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1.
J Hum Genet ; 68(4): 273-279, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36599954

RESUMO

Previously, we reported a series of families presenting with trichodiscomas, inherited in an autosomal dominant pattern. The phenotype was named familial multiple discoid fibromas (FMDF). The genetic cause of FMDF remained unknown so far. Trichodiscomas are skin lesions previously reported to be part of the same spectrum as the fibrofolliculoma observed in Birt-Hogg-Dubé syndrome (BHD), an inherited disease caused by pathogenic variants in the FLCN gene. Given the clinical and histological differences with BHD and the exclusion of linkage with the FLCN locus, the phenotype was concluded to be distinct from BHD. We performed extensive clinical evaluations and genetic testing in ten families with FMDF. We identified a FNIP1 frameshift variant in nine families and genealogical studies showed common ancestry for eight families. Using whole exome sequencing, we identified six additional rare variants in the haplotype surrounding FNIP1, including a missense variant in the PDGFRB gene that was found to be present in all tested patients with FMDF. Genome-wide linkage analysis showed that the locus on chromosome 5 including FNIP1 was the only region reaching the maximal possible LOD score. We concluded that FMDF is linked to a haplotype on chromosome 5. Additional evaluations in families with FMDF are required to unravel the exact genetic cause underlying the phenotype. When evaluating patients with multiple trichodisomas without a pathogenic variant in the FLCN gene, further genetic testing is warranted and can include analysis of the haplotype on chromosome 5.


Assuntos
Síndrome de Birt-Hogg-Dubé , Fibroma , Neoplasias Renais , Humanos , Neoplasias Renais/genética , Cromossomos Humanos Par 5/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Proto-Oncogênicas/genética , Síndrome de Birt-Hogg-Dubé/genética , Síndrome de Birt-Hogg-Dubé/patologia , Fibroma/genética , Proteínas de Transporte/genética
2.
Am J Med Genet A ; 188(6): 1752-1760, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35212137

RESUMO

Huriez syndrome (HRZ, OMIM181600) is a rare genodermatosis characterized by scleroatrophic hands and feet, hypoplastic nails, palmoplantar keratoderma, and predisposition to cutaneous squamous cell carcinoma (cSCC). We report herein three HRZ families from Croatia, the Netherlands, and Germany. Deep sequencing followed by Sanger validation, confirmed the presence of germline causative SMARCAD1 heterozygous pathogenic variants. All seven HRZ patients displayed hypohidrosis, adermatoglyphia, and one patient developed cSCC at 32 years of age. Two novel monoallelic germline mutations were identified which are predicted to disrupt the first exon-intron boundary of the skin-specific SMARCAD1 isoform. On the basis of phenotypic and genotypic convergence with Adermatoglyphia (OMIM136000) and Basan syndrome (OMIM129200), our results lend credence to the notion that these three Mendelian disorders are allelic. We propose adding Huriez syndrome to the previously suggested SMARCAD syndrome designation, which was originally invoked to describe the spectrum of monogenic disorders between Adermatoglyphia and Basan syndrome.


Assuntos
Carcinoma de Células Escamosas , Ceratodermia Palmar e Plantar , Neoplasias Cutâneas , Carcinoma de Células Escamosas/complicações , DNA Helicases/genética , Displasia Ectodérmica , Humanos , Ceratodermia Palmar e Plantar/genética , Ceratose , Unhas Malformadas , Esclerodermia Localizada , Dermatopatias Genéticas , Neoplasias Cutâneas/etiologia , Síndrome
3.
BMC Dev Biol ; 16(1): 23, 2016 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-27391801

