scholarly journals Missplicing due to a synonymous, T96= exonic substitution in the T-box transcription factor TBX19 resulting in isolated ACTH deficiency

2021 ◽  
Vol 2021 ◽  
Author(s):  
Ashwini Maudhoo ◽  
Avinaash Maharaj ◽  
Federica Buonocore ◽  
Gabriel Angel Martos-Moreno ◽  
Jesús Argente ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Serum Cortisol ◽  
List Type ◽  
Normal Range ◽  
Plasma Acth ◽  
Exon 2 ◽  
Isolated Acth Deficiency ◽  
Acth Deficiency ◽  
T Box

Summary Congenital isolated ACTH deficiency (IAD) is a rare condition characterised by low plasma ACTH and serum cortisol with normal production of other pituitary hormones. TBX19 (also known as TPIT) is a T-box pituitary restricted transcription factor important for POMC gene transcription and terminal differentiation of POMC-expressing cells. TBX19 gene mutations have been shown to cause neonatal-onset congenital IAD. We report a neonate of Romanian origin, who presented at 15 h of life with respiratory arrest and hypoglycaemia which recurred over the following 2 weeks. Biochemical investigations revealed IAD, with undetectable serum cortisol (cortisol < 1 μg/dL; normal range (NR): 7.8–26.2) and plasma ACTH levels within the normal range (22.1 pg/mL; NR: 4.7–48.8). He responded to hydrocortisone treatment. Patient DNA was analysed by a HaloPlex next-generation sequencing array targeting genes for adrenal insufficiency. A novel homozygous synonymous mutation p.Thr96= (Chr1:168260482; c.288G>A; rs376493164; allele frequency 1 × 10−5, no homozygous) was found in exon 2 of the TBX19 gene. The effect of this was assessed by an in vitro splicing assay, which revealed aberrant splicing of exon 2 giving rise to a mutant mRNA transcript whereas the WT vector spliced exon 2 normally. This was identified as the likely cause of IAD in the patient. The predicted protein product would be non-functional in keeping with the complete loss of cortisol production and early presentation in the patient. Learning points Synonymous variants (a nucleotide change that does not alter protein sequence) usually thought to be benign may still have detrimental effects on RNA and protein function causing disease. Hence, they should not be ignored, especially if very rare in public databases. In vitro splicing assays can be employed to characterise the consequence of intronic and exonic nucleotide gene changes that may alter splicing. Establishing a diagnosis due to a TBX19 mutation is important as it defines a condition of isolated ACTH deficiency not associated with additional pituitary deficiencies.

Missplicing due to a silent exonic substitution in the T-box transcription factor TBX19 resulting in Isolated ACTH deficiency

2018 ◽  
Author(s):  
Ashwini Maudhoo ◽  
Avinaash Maharaj ◽  
Federica Buonocore ◽  
Gabriel Angel Martos-Moreno ◽  
Jesus Argente ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Isolated Acth Deficiency ◽  
Acth Deficiency ◽  
T Box

scholarly journals TPIT mutations are associated with early-onset, but not late-onset isolated ACTH deficiency

2004 ◽  
pp. 463-465 ◽  
Author(s):  
LA Metherell ◽  
MO Savage ◽  
M Dattani ◽  
J Walker ◽  
PE Clayton ◽  
...  
Keyword(s):  
Dna Binding ◽  
Early Onset ◽  
Late Onset ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Nucleotide Polymorphisms ◽  
Exon 2 ◽  
Isolated Acth Deficiency ◽  
Acth Deficiency ◽  
T Box

OBJECTIVE: Congenital isolated ACTH deficiency (IAD) is a rare inherited disorder that is clinically and genetically heterogeneous. Patients are characterised by low or absent cortisol production secondary to low plasma ACTH despite normal secretion of other pituitary hormones and the absence of structural pituitary defects. Onset may occur in the neonatal period, but may first be observed in later childhood. Recently, mutations in the TPIT gene, a T-box factor selectively expressed in developing corticotroph cells, have been found in cases of early-onset IAD. DESIGN: Here we report the screening of the TPIT gene in seven patients with IAD, four of whom had neonatal onset. METHODS: Genomic DNA was extracted and the sequences of the 8 TPIT exons and their intron/exon junctions were determined by automated sequencing. RESULTS: Two siblings with early-onset IAD were both compound heterozygotes for mutations in exons 2 and 6. The missense mutation (Met86Arg) in exon 2 within the T-box (or DNA binding domain) is predicted to disrupt DNA binding. A frameshift mutation in exon 6 (782delA) introduces a premature stop codon and is likely to lead to a non-functional truncated protein. No nucleotide changes were observed in exonic sequences in the other two early- or the three later-onset cases. Fifteen single nucleotide polymorphisms that were not predicted to change the TPIT transcript were also detected. CONCLUSIONS: These findings provide a further illustration of the genetic heterogeneity of IAD and are highly suggestive of one or more other genes being implicated in this disorder.

