RESUMO
Noonan syndrome (NS) is one of the most common genetic conditions inherited mostly in an autosomal dominant manner with vast heterogeneity in clinical and genetic features. Patients with NS might have speech disturbances, memory and attention deficits, limitations in daily functioning, and decreased overall intelligence. Here, 34 patients with Noonan syndrome and 23 healthy controls were enrolled in a study involving gray and white matter volume evaluation using voxel-based morphometry (VBM), white matter connectivity measurements using diffusion tensor imaging (DTI), and resting-state functional magnetic resonance imaging (rs-fMRI). Fractional anisotropy (FA) and mean diffusivity (MD) probability distributions were calculated. Cognitive abilities were assessed using the Stanford Binet Intelligence Scales. Reductions in white matter connectivity were detected using DTI in NS patients. The rs-fMRI revealed hyper-connectivity in NS patients between the sensorimotor network and language network and between the sensorimotor network and salience network in comparison to healthy controls. NS patients exhibited decreased verbal and nonverbal IQ compared to healthy controls. The assessment of the microstructural alterations of white matter as well as the resting-state functional connectivity (rsFC) analysis in patients with NS may shed light on the mechanisms responsible for cognitive and neurofunctional impairments.
Assuntos
Imagem de Tensor de Difusão , Síndrome de Noonan , Humanos , Imagem de Tensor de Difusão/métodos , Proteínas Proto-Oncogênicas p21(ras) , Imageamento por Ressonância Magnética , Síndrome de Noonan/genética , Cognição , Proteínas Quinases Ativadas por Mitógeno , Transdução de SinaisRESUMO
Ectodermal dysplasias are a wide group of genetic disorders characterised by clinical symptoms in ectodermal derivatives (most frequently teeth, hair, nails and sweat glands). There is a number of genes, which, if mutated, can cause the specified phenotype. The molecular basis of many ectodermal dysplasias have been investigated. The phenotype often results from the imparied communication in molecular pathways important in embryonic morphogenesis or disturbed function of protein complexes involved in homeostasis, adhesion and stability of the cells in the tissue. Different classification systems have been proposed to group ectodermal dysplasias according to clinical symptoms or molecular basis. Molecular technologies have let recently to expand diagnostic abilities for ectodermal dysplasias patients. Certainly in the nearest years new genes and mutations will be discovered as a cause of ectodermal dysplasias.
Assuntos
Displasia Ectodérmica , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Humanos , Mutação , FenótipoRESUMO
BACKGROUND: Large and giant congenital melanocytic nevi (CMN), benign naevomelanocytic proliferations derived from neural crests, with a projected adult size (PAS) ≥ 20 cm, are connected to a high risk of melanoma and neurocutaneous melanosis. Among several factors, genetic alterations seem to be involved in tumorigenesis. The aim of the present study was to analyse the mutation status of NRAS and BRAF genes in resection specimens from large or giant CMN in a group of Polish patients. MATERIAL AND METHODS: The formalin-fixed, paraffin-embedded resection specimens from 18 patients, fixed in the years of 2006 to 2017, were included in the study. The regions containing the highest load of melanocytes were macrodissected prior to DNA isolation. The NRAS and BRAF mutation status was evaluated using qPCR. RESULTS: We detected activating mutations in NRAS gene (codons: 12 and 61) in 7 out of the 18 (38.9%) patients. No BRAF mutations were found. CONCLUSION: Our study, the first molecular analysis of large/giant CMN in Polish patients, supports the hypothesis that NRAS mutation in codon 61 are frequent, recurrent mutations in large/giant CMN. Moreover, we show, for the first time, that NRAS mutations in codon 12 (p.Gly12Asp) can be also detected in giant CMN. The exact role of these genetic alterations in CMN formation remains to be elucidated.
