36 research outputs found
The Genetic and Clinical Features of FOXL2-Related Blepharophimosis, Ptosis and Epicanthus Inversus Syndrome
Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a craniofacial
disorder caused by heterozygous variants of the forkhead box L2 (FOXL2) gene. It shows autosomal
dominant inheritance but can also occur sporadically. Depending on the mutation, two phenotypic
subtypes have been described, both involving the same craniofacial features: type I, which is
associated with premature ovarian failure (POF), and type II, which has no systemic features. The
genotype–phenotype correlation is not fully understood, but it has been hypothesised that type I
BPES involves more severe loss of function variants spanning the whole gene. Type II BPES has been
linked to frameshift mutations that result in elongation of the protein rather than complete loss of
function. A mutational hotspot has been identified within the poly-alanine domain, although the
exact function of this region is still unknown. However, the BPES subtype cannot be determined
genetically, necessitating informed genetic counselling and careful discussion of family planning
advice in view of the associated POF particularly as the patient may still be a child. Following
puberty, female patients should be referred for ovarian reserve and response assessment. Oculofacial
features can be managed with surgical intervention and regular monitoring to prevent amblyopia
MicroRNA and transcriptome analysis in periocular Sebaceous Gland Carcinoma
Fight For Sight Fellowship, UK; National
Institute for Health Research (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital NHSFoundation Trust and UCL Institute of Ophthalmology. J.W. and C.C. acknowledge support from Cancer
Research UK Centre of Excellence Award to Barts Cancer Centre [C16420/A18066
MicroRNA and transcriptome analysis in periocular Sebaceous Gland Carcinoma
Sebaceous gland carcinoma (SGC) is a rare, but life-threatening condition with a predilection for the periocular region. Eyelid SGC can be broadly categorised into two subtypes, namely either nodular or pagetoid with the latter being more aggressive and requiring radical excision to save life. We have identified key altered microRNAs (miRNA) involved in SGC shared by both subtypes, hsa-miR-34a-5p and hsa-miR-16-5p. However, their gene targets BCL2 and MYC were differentially expressed with both overexpressed in pagetoid but unchanged in nodular suggesting different modes of action of these two miRNAs on BCL/MYC expression. Hsa-miR-150p is nodular-specifically overexpressed, and its target ZEB1 was significantly downregulated in nodular SGC suggesting a tumour suppressor role. Invasive pagetoid subtype demonstrated specific overexpression of hsa-miR-205 and downregulation of hsa-miR-199a. Correspondingly, miRNA gene targets, EZH2 (by hsa-miR-205) and CD44 (by hsa-miR-199a), were both overexpressed in pagetoid SGC. CD44 has been identified as a potential cancer stem cell marker in head and neck squamous cell carcinoma and its overexpression in pagetoid cells represents a novel treatment target. Aberrant miRNAs and their gene targets have been identified in both SGC subtypes, paving the way for better molecular understanding of these tumours and identifying new treatment targets
XRN2 Links Transcription Termination to DNA Damage and Replication Stress
We thank the Proteomics Core Facility. We thank Dr. Robert J. Crouch for providing us with GFP- and GFP-RNase H expression plasmids. We also thank Dr. Stephen H. Leppla for providing us with antibodies directed against RNA:DNA hybrids (R loops) (S9.6). We thank Novus Biologicals for generously providing XRN2 and Rrp45 antibodies. We also thank the members of the Boothman lab for critical reading of this manuscript.Author Summary Genomic instability is one of the primary causes of disease states, in particular cancer. One major cause of genomic instability is the formation of DNA double strand breaks (DSBs), which are one of the most dangerous types of DNA lesions the cell can encounter. If not repaired in a timely manner, one DSB can lead not only to cell death. If misrepaired, one DSB can lead to a hazardous chromosomal aberration, such as a translocation, that can eventually lead to cancer. The cell encounters and repairs DSBs that arise from naturally occurring cellular processes on a daily basis. A number of studies have demonstrated that aberrant structures that form during transcription under certain circumstances, in particular RNA:DNA hybrids (R loops), can lead to DSB formation and genomic instability, especially during DNA synthesis. Thus, it is important to understand how the cell responds and repairs transcription-mediated DNA damage in general and R loop-related DNA damage in particular. This paper both demonstrates that the XRN transcription termination factor links transcription and DNA damage, but also provides a better understanding of how the cell prevents transcription-related DNA damage.Yeshttp://www.plosgenetics.org/static/editorial#pee
Differential expression of phosphorylated MEK and ERK correlates with aggressive BCC subtypes.
