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1.
Orv Hetil ; 163(2): 74-78, 2022 01 09.
Artigo em Húngaro | MEDLINE | ID: mdl-34999573

RESUMO

Összefoglaló. Az arthrogryposis-renalis diszfunkció-cholestasis (ARC) szindróma igen rossz prognózisú autoszomális recesszív kórkép. A három vezeto tünethez társulhat központi idegrendszeri érintettség, siketség, cardiovascularis anomália (pitvari és kamrai sövényhiány), thrombocytafunkció-zavar, rekurrens szepszisek, ichthyosis, valamint súlyfejlodésben való elmaradás. A háromnapos újszülöttet neuromuscularis betegség gyanúja miatt vettük át a szülészeti intézménybol. Fizikális vizsgálat során pes equinovarust és hypotrophiás küllemet tapasztaltunk. Kéthetes korában súlyos tubulopathia, valamint cholestasis igazolódott normális gamma-glutamil-transzferáz-szint mellett. A perifériás vérkenet vizsgálata során abnormális morfológiájú thrombocyták ábrázolódtak. Súlygyarapodást komplex felépített enteralis és parenteralis táplálás segítségével sem sikerült elérni. Három hónapos korára a gyermek súlya 15%-kal a születési súlya alatt volt. A kórkép szövodményeként ismétlodo bakteriális véráramfertozés súlyosbította az állapotát. Az újszülött klinikai képe az ARC-szindrómának felelt meg. A kóroki gének szekvenálása során a VPS33B-génben homozigóta c.498+1G>T variáns igazolódott, mely igazolja a betegség fennállását. Orv Hetil. 2022; 163(2): 74-78. Summary. Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is an autosomal recessive multisystem disorder that typically presents with arthrogryposis, renal tubular leak and neonatal cholestatic jaundice. It can be accompanied by nervous system abnormalities, deafness, structural cardiac defects, abnormal platelet morphology, recurrent sepsis, ichthyosis and failure to thrive. The three-day-old neonate was admitted for a suspected neuromuscular disorder. On examination, clubfoot, jaundice and hypotonia were found. Laboratory evaluation revealed tubulopathy and cholestasis with normal gamma-glutamyl transferase level. Peripheral blood smear evaluation revealed abnormally giant platelets. Despite the combined enteral and parenteral nutrition, the infant experienced severe failure to thrive. The phenotype of the presented neonate is consistent with ARC syndrome. Sequencing of the causal genes revealed a homozygous consensus splice site VPS33B mutation (c.498+1G>T), confirming the clinical diagnosis. Orv Hetil. 2022; 163(2): 74-78.


Assuntos
Artrogripose , Colestase , Insuficiência Renal , Humanos , Síndrome , Proteínas de Transporte Vesicular
2.
Eur J Med Genet ; 63(10): 104027, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32758661

RESUMO

The short arm of chromosome 16 (16p) is enriched for segmental duplications, making it susceptible to recurrent, reciprocal rearrangements implicated in the etiology of several phenotypes, including intellectual disability, speech disorders, developmental coordination disorder, autism spectrum disorders, attention deficit hyperactivity disorders, obesity and congenital skeletal disorders. In our clinical study 73 patients were analyzed by chromosomal microarray, and results were confirmed by fluorescence in situ hybridization or polymerase chain reaction. All patients underwent detailed clinical evaluation, with special emphasis on behavioral symptoms. 16p rearrangements were identified in 10 individuals. We found six pathogenic deletions and duplications of the recurrent regions within 16p11.2: one patient had a deletion of the distal 16p11.2 region associated with obesity, while four individuals had duplications, and one patient a deletion of the proximal 16p11.2 region. The other four patients carried 16p variations as second-site genomic alterations, acting as possible modifying genetic factors. We present the phenotypic and genotypic results of our patients and discuss our findings in relation to the available literature.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 16/genética , Deficiências do Desenvolvimento/genética , Transtorno do Espectro Autista/genética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Pré-Escolar , Aberrações Cromossômicas , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Ontologia Genética , Estudos de Associação Genética , Humanos , Hungria , Hibridização in Situ Fluorescente , Lactente , Deficiência Intelectual/genética , Imageamento por Ressonância Magnética , Masculino , Análise em Microsséries , Obesidade/genética , Fenótipo , Duplicações Segmentares Genômicas , Deleção de Sequência , Tomógrafos Computadorizados
3.
Proc Natl Acad Sci U S A ; 117(26): 15137-15147, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32554502