scholarly journals Yorkie and JNK revert syncytial muscles into myoblasts during Org-1 dependent lineage reprogramming

2019 ◽  
Author(s):  
Christoph Schaub ◽  
Marcel Rose ◽  
Manfred Frasch
Keyword(s):  
Cell Fate ◽  
Present Report ◽  
Cellular Reprogramming ◽  
List Type ◽  
T Box ◽  
Lineage Reprogramming ◽  
Kinase Cascade ◽  
Alary Muscles

SummaryLineage reprogramming has become a prominent focus in research since it was demonstrated that lineage restricted transcription factors can be used in vitro for direct reprogramming [1]. Recently, we reported that the ventral longitudinal musculature (VLM) of the adult Drosophila heart arises in vivo by direct lineage reprogramming from alary muscles (AM), a process which starts with dedifferentiation and fragmentation of syncytial alary muscles into mononucleate myoblasts. Central upstream activators of the genetic program regulating the development of VLMs from alary muscles are the T-box factor Org-1 (Drosophila Tbx1) and the LIM homeodomain factor Tup (Drosophila Islet1) [2]. However, the events downstream of Org-1 and Tup that exert dedifferentiation and fragmentation of alary muscles have been unknown. In the present report, we shed light on the initiation of this first step of transdifferentiation and show that AM lineage specific activation of Yorkie (Yki), the transcriptional co-activator of the transcription factor Scalloped (Sd), has a key role in initiating AM lineage reprogramming. An additional necessary input comes from active dJNK signaling, which contributes to the inactivation of the Hippo kinase cascade upstream of Yki and furthermore activates dJun. The synergistic activities of the Yki/Sd and dJun/dFos (AP-1) transcriptional activator complexes in the absence of Hippo activity initiate AM dedifferentiation and lead to the expression of Myc and piwi, which are crucial for different aspects of AM transdifferentiation. Our results provide new insights into the mechanisms that mediate muscle lineage plasticity during a cellular reprogramming process occurring in vivo.HighlightsDirect lineage reprogramming of alary muscles depends on Yorkie and JNKYorkie and JNK mediate reversal of syncytial muscle cell fateYki/Sd and AP-1 induce alary muscle dedifferentiation synergisticallyYki dependent Myc induces and Piwi mediates reprogramming of alary muscles

The Ets-1 transcription factor is required for Stat1-mediated T-bet expression and IgG2a class switching in mouse B cells

Blood ◽  
2012 ◽  
Vol 119 (18) ◽  
pp. 4174-4181 ◽  
Author(s):  
Hai Vu Nguyen ◽  
Enguerran Mouly ◽  
Karine Chemin ◽  
Romain Luinaud ◽  
Raymonde Despres ◽  
...  
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
Molecular Mechanisms ◽  
Wild Type ◽  
Transcriptional Enhancer ◽  
T Box ◽  
Class Switch ◽  
Ifn Γ

Abstract In response to antigens and cytokines, mouse B cells undergo class-switch recombination (CSR) and differentiate into Ig-secreting cells. T-bet, a T-box transcription factor that is up-regulated in lymphocytes by IFN-γ or IL-27, was shown to regulate CSR to IgG2a after T cell–independent B-cell stimulations. However, the molecular mechanisms controlling this process remain unclear. In the present study, we show that inactivation of the Ets-1 transcription factor results in a severe decrease in IgG2a secretion in vivo and in vitro. No T-bet expression was observed in Ets-1–deficient (Ets-1−/−) B cells stimulated with IFN-γ and lipopolysaccharide, and forced expression of T-bet in these cells rescued IgG2a secretion. Furthermore, we identified a transcriptional enhancer in the T-bet locus with an activity in B cells that relies on ETS-binding sites. After IFN-γ stimulation of Ets-1−/− B cells, activated Stat1, which forms a complex with Ets-1 in wild-type cells, no longer binds to the T-bet enhancer or promotes histone modifications at this site. These results demonstrate that Ets-1 is critical for IgG2a CSR and acts as an essential cofactor for Stat1 in the regulation of T-bet expression in B cells.