Assuntos
Nevo Pigmentado , Neoplasias Cutâneas , Adulto , Criança , Humanos , Recidiva Local de Neoplasia , Nevo Pigmentado/genética , Polônia , Estudos Retrospectivos , Neoplasias Cutâneas/genéticaRESUMO
KBG syndrome is a neurodevelopmental autosomal dominant disorder characterized by short stature, macrodontia, developmental delay, behavioral problems, speech delay and delayed closing of fontanels. Most patients with KBG syndrome are found to have a mutation in the ANKRD11 gene or a chromosomal rearrangement involving this gene. We hereby present clinical evaluations of 23 patients aged 4 months to 26 years manifesting clinical features of KBG syndrome. Mutation analysis in the patients was performed using panel or exome sequencing and array CGH. Besides possessing dysmorphic features typical of the KBG syndrome, nearly all patients had psychomotor hyperactivity (86%), 81% had delayed speech, 61% had poor weight gain, 56% had delayed closure of fontanel and 56% had a hoarse voice. Macrodontia and a height range of -1 SDs to -2 SDs were noted in about half of the patients; only two patients presented with short stature below -3 SDs. The fact that wide, delayed closing fontanels were observed in more than half of our patients with KBG syndrome confirms the role of the ANKRD11 gene in skull formation and suture fusion. This clinical feature could be key to the diagnosis of KBG syndrome, especially in young children. Hoarse voice is a previously undescribed phenotype of KBG syndrome and could further reinforce clinical diagnosis.
Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Deficiência Intelectual/genética , Proteínas Repressoras/genética , Anormalidades Dentárias/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Doenças do Desenvolvimento Ósseo/fisiopatologia , Criança , Pré-Escolar , Aberrações Cromossômicas , Cromossomos Humanos Par 16/genética , Hibridização Genômica Comparativa , Nanismo/genética , Nanismo/fisiopatologia , Fácies , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Masculino , Mutação/genética , Fenótipo , Anormalidades Dentárias/diagnóstico , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/fisiopatologia , Sequenciamento do Exoma , Adulto JovemRESUMO
Malformations of cortical development (MCDs) manifest with structural brain anomalies that lead to neurologic sequelae, including epilepsy, cerebral palsy, developmental delay, and intellectual disability. To investigate the underlying genetic architecture of patients with disorders of cerebral cortical development, a cohort of 54 patients demonstrating neuroradiologic signs of MCDs was investigated. Individual genomes were interrogated for single-nucleotide variants (SNV) and copy number variants (CNV) with whole-exome sequencing and chromosomal microarray studies. Variation affecting known MCDs-associated genes was found in 16/54 cases, including 11 patients with SNV, 2 patients with CNV, and 3 patients with both CNV and SNV, at distinct loci. Diagnostic pathogenic SNV and potentially damaging variants of unknown significance (VUS) were identified in two groups of seven individuals each. We demonstrated that de novo variants are important among patients with MCDs as they were identified in 10/16 individuals with a molecular diagnosis. Three patients showed changes in known MCDs genes and a clinical phenotype beyond the usual characteristics observed, i.e., phenotypic expansion, for a particular known disease gene clinical entity. We also discovered 2 likely candidate genes, CDH4, and ASTN1, with human and animal studies supporting their roles in brain development, and 5 potential candidate genes. Our findings emphasize genetic heterogeneity of MCDs disorders and postulate potential novel candidate genes involved in cerebral cortical development.
Assuntos
Variações do Número de Cópias de DNA , Exoma , Malformações do Desenvolvimento Cortical/genética , Polimorfismo de Nucleotídeo Único , Caderinas/genética , Feminino , Heterogeneidade Genética , Humanos , Masculino , Malformações do Desenvolvimento Cortical/patologia , Proteínas do Tecido Nervoso/genética , Receptores de Superfície Celular/genéticaRESUMO
Cardio-facio-cutaneous syndrome (CFCS), a rare congenital disorder of RASopathies, displays high phenotypic variability. Complications during pregnancy and in the perinatal period are commonly reported. Polyhydramnios is observed in over half of pregnancies and might occur with fetal macrocephaly, macrosomia, and/or heart defects. Premature birth is not uncommon and any complications like respiratory insufficiency, edema, and feeding difficulties are present and might delay accurate clinical diagnosis. Besides neonatal complications, CFCS newborns and later infants have distinctive dysmorphic features usually accompanied by neurological (hypotonia with motor delay, neurocognitive delay) findings. Also, heart defects usually present at birth. Herein, we present the case of a female baby born prematurely from a pregnancy complicated with polyhydramnios, presenting at birth with craniofacial features typical for RASopathies, heart defects, neurological abnormalities, and hyperkeratosis unusual for a neonatal period. Due to the presence of a heart defect and other complications related to premature birth, the course of the disease was severe with a fatal outcome at the age of 9 months. The RASopathy, particularly CFCS, clinical diagnosis was confirmed and de novo p.Phe57Ile mutation in MAP2K2 was identified.