RESUMO

RNA modifications play a fundamental role in cellular function. Pseudouridylation, the most abundant RNA modification, is catalyzed by the H/ACA small ribonucleoprotein (snoRNP) complex that shares four core proteins, dyskerin (DKC1), NOP10, NHP2, and GAR1. Mutations in DKC1, NOP10, or NHP2 cause dyskeratosis congenita (DC), a disorder characterized by telomere attrition. Here, we report a phenotype comprising nephrotic syndrome, cataracts, sensorineural deafness, enterocolitis, and early lethality in two pedigrees: males with DKC1 p.Glu206Lys and two children with homozygous NOP10 p.Thr16Met. Females with heterozygous DKC1 p.Glu206Lys developed cataracts and sensorineural deafness, but nephrotic syndrome in only one case of skewed X-inactivation. We found telomere attrition in both pedigrees, but no mucocutaneous abnormalities suggestive of DC. Both mutations fall at the dyskerin-NOP10 binding interface in a region distinct from those implicated in DC, impair the dyskerin-NOP10 interaction, and disrupt the catalytic pseudouridylation site. Accordingly, we found reduced pseudouridine levels in the ribosomal RNA (rRNA) of the patients. Zebrafish dkc1 mutants recapitulate the human phenotype and show reduced 18S pseudouridylation, ribosomal dysregulation, and a cell-cycle defect in the absence of telomere attrition. We therefore propose that this human disorder is the consequence of defective snoRNP pseudouridylation and ribosomal dysfunction.


Assuntos
Catarata/genética , Proteínas de Ciclo Celular/genética , Enterocolite/genética , Perda Auditiva Neurossensorial/genética , Síndrome Nefrótica/genética , Proteínas Nucleares/genética , Ribonucleoproteínas Nucleolares Pequenas/genética , Animais , Criança , Feminino , Predisposição Genética para Doença , Humanos , Longevidade , Masculino , Modelos Moleculares , Simulação de Dinâmica Molecular , Mutação , Linhagem , Conformação Proteica , RNA Ribossômico/genética , Peixe-Zebra
4.
Ann Hum Genet ; 84(1): 80-86, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31184778

RESUMO

We report on a sibling pair with the EPG5 c.1007A > G mutation who developed a severe form of Vici syndrome and died in infancy. The c.1007A > G (p.Gln336Arg) mutation, affecting the penultimate nucleotide and the splicing of exon 2 is the most common mutation of EPG5 and is typically associated with a less devastating prognosis: cardiomyopathy and cataract are less frequent consequences and the median survival time is 78 months compared to an overall median survival of 42 months. The less severe course related to c.1007A > G was formerly explained by the preserved canonical splicing in 25% of the transcripts. In contrast, we found the messenger RNA encoded by the c.1007A > G allele to be absent, explaining the severe course of the disease. This family provides another example of phenotypic variability related to a differential splicing.


Assuntos
Agenesia do Corpo Caloso/patologia , Proteínas Relacionadas à Autofagia/genética , Catarata/patologia , Mutação , Splicing de RNA , Proteínas de Transporte Vesicular/genética , Adolescente , Agenesia do Corpo Caloso/genética , Catarata/genética , Progressão da Doença , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Irmãos , Taxa de Sobrevida
5.
Mol Biol Rep ; 46(5): 5595-5601, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31338750

