Cushing’s syndrome in early infancy due to isolated sporadic bilateral micronodular adrenocortical disease associated with myosin heavy chain 8 mutation: diagnostic challenges, too many!

2020 ◽  
Vol 13 (10) ◽  
pp. e236850
Author(s):  
Sananda Majumder ◽  
Partha Pratim Chakraborty ◽  
Prakash Chandra Ghosh ◽  
Mitali Bera
Keyword(s):  
Myosin Heavy Chain ◽  
Cushing’S Syndrome ◽  
Heavy Chain ◽  
Mutational Analysis ◽  
Carney Complex ◽  
Cushing's Syndrome ◽  
Chromosome 17 ◽  
Chain Gene ◽  
High Dose ◽  
Diagnostic Challenge

Endogenous Cushing’s syndrome (CS) is rare in infancy. Bilateral micronodular adrenocortical disease (BMAD), either primary pigmented nodular adrenocortical disease or the non-pigmented isolated micronodular adrenocortical disease is an important aetiology of CS in this age group, which requires bilateral adrenalectomy for cure. BMAD may be isolated, or a component of Carney complex. Isolated sporadic BMAD without other systemic manifestations poses a diagnostic challenge. Paradoxical cortisol response to dexamethasone suggests, while adrenal histopathology and mutational analysis of the culprit genes confirm BMAD. BMAD was suspected in 6-year-old infant with midnormal adrenocorticotrophic hormone, inconclusive adrenal and pituitary imaging and paradoxical increase in cortisol following high dose of dexamethasone. Exome sequencing revealed heterozygous c.354+1G>C (5′ splice site) variant in the myosin heavy chain gene (MYH8), located in chromosome 17. This particular variant has not been reported in the literature. In view of suspected phenotype and its absence in the population databases, the variant was classified as pathogenic.

scholarly journals Splice-Junction Elements and Intronic Sequences Regulate Alternative Splicing of the Drosophila Myosin Heavy Chain Gene Transcript

Genetics ◽  
1997 ◽  
Vol 147 (2) ◽  
pp. 725-741 ◽  
Author(s):  
David M Standiford ◽  
Mary Beth Davis ◽  
Weitao Sun ◽  
Charles P Emerson
Keyword(s):  
Alternative Splicing ◽  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Mutational Analysis ◽  
Regulatory Elements ◽  
Alternative Exon ◽  
Chain Gene ◽  
Gene Transcript ◽  
Specific Alternative ◽  
Exon 11

The Drosophila muscle myosin heavy chain (Mhc) gene primary transcript contains five alternatively spliced exon groups (exons 3, 7, 9, 11 and 15), each of which contains two to five mutually exclusive members. Individual muscles typically select a specific alternative exon from each group for incorporation into the processed message. We report here on the cis-regulatory mechanisms that direct the processing of alternative exons in Mhc exon 11 in individual muscles using transgenic reporter constructs, RT-PCR and directed mutagenesis. The 6.0-kilobase exon 11 domain is sufficient to direct the correct processing of exon 11 alternatives, demonstrating that the alternative splicing cis-regulatory elements are local to Mhc exon 11. Mutational analysis of Mhc exon 11 reveals that the alternative exon nonconsensus 5′-splice donors are essential for alternative splicing regulation in general, but do not specify alternative exons for inclusion in individual muscles. Rather, we show, through exon substitutions and deletion analyses, that a 360-nucleotide intronic domain precisely directs the normal processing of one exon, Mhc exon 11e, in the indirect flight muscle. These and other data indicate that alternative exons are regulated in appropriate muscles through interactions between intronic alternative splice-specificity elements, nonconsensus exon 11 splice donors and, likely, novel exon-specific alternative splicing factors.