Assuntos
Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , MAP Quinase Quinase 2/genética , Fácies , Evolução Fatal , Feminino , Humanos , Recém-Nascido , Mutação , FenótipoRESUMO
OBJECTIVES: Genetic studies in adults/adolescent patients with chronic pancreatitis (CP) identified chymotrypsinogen C (CTRC) genetic variants but their association with CP risk has been difficult to replicate. To evaluate the risk of CP associated with CTRC variants in CP pediatric patients-control study. METHODS: The distribution of CTRC variants in CP pediatric cohort (nâ=â136, median age at CP onset 8 years) with no history of alcohol/smoking abuse was compared with controls (nâ=â401, median age 45). RESULTS: We showed that p.Arg254Trp (4.6%) and p.Lys247_Arg254del (5.3%) heterozygous mutations are frequent and significantly associated with CP risk in pediatric patients (odds ratio [OR]â=â19.1; 95% CI 2.8-160; Pâ=â0.001 and ORâ=â5.5; 95% CI 1.6-19.4; Pâ=â0.001, respectively). For the first time, we demonstrated that the c.180TT genotype of common p.Gly60Gly variant is strong, an independent CP risk factor (ORâ=â23; 95% CI 7.7-70; Pâ<â0.001) with effect size comparable to p.Arg254Trp mutation. The other novel observation is that common c.493+51C>A variant, both CA and AA genotype, is significantly underrepresented in CP compared with controls (15% vs 35%; ORâ=â0.33; 95% CI 0.19-0.59; Pâ<â0.001 and 2.8% vs 11%; ORâ=â0.24; 95% CI 0.06-0.85; Pâ=â0.027, respectively). CONCLUSIONS: Our study provides evidence that CTRC variants, including c.180TT (p.Gly60Gly) are strong CP risk factors. The c.493+51C>A variant may play a protective role against CP development.
Assuntos
Quimotripsinogênio/genética , Predisposição Genética para Doença , Pancreatite Crônica/genética , Serina Endopeptidases/genética , Adulto , Criança , Feminino , Variação Genética , Genótipo , Humanos , Masculino , Pancreatite Crônica/diagnóstico , Fatores de Risco , Inibidor da Tripsina Pancreática de Kazal/genéticaRESUMO
OBJECTIVES: The etiological factors of chronic pancreatitis (CP) in children differ from those in adults. To date, no study has assessed the clinical course of CP in young children. The aim of our study was to evaluate the etiology and the clinical presentation of the disease in children with disease onset before 5 years of age in comparison to later-onset of CP. METHODS: A total of 276 children with CP, hospitalized from 1988 to 2015, were enrolled in the study. Data on presentation, diagnostic findings, and treatment were reviewed. Two hundred sixty patients were screened for the most frequent mutations in major pancreatitis-associated genes, such as cationic trypsinogen/serine protease gene (PRSS1), serine protease inhibitor, Kazal type 1 gene (SPINK1), and cystic fibrosis transmembrane conductance regulator gene (CFTR). RESULTS: The disease onset before the age of 5 years occurred in 51 patients (group 1), the later onset in 225 patients (group 2). We found no significant discrepancies in distribution of the etiological factors between groups. The youngest patients (group 1) had more pancreatitis episodes (median 5.0 vs 3.00; Pâ<â0.05) and underwent surgeries more frequently (25.5% vs 8.9%; Pâ<â0.05). It could be associated with significantly longer follow-up in early onset group (median 6 vs 4 years; Pâ<â0.05). There were no differences in nutritional status or exocrine and endocrine pancreatic function. CONCLUSIONS: Early- and later-onset pancreatitis have similar etiological factors with predominance of gene mutations. The most frequent mutation found was p.Asn34Ser (N34S) in SPINK1 gene. The clinical presentation differed in number of pancreatitis episodes and frequency of surgeries.