RESUMO

Gonadal dysgenesis (GD) is a rare cause of differences of sex development (DSD) with highly variable clinical and genetic conditions. Although identification of the causative genetic alterations can offer a clearer prognosis and personalized management to patients, more than 50% of the DSD cases still do not have an accurate genetic diagnosis. NR5A1 (previously known as SF-1), is a transcriptional regulator of genes required for normal development and functional maintenance of the gonads and the adrenal glands. Nucleotide sequence variants of the NR5A1 gene have been reported in numerous patients with GD with or without adrenal failure, however, microdeletion or partial deletion in the NR5A1 gene have been described only in a few GD cases. In this case study, we present a subject with female phenotype, mild clitoromegaly, partial GD and normal adrenal function. Cytogenetic analysis revealed a 46,XY SRY + karyotype. Microarray analysis did not identify pathogenic copy number variations, nor did panel sequencing of the most common DSD genes. Subsequently, multiplex ligation-dependent probe amplification (MLPA) was performed to test for small deletion/duplication of the most frequently affected genes associated with GD. Using this method, we have identified a novel heterozygous deletion involving exons 5 and 6 of the NR5A1 gene as the cause of abnormal sexual development of the patient. This report expands our knowledge about the range and pathogenetic role of NR5A1 mutations associated with partial gonadal dysgenesis in 46,XY DSD. Furthermore, our data emphasises the indispensable role of MLPA in the diagnosis of DSD with unclear etiology.


Assuntos
Transtorno 46,XY do Desenvolvimento Sexual/genética , Reação em Cadeia da Polimerase Multiplex/métodos , Fator Esteroidogênico 1/genética , Testículo/anormalidades , Variações do Número de Cópias de DNA/genética , Transtorno 46,XY do Desenvolvimento Sexual/diagnóstico , Transtornos do Desenvolvimento Sexual/genética , Éxons/genética , Feminino , Heterozigoto , Humanos , Mutação/genética , Deleção de Sequência/genética , Desenvolvimento Sexual/genética
6.
Pediatr Nephrol ; 33(10): 1713-1721, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29956005

RESUMO

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is genetically one of the least heterogeneous ciliopathies, resulting primarily from mutations of PKHD1. Nevertheless, 13-20% of patients diagnosed with ARPKD are found not to carry PKHD1 mutations by sequencing. Here, we assess whether PKHD1 copy number variations or second locus mutations explain these cases. METHODS: Thirty-six unrelated patients with the clinical diagnosis of ARPKD were screened for PKHD1 point mutations and copy number variations. Patients without biallelic mutations were re-evaluated and screened for second locus mutations targeted by the phenotype, followed, if negative, by clinical exome sequencing. RESULTS: Twenty-eight patients (78%) carried PKHD1 point mutations, three of whom on only one allele. Two of the three patients harbored in trans either a duplication of exons 33-35 or a large deletion involving exons 1-55. All eight patients without PKHD1 mutations (22%) harbored mutations in other genes (PKD1 (n = 2), HNF1B (n = 3), NPHP1, TMEM67, PKD1/TSC2). Perinatal respiratory failure, a kidney length > +4SD and early-onset hypertension increase the likelihood of PKHD1-associated ARPKD. A patient compound heterozygous for a second and a last exon truncating PKHD1 mutation (p.Gly4013Alafs*25) presented with a moderate phenotype, indicating that fibrocystin is partially functional in the absence of its C-terminal 62 amino acids. CONCLUSIONS: We found all ARPKD cases without PKHD1 point mutations to be phenocopies, and none to be explained by biallelic PKHD1 copy number variations. Screening for copy number variations is recommended in patients with a heterozygous point mutation.


Assuntos
Variações do Número de Cópias de DNA , Heterozigoto , Fenótipo , Rim Policístico Autossômico Recessivo/genética , Receptores de Superfície Celular/genética , Adolescente , Alelos , Criança , Pré-Escolar , Análise Mutacional de DNA , Éxons/genética , Feminino , Testes Genéticos , Humanos , Lactente , Recém-Nascido , Masculino , Mutação Puntual , Rim Policístico Autossômico Recessivo/diagnóstico , Índice de Gravidade de Doença
7.
BMC Mol Biol ; 18(1): 12, 2017 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-28449660