Basal cell carcinoma (BCC) is associated with aberrant Hedgehog (HH) signalling through mutational inactivation of PTCH1; however, there is conflicting data regarding MEK/ERK signalling in BCC and the signalling pathway interactions in these carcinomas. To address this, expression of active phospho (p) MEK and ERK was examined in a panel of 15 non-aggressive and 14 aggressive BCCs. Although not uniformly expressed, both phospho-proteins were detected in the nuclei and/or cytoplasm of normal and tumour-associated epidermal cells however, whereas phospho-MEK (pMEK) was present in all non-aggressive BCCs (14/14), phospho-ERK (pERK) was rarely expressed (2/14). In contrast pERK expression was more prevalent in aggressive tumours (11/14). Interestingly, pMEK was only localized to the tumour mass whereas pERK was expressed in tumours and stroma of aggressive BCCs. Similarly, pERK (but not pMEK) was absent in mouse BCC-like tumours derived from X-ray irradiated Ptch1+/- mice with stromal pERK observed in myofibroblasts of the aggressive variant as well as in the tumour mass. RNA sequencing analysis of tumour epithelium and stroma of aggressive and non-aggressive BCC revealed the upregulation of epidermal growth factor receptor- and ERK-related pathways. Angiogenesis and immune response pathways were also upregulated in the stroma compared with the tumour. PTCH1 suppressed NEB1 immortalized keratinocytes (shPTCH1) display upregulated pERK that can be independent of MEK expression. Furthermore, epidermal growth factor pathway inhibitors affect the HH pathway by suppressing GLI1. These studies reveal differential expression of pERK between human BCC subtypes that maybe active by a pathway independent of MEK
Carney triad versus Carney Stratakis syndrome: two cases which illustrate the difficulty in distinguishing between these conditions in individual patients
Condroma pulmonar isolado: caso incompleto da trÃade de Carney? Isolated pulmonary chondroma: a case of incomplete Carney triad?
Um homem, de 45 anos, com infecções pulmonares de repetição havia quatro anos apresentou-se com tosse, secreção amarelada, escarros hemópticos e dor torácica não pleural. A tomografia revelou nódulo calcificado ocluindo brônquio lobar inferior direito. Realizada bilobectomia inferior e média, o exame histopatológico revelou condroma endobrônquico, bem circunscrito. O condroma pulmonar é um tumor raro, em geral associado à trÃade de Carney (condroma, leiomiossarcoma gástrico e paraganglioma extra-adrenal), sendo o menos freqüente dos três componentes. No presente caso, os outros dois componentes não foram observados. Podem, entretanto, se manifestar tardiamente, sendo, assim, necessário seguimento clÃnico em longo prazo do paciente.<br>A 45-year-old man presented with recurrent pulmonary infection for four years, cough, bloody sputum, yellowish excretion and nonpleuritic chest pain. Tomography of the chest revealed a calcified nodule occluding the right lower lobe bronchus. A right lower and middle lobectomy was performed, and the histopathological examination of the bronchi revealed chondroma, a rare pulmonary tumor usually associated with the Carney triad (pulmonary chondroma, gastric leiomyosarcoma and extra-adrenal paraganglioma), being the less common of the three components. In the present case, the other two components of the triad were not observed. Since these components may appear years later, long-term follow-up care is necessary