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1.
Mol Genet Genomic Med ; 7(5): e625, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30891959

RESUMO

BACKGROUND: Postzygotic KRAS, HRAS, NRAS, and FGFR1 mutations result in a group of mosaic RASopathies characterized by related developmental anomalies in eye, skin, heart, and brain. These oculocutaneous disorders include oculoectodermal syndrome (OES) encephalo-cranio-cutaneous lipomatosis (ECCL), and Schimmelpenning-Feuerstein-Mims syndrome (SFMS). Here, we report the results of the clinical and molecular characterization of a novel cohort of patients with oculocutaneous mosaic RASopathies. METHODS: Two OES, two ECCL, and two SFMS patients were ascertained in the study. In addition, two subjects with unilateral isolated epibulbar dermoids were also enrolled. Molecular analysis included PCR amplification and Sanger sequencing of KRAS, HRAS, NRAS, and FGFR1 genes in DNA obtained from biopsies (skin/epibulbar dermoids), buccal mucosa, and blood leukocytes. Massive parallel sequencing was employed in two cases with low-level mosaicism. RESULTS: In DNA from biopsies, mosaicism for pathogenic variants, including KRAS p.Ala146Thr in two OES subjects, FGFR1 p.Asn546Lys and KRAS p.Ala146Val in ECCL patients, and KRAS p.Gly12Asp in both SFMS patients, was demonstrated. No mutations were shown in DNA from conjunctival lesions in two subjects with isolated epibubar dermoids. CONCLUSION: Our study allowed the expansion of the clinical spectrum of mosaic RASopathies and supports that mosaicism for recurrent mutations in KRAS and FGFR1 is a commonly involved mechanism in these rare oculocutaneous anomalies.


Assuntos
Cisto Dermoide/genética , Displasia Ectodérmica/genética , Oftalmopatias/genética , Lipomatose/genética , Síndromes Neurocutâneas/genética , Nevo Sebáceo de Jadassohn/genética , Fenótipo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Cisto Dermoide/patologia , Displasia Ectodérmica/patologia , Oftalmopatias/patologia , GTP Fosfo-Hidrolases/genética , Humanos , Lipomatose/patologia , Proteínas de Membrana/genética , Mosaicismo , Síndromes Neurocutâneas/patologia , Nevo Sebáceo de Jadassohn/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética
3.
Am J Hum Genet ; 103(5): 752-768, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388402

RESUMO

The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.

5.
Pediatr Endocrinol Rev ; 14(2): 129-137, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28508606

RESUMO

OBJECTIVES: Results of surgery for focal CHI in 30 children PATIENTS AND METHODS: All showed an ABCC8 or KCNJ11 mutation. After PET/CT in 29 children and PET/MRT in 1 case, frozen-section guided resection was performed, in left-sided cases by laparoscopy. Mean age at surgery was 11.7 months (2-49). RESULTS: In 28/30 children, the PET/CT or MRT correlated with histopathology. In two cases, a focal lesion was undectable; one of these was cured, one not. In total, 24 children showed lesions with sizes of 5-12 mm. All were cured instantly. In four children with huge lesions in the pancreatic head, pathological cells remained at the resection margins. One child was cured instantly, two children after a 2nd surgery, and one child was not cured, even after three surgeries. The overall cure rate was 93%. CONCLUSIONS: Imaging, surgical findings, histopathology and clinical outcome in surgery for focal CHI match in most, but not all cases.


Assuntos
Hiperinsulinismo Congênito/cirurgia , Criança , Pré-Escolar , Estudos de Coortes , Hiperinsulinismo Congênito/genética , Feminino , Alemanha , Humanos , Lactente , Masculino , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Estudos Retrospectivos , Receptores Sulfonilureia/genética
6.
J Pediatr Endocrinol Metab ; 29(3): 281-7, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26581065

RESUMO

BACKGROUND: During conservative treatment, congenital hyperinsulinism (CHI) can resolve spontaneously. This study describes the hormonal and metabolic profiles in three patients with ABCC8/KCNJ11 mutations in clinical remission. METHODS: An age-adapted fasting and oral glucose tolerance test (OGTT) were performed. RESULTS: All patients (aged 6-9 years) tolerated age-adapted fasting durations (20, respectively 24 h), without reaching glucose concentrations ≤2.5 mmol/L, nor developing hypoglycemia-related symptoms. Nevertheless, insulin concentrations from all patients exceeded the 90th reference percentile at the end of the fasting test (range: 4.2-15.8 mU/L). During the OGTT, one patient (patient 2; BMI: 23.4 kg/m2; age: 7 years) reached a glucose concentration of 11.4 mmol/L after 2 h (concomitant insulin concentration: 148.3 mU/L). CONCLUSIONS: The insulin concentration profiles in CHI patients in apparent clinical remission range from almost complete normalization to persistent, yet attenuated, hypersecretion. The hyperglycemia, detected during the OGTT, must be further monitored.


