scholarly journals X-Linked Adrenal Hypoplasia Congenita in a Boy due to a Novel Deletion of the EntireNR0B1 (DAX1)andMAGEB1–4Genes

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Aleksandra Rojek ◽  
Maciej R. Krawczynski ◽  
Aleksander Jamsheer ◽  
Anna Sowinska-Seidler ◽  
Barbara Iwaniszewska ◽  
...  
Keyword(s):  
Genetic Defect ◽  
Point Mutations ◽  
Serum Cortisol ◽  
High Plasma ◽  
Blood Collection ◽  
Adrenal Hypoplasia Congenita ◽  
Number Variation ◽  
Pcr Method ◽  
Adrenal Hypoplasia

X-linked Adrenal Hypoplasia Congenita (AHC) is caused by deletions or point mutations in theNR0B1 (DAX1)gene. We present a boy with AHC who came at the age of 25 days in a severe state due to prolonged vomiting and progressive dehydration. Laboratory studies showed prominent hyponatremia and hyperkaliemia but not hypoglycemia. Primary adrenal insufficiency was confirmed with low serum cortisol levels and high plasma ACTH levels. Hydrocortisone therapy combined with saline and glucose infusions was started immediately after blood collection. Two exons of theNR0B1 (DAX1)gene were impossible to amplify using the standard PCR method. Array CGH was used to confirm the putative copy-number variation ofNR0B1 (DAX1)revealing a novel hemizygous deletion encompassing the entireNR0B1 (DAX1)gene together with theMAGEBgenes. This genetic defect was also present in heterozygosity in the patient’s mother. We show thatNR0B1 (DAX1)gene analysis is important for confirmation of AHC diagnosis and highlights the role of genetic counseling in families with AHC patients, particularly those with X chromosome microdeletions, covering more thanNR0B1 (DAX1)alone. We hope that further clinical follow-up of this patient and his family will shed a new light on the role ofMAGEBgenes.

scholarly journals Transcriptional Mutagenesis Prevents Ribosomal DNA Deterioration: The Role of Duplications and Deletions

2019 ◽  
Vol 11 (11) ◽  
pp. 3207-3217
Author(s):  
Enrico Sandro Colizzi ◽  
Paulien Hogeweg
Keyword(s):  
Genome Stability ◽  
Evolutionary Dynamics ◽  
Point Mutations ◽  
Gene Duplications ◽  
Genetic Operators ◽  
Theory Of Evolution ◽  
Long Term Stability ◽  
Number Variation

Abstract Clashes between transcription and replication complexes can cause point mutations and chromosome rearrangements on heavily transcribed genes. In eukaryotic ribosomal RNA genes, the system that prevents transcription–replication conflicts also causes frequent copy number variation. Such fast mutational dynamics do not alter growth rates in yeast and are thus selectively near neutral. It was recently found that yeast regulates these mutations by means of a signaling cascade that depends on the availability of nutrients. Here, we investigate the long-term evolutionary effect of the mutational dynamics observed in yeast. We developed an in silico model of single-cell organisms whose genomes mutate more frequently when transcriptional load is larger. We show that mutations induced by high transcriptional load are beneficial when biased toward gene duplications and deletions: they decrease mutational load even though they increase the overall mutation rates. In contrast, genome stability is compromised when mutations are not biased toward gene duplications and deletions, even when mutations occur much less frequently. Taken together, our results show that the mutational dynamics observed in yeast are beneficial for the long-term stability of the genome and pave the way for a theory of evolution where genetic operators are themselves cause and outcome of the evolutionary dynamics.

Role of key point Mutations in Receptor Binding Domain of SARS-CoV-2 Spike Glycoprotein

2020 ◽  
Vol 20 ◽  
Author(s):  
Bipin Singh
Keyword(s):  
Receptor Binding ◽  
Point Mutations ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Spike Glycoprotein ◽  
Angiotensin Converting Enzyme 2 ◽  
Recent Outbreak ◽  
Novel Coronavirus ◽  
Genomic Similarity

: The recent outbreak of novel coronavirus (SARS-CoV-2 or 2019-nCoV) and its worldwide spread is posing one of the major threats to human health and the world economy. It has been suggested that SARS-CoV-2 is similar to SARSCoV based on the comparison of the genome sequence. Despite the genomic similarity between SARS-CoV-2 and SARSCoV, the spike glycoprotein and receptor binding domain in SARS-CoV-2 shows the considerable difference compared to SARS-CoV, due to the presence of several point mutations. The analysis of receptor binding domain (RBD) from recently published 3D structures of spike glycoprotein of SARS-CoV-2 (Yan, R., et al. (2020); Wrapp, D., et al. (2020); Walls, A. C., et al. (2020)) highlights the contribution of a few key point mutations in RBD of spike glycoprotein and molecular basis of its efficient binding with human angiotensin-converting enzyme 2 (ACE2).