RESUMO

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is a dominantly inherited familial cancer syndrome characterised by the development of benign skin fibrofolliculomas, multiple lung and kidney cysts, spontaneous pneumothorax and susceptibility to renal cell carcinoma. BHD is caused by mutations in the gene encoding Folliculin (FLCN). Little is known about what FLCN does in a healthy individual and how best to treat those with BHD. As a first approach to developing a vertebrate model for BHD we aimed to identify the temporal and spatial expression of flcn transcripts in the developing zebrafish embryo. To gain insights into the function of flcn in a whole organism system we generated a loss of function model of flcn by the use of morpholino knockdown in zebrafish. RESULTS: flcn is expressed broadly and upregulated in the fin bud, somites, eye and proliferative regions of the brain of the Long-pec stage zebrafish embryos. Together with knockdown phenotypes, expression analysis suggest involvement of flcn in zebrafish embryonic brain development. We have utilised the zFucci system, an in vivo, whole organism cell cycle assay to study the potential role of flcn in brain development. We found that at the 18 somite stage there was a significant drop in cells in the S-M phase of the cell cycle in flcn morpholino injected embryos with a corresponding increase of cells in the G1 phase. This was particularly evident in the brain, retina and somites of the embryo. Timelapse analysis of the head region of flcn morpholino injected and mismatch control embryos shows the temporal dynamics of cell cycle misregulation during development. CONCLUSIONS: In conclusion we show that zebrafish flcn is expressed in a non-uniform manner and is likely required for the maintenance of correct cell cycle regulation during embryonic development. We demonstrate the utilisation of the zFucci system in testing the role of flcn in cell proliferation and suggest a function for flcn in regulating cell proliferation in vertebrate embryonic brain development.


Assuntos
Encéfalo/crescimento & desenvolvimento , Proteínas Proto-Oncogênicas/genética , Proteínas Supressoras de Tumor/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/embriologia , Animais , Encéfalo/metabolismo , Ciclo Celular , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Humanos , Proteínas Proto-Oncogênicas/metabolismo , Retina/crescimento & desenvolvimento , Retina/metabolismo , Somitos/crescimento & desenvolvimento , Somitos/metabolismo , Imagem com Lapso de Tempo , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo
4.
Hum Mol Genet ; 22(21): 4383-97, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-23784378

RESUMO

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder where patients are predisposed to kidney cancer, lung and kidney cysts and benign skin tumors. BHD is caused by heterozygous mutations affecting folliculin (FLCN), a conserved protein that is considered a tumor suppressor. Previous research has uncovered multiple roles for FLCN in cellular physiology, yet it remains unclear how these translate to BHD lesions. Since BHD manifests hallmark characteristics of ciliopathies, we speculated that FLCN might also have a ciliary role. Our data indicate that FLCN localizes to motile and non-motile cilia, centrosomes and the mitotic spindle. Alteration of FLCN levels can cause changes to the onset of ciliogenesis, without abrogating it. In three-dimensional culture, abnormal expression of FLCN disrupts polarized growth of kidney cells and deregulates canonical Wnt signalling. Our findings further suggest that BHD-causing FLCN mutants may retain partial functionality. Thus, several BHD symptoms may be due to abnormal levels of FLCN rather than its complete loss and accordingly, we show expression of mutant FLCN in a BHD-associated renal carcinoma. We propose that BHD is a novel ciliopathy, its symptoms at least partly due to abnormal ciliogenesis and canonical Wnt signalling.


Assuntos
Síndrome de Birt-Hogg-Dubé/fisiopatologia , Cílios/fisiologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Sequência de Bases , Síndrome de Birt-Hogg-Dubé/genética , Linhagem Celular , Polaridade Celular , Proliferação de Células , Centrossomo/fisiologia , Cílios/patologia , Humanos , Rim/fisiologia , Microtúbulos/fisiologia , Dados de Sequência Molecular , Análise de Sequência de DNA , Via de Sinalização Wnt
5.
Methods Mol Biol ; 1769: 183-195, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29564825

RESUMO

Lagging chromosomes that arise after chromosome mis-segregation during cell division can be encapsulated within small structures known as micronuclei. A link between whole-chromosome mis-segregation and chromothripsis has been demonstrated via micronuclear chromosome pulverization. Here, we describe methods to efficiently generate micronuclei and examine downstream cell fates, specifically with regard to DNA damage and chromosome pulverization.