RESUMO

BACKGROUND: Prevalence of fibroproliferative diseases, including chronic kidney disease is rapidly increasing and has become a major public health problem worldwide. Fibroproliferative diseases are characterized by increased expression of α smooth muscle actin (α-SMA) that belongs to the family of the six conserved actin isoforms showing high degree homology. The aim of the present study was to develop real-time PCRs that clearly discriminate α-SMA and ß-actin from other actin isoforms. RESULTS: Real-time PCRs using self-designed mouse, human and rat specific α-SMA or ß-actin primer pairs resulted in the specific amplification of the artificial DNA templates corresponding to mouse, human or rat α-SMA or ß-actin, however ß-actin showed cross-reaction with the housekeeping γ-cyto-actin. We have shown that the use of improperly designed literary primer pairs significantly affects the results of PCRs measuring mRNA expression of α-SMA or ß-actin in the kidney of mice underwent UUO. CONCLUSION: We developed a set of carefully designed primer pairs and PCR conditions to selectively determine the expression of mouse, human or rat α-SMA and ß-actin isoforms. We demonstrated the importance of primer specificity in experiments where the results are normalized to the expression of ß-actin especially when fibrosis and thus increased expression of α-SMA is occur.


Assuntos
Actinas/genética , Animais , Células Cultivadas , Primers do DNA , Fibrose , Expressão Gênica , Genes Essenciais , Humanos , Camundongos , RNA Mensageiro/genética , Ratos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Reação em Cadeia da Polimerase em Tempo Real/normas , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
8.
Clin Chem Lab Med ; 55(6): 809-816, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28002029

RESUMO

BACKGROUND: Nephronophthisis, an autosomal recessive nephropathy, is responsible for 10% of childhood chronic renal failure. The deletion of its major gene, NPHP1, with a minor allele frequency of 0.24% in the general population, is the most common mutation leading to a monogenic form of childhood chronic renal failure. It is challenging to detect it in the heterozygous state. We aimed to evaluate the sensitivity and the specificity of the quantitative multiplex PCR of short fluorescent fragments (QMPSF) in its detection. METHODS: After setting up the protocol of QMPSF, we validated it on 39 individuals diagnosed by multiplex ligation-dependent probe amplification (MLPA) with normal NPHP1 copy number (n=17), with heterozygous deletion (n=13, seven parents and six patients), or with homozygous deletion (n=9). To assess the rate of the deletions that arise from independent events, deleted alleles were haplotyped. RESULTS: The results of QMPSF and MLPA correlated perfectly in the identification of 76 heterozygously deleted and 56 homozygously deleted exons. The inter-experimental variability of the dosage quotient obtained by QMPSF was low: control, 1.05 (median; range, 0.86-1.33, n = 102 exons); heterozygous deletion, 0.51 (0.42-0.67, n = 76 exons); homozygous deletion, 0 (0-0, n = 56 exons). All patients harboring a heterozygous deletion were found to carry a hemizygous mutation. At least 15 out of 18 deletions appeared on different haplotypes and one deletion appeared de novo. CONCLUSIONS: The cost- and time-effective QMPSF has a 100% sensitivity and specificity in the detection of NPHP1 deletion. The potential de novo appearance of NPHP1 deletions makes its segregation analysis highly recommended in clinical practice.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Deleção de Genes , Heterozigoto , Proteínas de Membrana/genética , Reação em Cadeia da Polimerase/métodos , Sequência de Bases , Proteínas do Citoesqueleto , Éxons/genética , Humanos , Doenças Renais Císticas/congênito , Doenças Renais Císticas/genética , Limite de Detecção
9.
Acta Pol Pharm ; 72(5): 843-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26665390

RESUMO

Physical, chemical and microbiological stability of total parenteral nutrient (TPN) admixtures was studied as a function of storage time and temperature. Particle size analysis and zeta potential measurements were carried out to evaluate the possible changes in the kinetic stability of the emulsions as a function of storage time and temperature. The concentration changes of the applied additives, those of the ascorbic acid and L-alanyl-L-glutamine, were also determined under different storage conditions. Our results indicate that there were no significant differences in the particle size and zeta potential values of admixtures stored at the three examined temperatures. The best results were obtained in the case of admixtures stored at 30°C temperature. Rapid decomposition of vitamin C was found while the glutamine showed adequate stability as a function of storage time and temperature. According to the results of the physicochemical examinations 10-day storage period of this type of TPN admixtures can be accepted at room temperature. Their storage does not require refrigeration (2-8°C) thus they can be administered without special preheating ensuring better physiological tolerance. Ascorbic acid can be added to the system preceding the administration to the patient because of its rapid decomposition.


