to test the hypothesis that NBN heterozygotes have an increased cancer risk. METHODS: Medical information was compiled from 344 blood relatives of NBS patients in 24 different NBS families from January 1, 1998, through December 31, 2003. The 657del5 carrier status of subjects was unknown at the time of their recruitment but was later determined from blood samples collected at the time of the interview. Medical records and death certificates were used to confirm a diagnosis of cancer. For the relatives with cancer who are not obligate heterozygotes (such as parents and two grandparents in consanguineous families), the observed and expected number of mutation carriers were compared by use of the index-test method, which estimated the risk of cancer associated with carrying the mutation. All P values were two-sided. RESULTS: Thirteen of the 344 blood relatives had confirmed cases of any type of cancer; 11 of these 13 cancer patients carried the NBN 657del5 mutation, compared with 6.0 expected (P = .005). Among the 56 grandparents with complete data from 14 NBS families, 10 of the 28 carriers of 657del5, but only one of the 28 noncarriers, developed cancer (odds ratio = 10.7, 95% CI = 1.4 to 81.5; P<.004). CONCLUSIONS: The NBN 657del5 mutation appears to be associated with an elevated risk of cancer in heterozygotes.


Assuntos
Proteínas de Ciclo Celular/genética , Efeito Fundador , Mutação em Linhagem Germinativa , Neoplasias/epidemiologia , Neoplasias/genética , Síndrome de Quebra de Nijmegen/genética , Proteínas Nucleares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Quebra Cromossômica , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , República Tcheca/epidemiologia , Análise Mutacional de DNA , Feminino , Deleção de Genes , Triagem de Portadores Genéticos , Predisposição Genética para Doença , Neoplasias dos Genitais Femininos/epidemiologia , Neoplasias dos Genitais Femininos/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Quebra de Nijmegen/epidemiologia , Razão de Chances , Projetos de Pesquisa , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Eslováquia/epidemiologia , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/genética
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