Isolated ACTH deficiency accompanied by 'primary hypothyroidism' and hyperprolactinaemia

1983 ◽  
Vol 104 (4) ◽  
pp. 397-401 ◽  
Author(s):  
Tadayoshi Yoshida ◽  
Tetsuya Arai ◽  
Jinpei Sugano ◽  
Hiroshi Yarita ◽  
Hideo Yanagisawa
Keyword(s):  
Pituitary Gland ◽  
Primary Hypothyroidism ◽  
Hormonal Changes ◽  
Plasma Acth ◽  
Isolated Acth Deficiency ◽  
Acth Deficiency ◽  
Corticotrophin Releasing Factor ◽  
Lysine Vasopressin ◽  
Before And After

Abstract. A 55 year old man with isolated ACTH deficiency is reported. The lesion would appear to be located in the pituitary gland since plasma ACTH and cortisol did not respond to lysine vasopressin and corticotrophin releasing factor (CRF). A fall in T4, a rise in basal values of TSH, prolactin (Prl), LH and FSH, excessive responses of TSH and Prl to TRH, and hyperreactive responses of LH and FSH to LRH were observed. These hormonal changes were examined before and after administration of cortisol. The abnormality in these hormones might be caused by deficiency of long-term glucocorticoid.

scholarly journals Variants in a cis-regulatory element of TBX1 in conotruncal heart defect patients impair GATA6-mediated transactivation

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Xuechao Jiang ◽  
Tingting Li ◽  
Sijie Liu ◽  
Qihua Fu ◽  
Fen Li ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Regulatory Element ◽  
Expression Patterns ◽  
Human Embryos ◽  
Mobility Shift ◽  
T Box ◽  
Conotruncal Heart Defect ◽  
Velo Cardio Facial Syndrome ◽  
Electrophoretic Mobility Shift Assays

Abstract Background TBX1 (T-box transcription factor 1) is a major candidate gene that likely contributes to the etiology of velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS). Although the haploinsufficiency of TBX1 in both mice and humans results in congenital cardiac malformations, little has been elucidated about its upstream regulation. We aimed to explore the transcriptional regulation and dysregulation of TBX1. Methods Different TBX1 promoter reporters were constructed. Luciferase assays and electrophoretic mobility shift assays (EMSAs) were used to identify a cis-regulatory element within the TBX1 promoter region and its trans-acting factor. The expression of proteins was identified by immunohistochemistry and immunofluorescence. Variants in the cis-regulatory element were screened in conotruncal defect (CTD) patients. In vitro functional assays were performed to show the effects of the variants found in CTD patients on the transactivation of TBX1. Results We identified a cis-regulatory element within intron 1 of TBX1 that was found to be responsive to GATA6 (GATA binding protein 6), a transcription factor crucial for cardiogenesis. The expression patterns of GATA6 and TBX1 overlapped in the pharyngeal arches of human embryos. Transfection experiments and EMSA indicated that GATA6 could activate the transcription of TBX1 by directly binding with its GATA cis-regulatory element in vitro. Furthermore, sequencing analyses of 195 sporadic CTD patients without the 22q11.2 deletion or duplication identified 3 variants (NC_000022.11:g.19756832C > G, NC_000022.11:g.19756845C > T, and NC_000022.11:g. 19756902G > T) in the non-coding cis-regulatory element of TBX1. Luciferase assays showed that all 3 variants led to reduced transcription of TBX1 when incubated with GATA6. Conclusions Our findings showed that TBX1 might be a direct transcriptional target of GATA6, and variants in the non-coding cis-regulatory element of TBX1 disrupted GATA6-mediated transactivation.

scholarly journals A Case of Transient ACTH Deficiency Associated with Polymyalgia Rheumatica

2010 ◽  
Vol 1 ◽  
pp. JCM.S6215
Author(s):  
Hitoo Nishi ◽  
Yuichi Nishi ◽  
Masato Yagita ◽  
Yoshiko Tamaru ◽  
Sadayuki Matsumoto ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Polymyalgia Rheumatica ◽  
Serum Cortisol ◽  
Final Diagnosis ◽  
Pituitary Hormones ◽  
Sudden Onset ◽  
Plasma Acth ◽  
Acth Deficiency ◽  
Normal Increase ◽  
Short Time