Assuntos
Idade de Início , Pancreatite Crônica/fisiopatologia , Adolescente , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Estudos Longitudinais , Masculino , Mutação , Pancreatite Crônica/etiologia , Pancreatite Crônica/genética , Fatores de RiscoRESUMO
BACKGROUND: Available data from adult patients do not reflect natural course of hereditary pancreatitis (HP) in children. To date, no study has assessed the clinical course of HP in children. OBJECTIVE: To investigate the clinical course of HP in children and compare it to non-HP group with chronic pancreatitis (CP). METHODS: A group of 265 children with CP, hospitalized from 1988 to 2014, were enrolled in the study. Medical records of those patients were reviewed for data on presentation, diagnostic findings and treatment. All children were screened for mutations in major pancreatitis-associated genes, i.e. PRSS1, SPINK1, and CFTR. RESULTS: HP was diagnosed in 41 children (15.5%). Family history was positive in 88% of children with HP. Mutations of PRSS1 gene were found in 80% (33/41) of HP patients. We detected p.R122H, p.R122C, p.N29I, and p.E79K mutation in 34% (14/41), 27% (11/41), 12% (5/41), and 7% (3/41) of HP patients, respectively. Patients with paternal inheritance had first symptoms earlier than those with maternal inheritance (5.9 vs. 9.1 years; P < 0.05). Children with HP showed more severe changes in ERCP then those from non-HP group (2.05 Cambridge grade, vs. 1.6°; P < 0.05). ESWL was performed more frequently in HP group (12.2% vs. 3.1%; P < 0.05). There was no difference in age of disease onset (7.98 vs. 8.9 years; NS), pancreatic duct stenting (46.3% vs. 33%; NS), or number of surgical interventions (12.2% vs. 14.3%; NS) between both groups. CONCLUSIONS: Children with HP reveal significantly more severe clinical presentation of the disease than non-HP patients, despite the same age of onset.
Assuntos
Pancreatite/genética , Pancreatite/patologia , Adolescente , Idade de Início , Índice de Massa Corporal , Proteínas de Transporte/genética , Criança , Pré-Escolar , Estudos de Coortes , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Progressão da Doença , Éxons , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Mutação/genética , Ductos Pancreáticos/patologia , Pancreatite Crônica/genética , Pancreatite Crônica/patologia , Polimorfismo de Fragmento de Restrição , Estudos Retrospectivos , Tripsina/genética , Inibidor da Tripsina Pancreática de Kazal , Adulto JovemRESUMO
Connexins belong to the family of gap junction proteins which enable direct cell-to-cell communication by forming channels in adjacent cells. Mutations in connexin genes cause a variety of human diseases and, in a few cases, result in skin disorders. There are significant differences in the clinical picture of two rare autosomal dominant syndromes: keratitis-ichthyosis-deafness (KID) syndrome and hidrotic ectodermal dysplasia (Clouston syndrome), which are caused by GJB2 and GJB6 mutations, respectively. This is despite the fact that, in both cases, malfunctioning of the same family proteins and some overlapping clinical features (nail dystrophy, hair loss, and palmoplantar keratoderma) is observed. KID syndrome is characterized by progressive vascularizing keratitis, ichthyosiform erythrokeratoderma, and neurosensory hearing loss, whereas Clouston syndrome is characterized by nail dystrophy, hypotrichosis, and palmoplantar keratoderma. The present paper presents a Polish patient with sporadic KID syndrome caused by the mutation of p.Asp50Asn in GJB2. The patient encountered difficulties in obtaining a correct diagnosis. The other case presented is that of a family with Clouston syndrome (caused by p.Gly11Arg mutation in GJB6), who are the first reported patients of Polish origin suffering from this disorder. Phenotype diversity among patients with the same genotypes reported to date is also summarized. The conclusion is that proper diagnosis of these syndromes is still challenging and should always be followed by molecular verification.
Assuntos
Conexinas/genética , Displasia Ectodérmica/genética , Junções Comunicantes/genética , Adulto , Pré-Escolar , Conexina 26 , Conexina 30 , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Ceratite/genética , Masculino , Linhagem , Fenótipo , PolôniaRESUMO
Chronic pancreatitis (CP) is characterized by progressive damage to the exocrine and endocrine cell structures and pancreatic ducts with subsequent fibrosis of the organ. Patients with no apparent etiological factor are classified as having idiopathic CP (ICP). Genetic studies indicate the importance of mutations in the serine protease inhibitor, Kazal type 1 gene (SPINK1) in the pathogenesis of CP This report describes a case of a 29-year-old Polish-Vietnamese patient with the p.Asn34Ser (p.N34S) homozygous mutation in the SPINK1 gene. The patient was hospitalized due to pain of average intensity in the epigastric area which occurred for the first time in his life. Imaging examination showed the atrophy of the pancreatic parenchyma with the presence of numerous small calcifications and a single calcified lodgement with a diameter of 22 mm in the distal segment of Wirsung 's duct. Clinical interview did not reveal any obvious etiological pancreatitis risk factors implying the causative role of the p.Asn34Ser homozygous mutation of SPINK1 in this case as proven in our investigation.