Assuntos
Nutrição Parenteral Total , Ácido Ascórbico/química , Dipeptídeos/química , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Humanos , Lactente , Tamanho da Partícula , Temperatura
10.
Pediatr Nephrol ; 28(10): 2061-4, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23800802

RESUMO

BACKGROUND: The pathogenicity of the NPHS2 homozygous p.R229Q variant in steroid-resistant nephrotic syndrome (SRNS) is doubtful. While it has been reported in unaffected controls, it is enriched in patients with SRNS, suggesting pathogenicity. CASE-DIAGNOSIS/TREATMENT: A family with three members homozygous for the NPHS2 p.R229Q variant is presented: a 37-year-old patient who was diagnosed with proteinuria at age 7 months, focal segmental glomerulosclerosis (FSGS) at age 20 years, and end-stage renal disease (ESRD) at age 33 years, his 59 year-old father and his 40 year-old brother, both unaffected with no proteinuria. The affected son also harbors a heterozygous de novo, truncating PAX2 mutation (c.76dupG, p.V26Gfs*28), which can explain his chronic renal failure but which is rarely associated with FSGS. CONCLUSIONS: This family provides further evidence that homozygous p.R229Q in itself may not cause FSGS. Nevertheless, the rare association of FSGS to a PAX2 mutation may reflect the modifier effect of p.R229Q in the homozygous state. Such a modifier effect can also explain its enrichment in SRNS patients. Patients with homozygous p.R229Q should be screened for the causative mutation in a second gene.


Assuntos
Genes Modificadores , Variação Genética , Glomerulosclerose Segmentar e Focal/genética , Homozigoto , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Adulto , Análise Mutacional de DNA , Progressão da Doença , Predisposição Genética para Doença , Glomerulosclerose Segmentar e Focal/complicações , Glomerulosclerose Segmentar e Focal/diagnóstico , Glomerulosclerose Segmentar e Focal/terapia , Hereditariedade , Humanos , Falência Renal Crônica/genética , Laminina/genética , Masculino , Pessoa de Meia-Idade , Mutação , Fator de Transcrição PAX2/genética , Linhagem , Fenótipo , Proteinúria/genética , Fatores de Risco
11.
Ideggyogy Sz ; 61(11-12): 417-22, 2008 Nov 30.
Artigo em Húngaro | MEDLINE | ID: mdl-19070318

RESUMO

Authors summarized the etiology of convulsions in neonatal period and infancy (hypoxia, intracranial hemorrhage, infections of central nervous system, metabolic background, chromosomal abnormalities, brain developmental abnormalities, benign neonatal convulsions, benign neonatal familial convulsions, drug withdrawal, inborn error of metabolism). They suggest screening examinations after convulsion, summarized the basic principle of tandem examination and review a proposal at suspicion of inborn error of enzyme defects (aminoacidemias, defects of fatty acid oxidation, organic acidemias). They present case history of two patients suffered in extraordinary inborn error of enzyme defect (SCO2 gene mutation, propionic acidemia). Diagnosis originated in Helm P61 Hospital (settlement Madarász Hospital) with a Hungarian and international cooperation.


Assuntos
Epilepsia Neonatal Benigna/etiologia , Epilepsia Neonatal Benigna/metabolismo , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Proteínas de Transporte/genética , Hemorragia Cerebral/complicações , Aberrações Cromossômicas , Eletroencefalografia , Epilepsia Neonatal Benigna/diagnóstico por imagem , Epilepsia Neonatal Benigna/genética , Feminino , Testes Genéticos , Humanos , Hipóxia/complicações , Lactente , Recém-Nascido , Doença de Leigh/complicações , Masculino , Proteínas de Membrana/genética , Erros Inatos do Metabolismo/metabolismo , Proteínas Mitocondriais/genética , Chaperonas Moleculares , Mutação , Ultrassonografia Doppler
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