Assuntos
Hiperinsulinismo Congênito/tratamento farmacológico , Hiperinsulinismo Congênito/genética , Mutação/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Receptores Sulfonilureia/genética , Glicemia/metabolismo , Criança , Pré-Escolar , Tratamento Conservador , Jejum , Feminino , Seguimentos , Predisposição Genética para Doença , Teste de Tolerância a Glucose , Humanos , Insulina/metabolismo , Masculino , Prognóstico , Indução de Remissão
7.
Invest Ophthalmol Vis Sci ; 56(12): 7427-37, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26580852

RESUMO

PURPOSE: Numerous animal studies demonstrated the importance of components of the ephrin/Eph system for correct visual system development. Analogous investigations in humans are entirely missing. Here, we examined the visual system in humans with ephrin-B1 deficiency, which is x-linked and associated with the cranio-fronto-nasal syndrome (CFNS) in heterozygous females. METHODS: For one male hemizygous for ephrin-B1 deficiency and three affected heterozygous females with molecular-genetically confirmed mutations, the integrity of the partial decussation of the optic nerves was assessed with visual evoked potentials (VEPs) and compared with albinotic, achiasmic, and control participants with healthy vision. Further, retinal morphology and function and the gross-retinotopic representation of the primary visual cortex were examined with spectral-domain optical coherence tomography (SD-OCT), ERG, and multifocal (mf) VEPs for the male participant and part of the carriers. RESULTS: Strabismus and lack of stereovision was evident in the male and two of the females. Other characteristics of the visual system organization and function were normal: (1) retina: SD-OCT and funduscopy indicated normal foveal and optic nerve head morphology. Electroretinograms indicated normal retinal function, (2) optic chiasm: conventional (c)VEP showed no evidence for misrouting and mfVEPs were only suggestive of, if any, very minor local misrouting, and (3) visual cortex: mfVEP characteristics indicated normal retinotopic gross-representations of the contralateral visual hemifield in each hemisphere. CONCLUSIONS: While ephrin-B1 deficiency leads to abnormal visual pathways in mice, it leaves the human visual system, apart from deficits in binocular vision, largely normal. We presume that other components of the ephrin-system can substitute the lack of ephrin-B1 in humans.


Assuntos
Anormalidades Craniofaciais/genética , DNA/genética , Efrina-B1/genética , Mutação , Vias Visuais/fisiopatologia , Adulto , Animais , Anormalidades Craniofaciais/metabolismo , Anormalidades Craniofaciais/fisiopatologia , Análise Mutacional de DNA , Efrina-B1/deficiência , Potenciais Evocados Visuais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Síndrome , Tomografia de Coerência Óptica , Vias Visuais/patologia , Adulto Jovem
9.
Urol Int ; 95(4): 386-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25660097

RESUMO

INTRODUCTION: Prostate cancer is the most frequent malignancy found to occur in Caucasian men, but its genetic basis remains elusive. A prostate cancer-susceptibility locus has been identified on chromosome 13q14. The tumour suppressor gene deleted in cancer cells 1 (DICE1/INTS6) is located within this interval on 13q14.3. MATERIALS AND METHODS: We performed mutation analysis of the DICE1/INTS6 gene in thirteen German prostate cancer families. RESULTS AND CONCLUSION: None of the patients harboured DICE1 mutations, and similar frequencies of the previously identified 13 bp deletion polymorphism in the DICE1 promoter were observed in the familial prostate cancer patients as compared with sporadic prostate cancer patients and controls. However, in one family with three affected brothers, the variations c.1215A>C (p.T405T) in exon 10 and c.2568A>G (p.S856S) in exon 17 were detected in a heterozygous pattern. In sporadic prostate cancer patients, variant c.2568A>G (p.S856S) was detected in 10/325 (3.08%) compared with 5/207 (2.42%) control samples (p > 0.05). We conclude that DICE1 appears to be involved in prostate cancer progression rather than in the initiation of prostate cancer.