Assuntos
Proteínas de Transporte/genética , Pancreatite Crônica/diagnóstico , Pancreatite Crônica/genética , Polimorfismo Genético , Inibidor da Tripsina Pancreática de Kazal/genética , Adulto , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , MutaçãoRESUMO
OBJECTIVE: To examine the role of the IRF6 mutations in Polish families with Van der Woude syndrome and popliteal pterygium syndrome and to determine the effect of IRF6 single nucleotide polymorphisms (rs7552506, rs2013162, and rs2235375) on cleft lip and/or palate susceptibility. DESIGN: IRF6 mutation screening was performed by direct sequencing of all coding exons of the gene and their flanking intronic regions. Cosegregation analysis was performed to establish the relation of single nucleotide polymorphisms and cleft lip and/or palate phenotypes. PATIENTS: We screened the IRF6 gene in eight families with clinical recognition of Van der Woude syndrome and popliteal pterygium syndrome. RESULTS: In five families we identified pathogenic mutations, all affecting the DNA-binding or the protein-binding domain of IRF6. Two of the mutations were novel-a missense mutation Arg31Thr and a small deletion Trp40Glyfs*23. In most cases we found also a haplotype of three single nucleotide polymorphisms-rs7552506, rs2013162, and rs2235375. The association of the single nucleotide polymorphisms and cleft lip and/or palate susceptibility has been previously published. The variants did not cosegregate with phenotype in examined families nor did they cosegregate with pathogenic mutations. The single nucleotide polymorphisms were deemed not causative, due to their presence in unaffected family members. CONCLUSIONS: Two novel mutations (Arg31Thr and Trp40Glyfs*23) in the IRF6 gene were identified to be causative for Van der Woude and popliteal pterygium syndromes. In the present study no association between the single nucleotide polymorphisms rs7552506, rs2013162, and rs2235375 and the cleft lip and/or palate phenotype was found. The hypothesis, whether the haplotype of the three single nucleotide polymorphisms was correlated with IRF6 expression level, demands further investigation.
Assuntos
Anormalidades Múltiplas/genética , Fenda Labial/genética , Fissura Palatina/genética , Cistos/genética , Anormalidades do Olho/genética , Dedos/anormalidades , Fatores Reguladores de Interferon/genética , Articulação do Joelho/anormalidades , Lábio/anormalidades , Deformidades Congênitas das Extremidades Inferiores/genética , Polimorfismo de Nucleotídeo Único , Sindactilia/genética , Anormalidades Urogenitais/genética , Feminino , Haplótipos , Humanos , Masculino , Mutação de Sentido Incorreto , Linhagem , Fenótipo , PolôniaRESUMO
Cystic fibrosis is one of the most common recessively inherited monogenic disorders in the Caucasian population. The disease develops when pathogenic mutations of the CFTR gene, encoding a transmembrane conductance regulator, are present in both alleles. Cystic fibrosis is a multi-organ disease with heterozygous clinical course. High mortality of the disease is mainly due to progressive and irreversible changes in the lungs, leading to respiratory failure. Therefore, chronic obstructive pulmonary disease is the primary target in the search for effective therapeutic solutions. In recent years there has been a significant progress in the research on early diagnosis and treatment of cystic fibrosis. The newest strategies focus not only on the main symptoms of pulmonary disease (inflammation caused by bacterial infection and obstruction due to thickened mucus), but also on the correction of the cystic fibrosis cause - defective CFTR gene and its protein product. Therapeutics like VX-770 and PTC124, intended for patients with a specific genotype, have already emerged on the U.S. and European medical market. They modulate the defective CFTR protein function or act on the level of abnormal CFTR mRNA, respectively. At the same time scientists develop new solutions in the field of somatic gene therapy in order to increase the efficiency of corrected CFTR delivery to the respiratory tract cells and to maintain its expression in the target cells. In this review we discuss the progress achieved in the development of therapy that is at the stage of both preclinical and clinical phases.