We report a case of 79-year-old man, who was diagnosed to have transient ACTH deficiency associated with polymyalgia rheumatica (PMR). The patient presented with sudden onset bilateral shoulder pain, which was gradually aggravated. Plasma ACTH was undetectable, and both serum cortisol and urinary 17-OHCS were very low. Other pituitary hormones were normal, suggesting that hypothalamo-pituitary-adrenal (HPA) axis is selectively damaged. However, within several weeks, plasma ACTH returned to normal, and showed a normal increase response to corticotropin-releasing hormone stimulation test. These results indicated that ACTH deficiency was only transient. After hydrocortisone (10 mg/day) was administered, his symptoms became suddenly improved. Based on those results and clinical course, ie, elevated erythrocyte sedimentation rate, negative rheumatoid factor and the typical symptoms, which showed improvement to glulcocorticoid therapy, the final diagnosis was PMR, which was associated with transient ACTH deficiency. This is the first report of a case of PMR, in which the HPA axis was examined in its very acute phase. It was demonstrated that the case was associated with the transient adrenocortical hypofunction, which was recovered during a short time. It is therefore possible that PMR may show a different responsiveness of HPA axis depending on its phases.

scholarly journals Isolated ACTH deficiency during single-agent pembrolizumab for squamous cell lung carcinoma: a case report

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Sho Tanaka ◽  
Masaru Kushimoto ◽  
Tsukasa Nishizawa ◽  
Masahiro Takubo ◽  
Kazutaka Mitsuke ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adrenal Insufficiency ◽  
Squamous Cell ◽  
Single Agent ◽  
Serum Cortisol ◽  
Bright Spot ◽  
Advanced Lung Cancer ◽  
Cortisol Response ◽  
Isolated Acth Deficiency ◽  
Acth Deficiency

Abstract Background The programmed cell death 1 (PD-1) inhibitor pembrolizumab is a promising agent for treatment of several different malignancies, but as with all immunotherapy there is a potential risk of immune-related adverse events. Adrenocorticotropic hormone (ACTH) deficiency and hypophysitis have been reported in patients treated with a different PD-1 inhibitor, nivolumab. However, clinical characteristics of these side effects associated with pembrolizumab have yet to be described in detail. Case presentation An 85-year-old Japanese woman was diagnosed with advanced squamous cell lung cancer. The patient was treated with 200 mg pembrolizumab every three weeks as first-line therapy. Routine examination including thyroid function, complete blood count, serum cortisol and sodium levels before each pembrolizumab infusion had shown no significant changes up to the eighth cycle. However, 8 days after the eighth cycle of single-agent pembrolizumab, she presented with rapidly worsening general fatigue and appetite loss over two days. Laboratory data revealed a low serum cortisol level (0.92 μg/dL) with inappropriately low ACTH (8.3 pg/mL), hyponatremia (122 mmol/L) and hypoglycemia (68 mg/dL). Standard-dose short ACTH testing showed an unsatisfactory cortisol response, indicating adrenal insufficiency. Pituitary magnetic resonance imaging showed diffuse substantial gadolinium enhancement, T2 hyperintensity, loss of pituitary bright spot, but no pituitary enlargement. Serum cortisol and ACTH levels were low throughout the day, and urinary free cortisol excretion fell below the lower normal limit. There was no ACTH and cortisol response in the corticotropin-releasing hormone test, despite significant responses of other anterior pituitary hormones to their corresponding challenge tests. Thus, isolated ACTH deficiency was diagnosed, and hypophysitis was suspected as the etiology. After administration of 15 mg/day hydrocortisone, the patient’s debilitation, hyponatremia, and hypoglycemia swiftly disappeared. Conclusion This is a case of isolated ACTH deficiency possibly due to hypophysitis in a patient with advanced lung cancer, in whom recent routine examinations had shown unremarkable results. We therefore conclude that isolated ACTH deficiency can suddenly arise during pembrolizumab monotherapy, albeit probably only rarely. Caution should be exercised to make sure that adrenal insufficiency is recognized immediately in order to achieve swift recovery by steroid replacement.

Sign in / Sign up

Export Citation Format

Share Document