Assuntos
DNA de Neoplasias/análise , Família , Predisposição Genética para Doença/epidemiologia , Variação Genética , Neoplasias da Próstata/genética , Proteínas Ribossômicas/genética , Proteínas Supressoras de Tumor/genética , Idoso , Análise Mutacional de DNA , Frequência do Gene , Predisposição Genética para Doença/genética , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo Genético , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/metabolismo , Proteínas Ribossômicas/metabolismo , Proteínas Supressoras de Tumor/metabolismo
10.
Cleft Palate Craniofac J ; 52(2): 234-6, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24919122

RESUMO

Craniofrontonasal syndrome (CFNS; OMIM # 304110) is a rare X-linked disorder with greater severity in heterozygous females than in hemizygous males. CFNS is characterized by coronal craniosynostosis, frontal bossing, severe hypertelorism, craniofacial asymmetry, downslant palpebral fissure, broad nasal root, bifid nasal tip, grooved fingernails, curly wiry hair, and abnormalities of the thoracic skeleton. There are very few cases describing association of CFNS with heart defects. We discuss a very rare feature: atrial septal defect in a molecularly confirmed case of CFNS.


Assuntos
Anormalidades Craniofaciais/genética , Efrina-B1/genética , Hipertelorismo/genética , Mutação , Anormalidades Craniofaciais/diagnóstico por imagem , Feminino , Humanos , Hipertelorismo/diagnóstico por imagem , Lactente
12.
Horm Res Paediatr ; 81(3): 156-68, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24401662

RESUMO

Congenital hyperinsulinism (CHI) causes hypoglycemia due to irregular insulin secretion. In infants, a rapid diagnosis and appropriate management to avoid severe hypoglycemia is mandatory. CHI is a heterogeneous condition at the clinical and genetic level, and disease-causing genes have been identified in about half of the patients. The majority of mutations have been identified in the ABCC8 and KCNJ11 genes encoding subunits of the KATP channel responsible for two distinct histological forms. The diffuse form is caused by autosomal recessive or dominant inherited mutations, whereas the focal form is caused by a paternally transmitted recessive mutation and a second somatic event. We report on an unselected cohort of 136 unrelated patients from the German CHI registry. Mutations in either the ABCC8 or KCNJ11 gene were identified in 61 of these patients (45%). In total, 64 different mutations including 38 novel ones were detected in this cohort. We observed biparental (recessive) inheritance in 34% of mutation-positive patients, dominant inheritance in 11% and paternal transmission of a mutation associated with a focal CHI type in 38%. In addition, we observed inheritance patterns that do not exactly follow the classical recessive or dominant mode, further adding to the genetic complexity of this disease.


Assuntos
Hiperinsulinismo Congênito/genética , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Sistema de Registros , Receptores Sulfonilureia/genética , Hiperinsulinismo Congênito/metabolismo , Hiperinsulinismo Congênito/patologia , Feminino , Alemanha , Humanos , Masculino , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Receptores Sulfonilureia/metabolismo
13.
Am J Med Genet A ; 164A(2): 346-52, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24376213

RESUMO

Frontonasal dysplasia (FND) is a genetically heterogeneous malformation spectrum with marked hypertelorism, broad nasal tip and bifid nose. Only a small number of genes have been associated with FND phenotypes until now, the first gene being EFNB1, related to craniofrontonasal syndrome (CFNS) with craniosynostosis in addition, and more recently the aristaless-like homeobox genes ALX3, ALX4, and ALX1, which have been related with distinct phenotypes named FND1, FND2, and FND3 respectively. We here report on a female patient presenting with severe FND features along with partial alopecia, hypogonadism and intellectual disability. While molecular investigations did not reveal mutations in any of the known genes, ALX4, ALX3, ALX1 and EFNB1, comparative genomic hybridization (array CGH) techniques showed a large heterozygous de novo deletion at 11p11.12p12, encompassing the ALX4 gene. Deletions in this region have been described in patients with Potocki-Shaffer syndrome (PSS), characterized by biparietal foramina, multiple exostoses, and intellectual disability. Although the patient reported herein manifests some overlapping features of FND and PPS, it is likely that the observed phenotype maybe due to a second unidentified mutation in the ALX4 gene. The phenotype will be discussed in view of the deleted region encompassing the ALX4 gene.