Assuntos
Aberrações Cromossômicas , Micronúcleos com Defeito Cromossômico , Testes para Micronúcleos , Aneuploidia , Ciclo Celular , Linhagem Celular , Segregação de Cromossomos , Cromotripsia , Dano ao DNA , Citometria de Fluxo , Humanos , Cariotipagem , Mitose
6.
Oncogenesis ; 7(8): 62, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30108207

RESUMO

Chromosomal instability (CIN), a high rate of chromosome loss or gain, is often associated with poor prognosis and drug resistance in cancers. Aneuploid, including near-polyploid, cells contain an abnormal number of chromosomes and exhibit CIN. The post-mitotic cell fates following generation of different degrees of chromosome mis-segregation and aneuploidy are unclear. Here we used aneuploidy inducers, nocodazole and reversine, to create different levels of aneuploidy. A higher extent of aneuploid and near-polyploid cells in a given population led to senescence. This was in contrast to cells with relatively lower levels of abnormal ploidy that continued to proliferate. Our findings revealed that senescence was accompanied by DNA damage and robust p53 activation. These senescent cells acquired the senescence-associated secretory phenotype (SASP). Depletion of p53 reduced the number of senescent cells with concomitant increase in cells undergoing DNA replication. Characterisation of these SASP factors demonstrated that they conferred paracrine pro-tumourigenic effects such as invasion, migration and angiogenesis both in vitro and in vivo. Finally, a correlation between increased aneuploidy and senescence was observed at the invasive front in breast carcinomas. Our findings demonstrate functional non-equivalence of discernable aneuploidies on tumourigenesis and suggest a cell non-autonomous mechanism by which aneuploidy-induced senescent cells and SASP can affect the tumour microenvironment to promote tumour progression.

7.
Mol Cancer Res ; 16(11): 1625-1640, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30037855

RESUMO

The most commonly utilized class of chemotherapeutic agents administered as a first-line therapy are antimitotic drugs; however, their clinical success is often impeded by chemoresistance and disease relapse. Hence, a better understanding of the cellular pathways underlying escape from cell death is critical. Mitotic slippage describes the cellular process where cells exit antimitotic drug-enforced mitotic arrest and "slip" into interphase without proper chromosome segregation and cytokinesis. The current report explores the cell fate consequence following mitotic slippage and assesses a major outcome following treatment with many chemotherapies, therapy-induced senescence. It was found that cells postslippage entered senescence and could impart the senescence-associated secretory phenotype (SASP). SASP factor production elicited paracrine protumorigenic effects, such as migration, invasion, and vascularization. Both senescence and SASP factor development were found to be dependent on autophagy. Autophagy induction during mitotic slippage involved the autophagy activator AMPK and endoplasmic reticulum stress response protein PERK. Pharmacologic inhibition of autophagy or silencing of autophagy-related ATG5 led to a bypass of G1 arrest senescence, reduced SASP-associated paracrine tumorigenic effects, and increased DNA damage after S-phase entry with a concomitant increase in apoptosis. Consistent with this, the autophagy inhibitor chloroquine and microtubule-stabilizing drug paclitaxel synergistically inhibited tumor growth in mice. Sensitivity to this combinatorial treatment was dependent on p53 status, an important factor to consider before treatment.Implications: Clinical regimens targeting senescence and SASP could provide a potential effective combinatorial strategy with antimitotic drugs. Mol Cancer Res; 16(11); 1625-40. ©2018 AACR.


Assuntos
Autofagia/fisiologia , Senescência Celular/fisiologia , Mitose/fisiologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Quinases Proteína-Quinases Ativadas por AMP , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Autofagia/efeitos dos fármacos , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Citocinas/metabolismo , Feminino , Células HCT116 , Células HEK293 , Xenoenxertos , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitose/efeitos dos fármacos , Neoplasias/metabolismo , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Quinases/metabolismo , Transfecção , Peixe-Zebra
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