Transcriptional regulation of the type I myosin heavy chain gene in denervated rat soleus

2003 ◽  
Vol 284 (3) ◽  
pp. C738-C748 ◽  
Author(s):  
K. A. Huey ◽  
F. Haddad ◽  
A. X. Qin ◽  
K. M. Baldwin
Keyword(s):  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Molecular Mechanisms ◽  
Mutational Analysis ◽  
Chain Gene ◽  
Type I ◽  
Slow Type ◽  
Actin Promoter ◽  
Mrna Analysis

Denervation (DEN) of rat soleus is associated with a decreased expression of slow type I myosin heavy chain (MHC) and an increased expression of the faster MHC isoforms. The molecular mechanisms behind these shifts remain unclear. We first investigated endogenous transcriptional activity of the type I MHC gene in normal and denervated soleus muscles via pre-mRNA analysis. Our results suggest that the type I MHC gene is regulated via transcriptional processes in the denervated soleus. Deletion and mutational analysis of the rat type I MHC promoter was then used to identify cis elements or regions of the promoter involved in this response. DEN significantly decreased in vivo activity of the −3,500, −2,500, −914, −408, −299, and −215 bp type I MHC promoters, relative to the α-skeletal actin promoter. In contrast, normalized −171 promoter activity was unchanged. Mutation of the βe3 element (−214/−190) in the −215 promoter and deletion of this element (−171 promoter) blunted type I downregulation with DEN. In contrast, βe3 mutation in the −408 promoters was not effective in attenuating the DEN response, suggesting the existence of additional DEN-responsive sites between −408 and −215. Western blotting and gel mobility supershift assays demonstrated decreased expression and DNA binding of transcription enhancer factor 1 (TEF-1) with DEN, suggesting that this decrease may contribute to type I MHC downregulation in denervated muscle.

scholarly journals Tissue-specific regulation of the alpha-myosin heavy chain gene promoter in transgenic mice.

1991 ◽  
Vol 266 (36) ◽  
pp. 24613-24620
Author(s):  
A. Subramaniam ◽  
W.K. Jones ◽  
J. Gulick ◽  
S. Wert ◽  
J. Neumann ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Gene Promoter ◽  
Chain Gene ◽  
Heavy Chain Gene ◽  
Myosin Heavy Chain Gene ◽  
Tissue Specific ◽  
Specific Regulation

scholarly journals The Ku Protein Complex Interacts with YY1, Is Up-Regulated in Human Heart Failure, and Represses α Myosin Heavy-Chain Gene Expression

2004 ◽  
Vol 24 (19) ◽  
pp. 8705-8715 ◽  
Author(s):  
Carmen C. Sucharov ◽  
Steve M. Helmke ◽  
Stephen J. Langer ◽  
M. Benjamin Perryman ◽  
Michael Bristow ◽  
...  
Keyword(s):  
Heart Failure ◽  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Human Heart ◽  
Ventricular Myocytes ◽  
Major Effect ◽  
Neonatal Rat ◽  
Chain Gene ◽  
Human Heart Failure ◽  
Peptide Mass

ABSTRACT Human heart failure is accompanied by repression of genes such as α myosin heavy chain (αMyHC) and SERCA2A and the induction of fetal genes such as βMyHC and atrial natriuretic factor. It seems likely that changes in MyHC isoforms contribute to the poor contractility seen in heart failure, because small changes in isoform composition can have a major effect on the contractility of cardiac myocytes and the heart. Our laboratory has recently shown that YY1 protein levels are increased in human heart failure and that YY1 represses the activity of the human αMyHC promoter. We have now identified a region of the αMyHC promoter that binds a factor whose expression is increased sixfold in failing human hearts. Through peptide mass spectrometry, we identified this binding activity to be a heterodimer of Ku70 and Ku80. Expression of Ku represses the human αMyHC promoter in neonatal rat ventricular myocytes. Moreover, overexpression of Ku70/80 decreases αMyHC mRNA expression and increases skeletal α-actin. Interestingly, YY1 interacts with Ku70 and Ku80 in HeLa cells. Together, YY1, Ku70, and Ku80 repress the αMyHC promoter to an extent that is greater than that with YY1 or Ku70/80 alone. Our results suggest that Ku is an important factor in the repression of the human αMyHC promoter during heart failure.

Sign in / Sign up

Export Citation Format

Share Document