RESUMO
Newborn screening for cystic fibrosis (NBS CF) in Poland was started in September 2006. Summary from 4 years' experience is presented in this study. The immunoreactive trypsin/DNA sequencing strategy was implemented. The group of 1,212,487 newborns were screened for cystic fibrosis during the programme. We identified a total of 221 CF cases during this period, including, 4 CF cases were reported to be omitted by NBS CF. Disease incidence in Poland based on the programme results was estimated as 1/4394 and carrier frequency as 1/33. The frequency of the F508del was similar (62%) to population data previously reported. This strategy allowed us to identify 29 affected infants with rare genotypes. The frequency of some mutations (eg, 2184insA, K710X) was assessed in Poland for the first time. Thus, sequencing assay seems to be accurate method for screening programme using blood spots in the Polish population.
Assuntos
Fibrose Cística/diagnóstico , Triagem Neonatal , Análise de Sequência de DNA , Fibrose Cística/epidemiologia , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Frequência do Gene , Genótipo , Heterozigoto , Humanos , Incidência , Recém-Nascido , Mutação , Polônia/epidemiologiaRESUMO
THE AIM OF THE STUDY: Verification of the hypothesis concerning the association between polymorphic variants of the following genes: COLIA1, VDR and CALCR considered to be risk factors of bone metabolism disturbances and decreased bone mineral density (BMD) in children with cystic fibrosis (CF). MATERIAL AND METHODS: Clinical evaluation of CF phenotype progression in 101 patients was assessed according to the Shwachman-Kulczycki score. In the project the best value of forced expiratory volume of one second (FEV1) from the six months before densitometric measurements was used. Evaluation of bone tissue condition parameters was always correlated with the analysis of calcium-phosphate metabolism and bone turnover parameters. Densitometric measurements of L1-L4 lumbar spine were made using Lunar DPX IQ 2898. Age and sex of examined persons were standardized in respect to clinical and biochemical parameters. Molecular analysis was performed in CF patients with the following genotypes: F508del/F508del--55 persons, F508del/m--37 persons, m/m--9 persons. In this project 102 persons formed the control group. Presence of polymorphisms in studied genes was compared with bone tissue parameters. RESULTS: Low bone mineral density (Z-score < -1 SD) was observed in 53.5% patients and in 26.7% of them BMD was below -2 SD. Patients with low BMD had worse BMI, FEV1 and more severe symptoms of CF. Allele T (Ball) in COLIA I and allele C (L447P) in CALCR were found to be more frequent in CF patients than in the control group. Allele C in CALCR gene was associated with reduced bone mass. No significant correlation was found between COLIA1 and VDR polymorphisms and BMD. CONCLUSIONS: Process of bone loss in CF patients starts in early childhood and recurrent respiratory infection, malnutrition and corticosteroid therapy are the main factors disturbing metabolic balance of bone tissue. There is a correlation between bone mass loss in CF patients and the appearance of defined gene alleles of bone metabolism. However, we have to emphasize that this type of study needs confirmation on larger groups of patients.
Assuntos
Densidade Óssea/genética , Proteína Semelhante a Receptor de Calcitonina/genética , Colágeno Tipo I/genética , Fibrose Cística/complicações , Osteoporose/genética , Polimorfismo Genético , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Frequência do Gene , Marcadores Genéticos , Humanos , Masculino , Fenótipo , Receptores de Calcitriol/genética , Adulto JovemRESUMO
Epigenetics, one of the widely investigated topics in human genetics, refers to phenotypic or gene expression changes caused by specific regulatory mechanisms (eg. DNA methylation, histone proteins modifications, antisense RNA or RNAi expression) that do not involve changes in DNA sequence. The disturbances in epigenetic gene expression regulatory mechanisms might lead to oncogenic transformation as well as monogenic or complex diseases. On the other side, better knowledge about epigenetic causes of certain diseases, gives an opportunity to potential therapies. One of the epigenetic research models in Angelman syndrome (AS). This neurologic disorder associated with improper central nervous system development and function, together with Prader-Willi syndrome are caused by the defects of epigenetic regulation. These disturbances are related to the defects of genomic imprinting, a phenomenon that contributes to allele specific, depending from parental origin, gene expression. In the majority of AS cases, the large deletion in chromosome 15 (15q11-13) of maternal origin (65-75%) or paternal disomy of chromosome 15 (3-7%) are observed. However, in a limited number of cases, other imprinting defects or mosaicism can be found and confirmed by new molecular biology techniques. Investigation of the etiology of the diseases caused by the defects in epigenetic regulation gives a basis to the development of epi-therapy that might be a promising alternative for their treatment. Moreover, knowledge about the epigenome gives an opportunity for prevention of human genetic disorders.