Assuntos
Transtornos Cromossômicos/genética , Anormalidades Craniofaciais/genética , Proteínas de Ligação a DNA/genética , Exostose Múltipla Hereditária/genética , Face/anormalidades , Fenótipo , Deleção de Sequência , Fatores de Transcrição/genética , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Cromossomos Humanos Par 11/genética , Hibridização Genômica Comparativa , Anormalidades Craniofaciais/diagnóstico , Éxons , Exostose Múltipla Hereditária/diagnóstico , Ossos Faciais/anormalidades , Facies , Feminino , Heterozigoto , Humanos , Imagem Tridimensional/métodos , Polimorfismo de Nucleotídeo Único , Adulto Jovem
15.
BMC Med Genet ; 11: 98, 2010 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-20565770

RESUMO

BACKGROUND: Mutations of EFNB1 cause the X-linked malformation syndrome craniofrontonasal syndrome (CFNS). CFNS is characterized by an unusual phenotypic pattern of inheritance, because it affects heterozygous females more severely than hemizygous males. This sex-dependent inheritance has been explained by random X-inactivation in heterozygous females and the consequences of cellular interference of wild type and mutant EFNB1-expressing cell populations. EFNB1 encodes the transmembrane protein ephrin-B1, that forms bi-directional signalling complexes with Eph receptor tyrosine kinases expressed on complementary cells. Here, we studied the effects of patient-derived EFNB1 mutations predicted to give rise to truncated ephrin-B1 protein or to disturb Eph/ephrin-B1 reverse ephrin-B1 signalling. Five mutations are investigated in this work: nonsense mutation c.196C > T/p.R66X, frameshift mutation c.614_615delCT, splice-site mutation c.406 + 2T > C and two missense mutations p.P54L and p.T111I. Both missense mutations are located in the extracellular ephrin domain involved in Eph-ephrin-B1 recognition and higher order complex formation. METHODS: Nonsense mutation c.196C > T/p.R66X, frameshift mutation c.614_615delCT and splice-site mutation c.406+2T > C were detected in the primary patient fibroblasts by direct sequencing of the DNA and were further analysed by RT-PCR and Western blot analyses.The impact of missense mutations p.P54L and p.T111I on cell behaviour and reverse ephrin-B1 cell signalling was analysed in a cell culture model using NIH 3T3 fibroblasts. These cells were transfected with the constructs generated by in vitro site-directed mutagenesis. Investigation of missense mutations was performed using the Western blot analysis and time-lapse microscopy. RESULTS AND DISCUSSION: Nonsense mutation c.196C > T/p.R66X and frameshift mutation c.614_615delCT escape nonsense-mediated RNA decay (NMD), splice-site mutation c.406+2T > C results in either retention of intron 2 or activation of a cryptic splice site in exon 2. However, c.614_615delCT and c.406+2T > C mutations were found to be not compatible with production of a soluble ephrin-B1 protein. Protein expression of the p.R66X mutation was predicted unlikely but has not been investigated.Ectopic expression of p.P54L ephrin-B1 resists Eph-receptor mediated cell cluster formation in tissue culture and intracellular ephrin-B1 Tyr324 and Tyr329 phosphorylation. Cells expressing p.T111I protein show similar responses as wild type expressing cells, however, phosphorylation of Tyr324 and Tyr329 is reduced. CONCLUSIONS: Pathogenic mechanisms in CFNS manifestation include impaired ephrin-B1 signalling combined with cellular interference.


Assuntos
Craniossinostoses/genética , Efrina-B1/genética , Mutação , Códon sem Sentido , Efrina-B1/biossíntese , Efrina-B1/metabolismo , Efrinas/genética , Efrinas/metabolismo , Éxons , Feminino , Mutação da Fase de Leitura , Heterozigoto , Humanos , Masculino , Mutagênese Sítio-Dirigida , Mutação de Sentido Incorreto , Sítios de Splice de RNA , Receptores da Família Eph , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Síndrome , Inativação do Cromossomo X
16.
Cancer Cell Int ; 9: 28, 2009 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-19906297