Assuntos
Síndrome de Angelman/genética , Regulação da Expressão Gênica/genética , Epigênese Genética , Impressão Genômica/genética , Humanos , Mosaicismo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
As predictions show infectious diseases were, are and will be, responsible for a significant percentage (more than 12% in the year 2030) of deaths worldwide. Infectious diseases are, according to J.B.S. Haldane's theory, the major agent determining natural selection, as they lead to elimination of more susceptible people and only leave to survive these, who are more resistant. It has been revealed that susceptibility to pathogens varies among ethnic groups. Explanation of this phenomenon can be found in the human genome. Standard genetic analysis led to identification of several gene variants which modulate susceptibility to particular infectious disease as well as its progression. HLA genes encoding major histocompatibility complex are one of the most interesting ones as they are reported to influence the susceptibility to a wide range of pathogens. It is also proved that in several cases many other genes take part in modulation of clinical outcome of the diseases. Alleles conferring partial or total protection against disease development have already been identified. This review presents results of selected research concerning genetically determined susceptibility to malaria, cholera, leprosy and HIV.
Assuntos
Infecções Bacterianas/genética , Toxinas Bacterianas/genética , Enterotoxinas/genética , Predisposição Genética para Doença/genética , Antígenos HLA-DR/genética , Cólera/genética , Regulação Bacteriana da Expressão Gênica , HIV/genética , Humanos , Hanseníase/genética , Malária/genética , Polimorfismo GenéticoRESUMO
Polycystic ovary syndrome (PCOS) is a common disorder which affects about 10% of women in reproductive age. According to the Rotterdam consensus criteria, PCOS is diagnosed in the presence of two out of three following symptoms: (1) oligomenorrhoea, anovulation, (2) hyperandrogenism, (3) polycystic ovaries at ultrasound scan. Etiology of the syndrome, although widely speculated, still remains unknown. Analysis of the prevalence of PCOS among the families reveals that genetic contribution to the outcome of the syndrome is highly probable. However, the pattern of inheritance is not clear. On the basis of common clinical symptoms, disorders in metabolic pathways involved in biosynthesis and action of steroid hormones and insulin, as well as in development of inflammatory state, have been searched. As part of the research, large-scale analysis of "candidate genes", whose protein products are engaged in several metabolic processes, have been performed. According to research, at least in some of them mutations or polymorphisms, mainly SNP-type, affecting transcription of the gene or protein properties, have been found. Nevertheless, none of them seem to play a key role in the pathogenesis of the syndrome, indicating that PCOS may be a result of several genes abnormalities interactions. In this review we present the current state of knowledge concerning particular genes, products of which seem to take part in the modulation of the clinical sings of the disease.
Assuntos
Síndrome do Ovário Policístico/genética , Feminino , Predisposição Genética para Doença , Humanos , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Cystic fibrosis (CF) is the most common recessively inherited lethal disease among the Caucasian population. CF is caused by mutations in the CFTR gene. Although several organs and tracts are affected, severe lung disease is the cause of the most of the morbidity and mortality in CF individuals. Current treatment is aimed at slowing the inevitable progression of lung disease, rather than halting it, or preventing its onset. The isolation of the gene responsible for CF suggested the feasibility of new therapeutic possibilities based on the CFTR gene transfer to CF patients. At present, somatic CF gene therapy clinical trials, using mostly animals but also CF patients, are being conducted. Gene therapy development is restricted by the lack of the appropriate gene vector systems, which could be successfully used to transfer in vivo and protect the therapeutic gene. This is because of the many extracellular, intracellular and immunological barriers, which protect living organisms against invasion of foreign genetic material. Future improvement in gene therapy depends on the more effective ways of the gene transfer methods, creation animal models of the human diseases and development of strategies involved in the new gene construct formulation, which facilitate to control gene transcription activity.