RESUMO

BACKGROUND: The gene encoding integrator complex subunit 6 (INTS6), previously known as deleted in cancer cells 1 (DICE1, OMIM 604331) was found to be frequently affected by allelic deletion and promoter hypermethylation in prostate cancer specimens and cell lines. A missense mutation has been detected in prostate cancer cell line LNCaP. Together, these results suggest INTS6/DICE1 as a putative tumor suppressor gene in prostate cancer. In this study, we examined the growth inhibitory effects of INTS6/DICE1 on prostate cancer cells. RESULTS: Markedly decreased INTS6/DICE1 mRNA levels were detected in prostate cancer cell lines LNCaP, DU145 and PC3 as well as CPTX1532 as compared to a cell line derived from normal prostate tissue, NPTX1532. Exogenous re-expression of INTS6/DICE1 cDNA in androgen-independent PC3 and DU145 cell lines substantially suppressed their ability to form colonies in vitro. This growth inhibition was not due to immediate induction of apoptosis. Rather, prostate cancer cells arrested in G1 phase of the cell cycle. Expression profiling of members of the Wnt signaling pathway revealed up-regulation of several genes including disheveled inhibitor CXXC finger 4 (CXXC4), frizzled homologue 7 (FZD7), transcription factor 7-like 1 (TCF7L1), and down-regulation of cyclin D1. CONCLUSION: These results show for the first time a link between INTS6/DICE1 function, cell cycle regulation and cell-cell communication involving members of the Wnt signaling pathway.

19.
Eur J Hum Genet ; 16(2): 184-91, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18043713

RESUMO

Craniofrontonasal syndrome (CFNS) is an X-linked malformation syndrome with variable phenotype that is caused by mutations in the ephrin-B1 gene (EFNB1). Over 50% of EFNB1 mutations result in premature termination codons that may elicit mRNA degradation by the nonsense-mediated decay pathway. To assess the effects of various mutations at the transcript level, expression of EFNB1 mRNA was studied by RT-PCR in fibroblast cultures established from CFNS female patients. Compared to the wild-type and two missense mutation alleles, severe depletion of transcripts was observed for mutant alleles harbouring either splice site mutation c.407-2A>T at the exon 2/3 boundary or frameshift mutation c.377_384delTCAAGAAG in exon 2. In contrast, escape from mRNA decay was observed for mutation c.614_615delCT, which generates a premature termination codon close to the 3'-end of the penultimate exon 4 disobeying the '50-55 bp' rule. These results suggest differential degradation of mutant EFNB1 transcripts by the nonsense-mediated mRNA decay pathway. Although the clinical phenotypes of the patients were not highly suggestive of a phenotype-genotype correlation, the two female patients were diagnosed with diaphragmatic hernia harbouring putative ephrin-B1 truncating mutations. Previously, disease manifestation in heterozygous females had been attributed mainly to cellular interference of divergent cell populations expressing wild-type or mutant EFNB1, depending on the pattern of X-inactivation. Upon clonal expansion of patient cells with either the wild-type or mutant EFNB1 on the active X-chromosome, we were able to separate mutant and wild-type EFNB1-expressing cells in vitro, further supporting the concept of cellular interference in CFNS.


Assuntos
Anormalidades Craniofaciais/genética , Efrina-B1/genética , Mutação da Fase de Leitura , Mutação de Sentido Incorreto , Sítios de Splice de RNA , RNA Mensageiro/biossíntese , Adulto , Sequência de Aminoácidos , Sequência de Bases , Células Cultivadas , Criança , Códon sem Sentido/genética , Anormalidades Craniofaciais/patologia , Efrina-B1/biossíntese , Feminino , Mutação da Fase de Leitura/fisiologia , Heterozigoto , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Mutação de Sentido Incorreto/fisiologia , Sítios de Splice de RNA/fisiologia , RNA Mensageiro/genética , Distribuição Aleatória , Síndrome
20.
Appl Clin Genet ; 1: 19-22, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-23776344

RESUMO

We report on a six years old boy with several features of Greig cephalopolysyndactyly syndrome (GCPS) including craniofacial dysmorphism, hypertelorism, heart defect, preaxial hexadactyly of toes, partial agenesis of corpus callosum, and severe developmental delay. Greig cephalopolysyndactyly (GCPS) can be caused by GLI3 deletions. In patients with large deletions which include additional genes, it is termed Greig cephalopolysyndactyly-contiguous gene syndrome (GCPS-CGS). It is generally believed that the deletion size correlates with disease severity. Nearly all cases appear to be a result of GLI3 de novo deletions. Chromosome analysis of our patient revealed a large deletion in chromosome 7(p13-p14). Unlike most previously described cases, we found that this deletion resulted from a paternal balanced insertional translocation of 7p13-14 into the long arm of chromosome 5.

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