Novel Mutations in DAX1 of X-Linked Adrenal Hypoplasia Congenita Over Several Generations in One Family

2013 ◽  
Vol 19 (4) ◽  
pp. e105-e111 ◽  
Author(s):  
Xu Xiao-qin ◽  
Feng Yue-ying ◽  
Yuan Wen-xia ◽  
Huang Ke ◽  
Liang Li ◽  
...  
Keyword(s):  
Novel Mutations ◽  
Adrenal Hypoplasia Congenita ◽  
Adrenal Hypoplasia

Delayed diagnosis of adrenal hypoplasia congenita in two adult brothers

1995 ◽  
Vol 28 (3) ◽  
pp. 333
Author(s):  
V. Chetty ◽  
J.D. Booth ◽  
E. Dunn ◽  
S. Hill ◽  
G. Luxton
Keyword(s):  
Delayed Diagnosis ◽  
Adrenal Hypoplasia Congenita ◽  
Adrenal Hypoplasia

Block of Human Heart hH1 Sodium Channels by the Enantiomers of Bupivacaine

2000 ◽  
Vol 93 (4) ◽  
pp. 1022-1033 ◽  
Author(s):  
Carla Nau ◽  
Sho-Ya Wang ◽  
Gary R. Strichartz ◽  
Ging Kuo Wang
Keyword(s):  
Human Heart ◽  
Point Mutations ◽  
Cell Voltage ◽  
Site Directed Mutagenesis ◽  
Na Channel ◽  
Amino Acid Residues ◽  
Na Channels ◽  
State Dependent ◽  
Positively Charged

Background S(-)-bupivacaine reportedly exhibits lower cardiotoxicity but similar local anesthetic potency compared with R(+)-bupivacaine. The bupivacaine binding site in human heart (hH1) Na+ channels has not been studied to date. The authors investigated the interaction of bupivacaine enantiomers with hH1 Na+ channels, assessed the contribution of putatively relevant residues to binding, and compared the intrinsic affinities to another isoform, the rat skeletal muscle (mu1) Na+ channel. Methods Human heart and mu1 Na+ channel alpha subunits were transiently expressed in HEK293t cells and investigated during whole cell voltage-clamp conditions. Using site-directed mutagenesis, the authors created point mutations at positions hH1-F1760, hH1-N1765, hH1-Y1767, and hH1-N406 by introducing the positively charged lysine (K) or the negatively charged aspartic acid (D) and studied their influence on state-dependent block by bupivacaine enantiomers. Results Inactivated hH1 Na+ channels displayed a weak stereoselectivity with a stereopotency ratio (+/-) of 1.5. In mutations hH1-F1760K and hH1-N1765K, bupivacaine affinity of inactivated channels was reduced by approximately 20- to 40-fold, in mutation hH1-N406K by approximately sevenfold, and in mutations hH1-Y1767K and hH1-Y1767D by approximately twofold to threefold. Changes in recovery of inactivated mutant channels from block paralleled those of inactivated channel affinity. Inactivated hH1 Na+ channels exhibited a slightly higher intrinsic affinity than mu1 Na+ channels. Conclusions Differences in bupivacaine stereoselectivity and intrinsic affinity between hH1 and mu1 Na+ channels are small and most likely of minor clinical relevance. Amino acid residues in positions hH1-F1760, hH1-N1765, and hH1-N406 may contribute to binding of bupivacaine enantiomers in hH1 Na+ channels, whereas the role of hH1-Y1767 remains unclear.

scholarly journals The Human Genome Puzzle — the Role of Copy Number Variation in Somatic Mosaicism

2010 ◽  
Vol 11 (6) ◽  
pp. 426-431 ◽  
Author(s):  
Hasmik Mkrtchyan ◽  
Madeleine Gross ◽  
Sophie Hinreiner ◽  
Anna Polytiko ◽  
Marina Manvelyan ◽  
...  
Keyword(s):  
Copy Number Variation ◽  
Human Genome ◽  
Copy Number ◽  
Somatic Mosaicism ◽  
Number Variation

scholarly journals Spontaneous remission of hypercortisolism presumed due to asymptomatic tumor apoplexy in ACTH-producing pituitary macroadenoma

2013 ◽  
Vol 57 (6) ◽  
pp. 486-489 ◽  
Author(s):  
Marcio Carlos Machado ◽  
Patricia Sampaio Gadelha ◽  
Marcello Delano Bronstein ◽  
Maria Candida Barisson Vilares Fragoso
Keyword(s):  
Salivary Cortisol ◽  
Signs And Symptoms ◽  
Spontaneous Remission ◽  
Pituitary Surgery ◽  
Serum Cortisol ◽  
Urinary Free Cortisol ◽  
High Plasma ◽  
Imaging Data ◽  
Cystic Component ◽  
Free Cortisol

Cushing's disease (CD) is usually caused by secretion of ACTH by a pituitary corticotroph microadenoma. Nevertheless, 7%-20% of patients present with ACTH-secreting macroadenomas. Our aim is to report a 36-year-old female patient with CD due to solid-cystic ACTH-macroadenoma followed up during 34 months. The patient presented spontaneous remission due to presumed asymptomatic tumor apoplexy. She showed typical signs and symptoms of Cushing's syndrome (CS). Initial tests were consistent with ACTH-dependent CS: elevated urinary free cortisol, abnormal serum cortisol after low dose dexamethasone suppression test, and elevated midnight salivary cortisol, associated with high plasma ACTH levels. Pituitary magnetic resonance imaging (MRI) showed a sellar mass of 1.2 x 0.8 x 0.8 cm of diameter with supra-sellar extension leading to slight chiasmatic impingement, and showing hyperintensity on T2-weighted imaging, suggesting a cystic component. She had no visual impairment. After two months, while waiting for pituitary surgery, she presented spontaneous resolution of CS. Tests were consistent with remission of hypercortisolism: normal 24-h total urinary cortisol and normal midnight salivary cortisol. Pituitary MRI showed shrinkage of the tumor with disappearance of the chiasmatic compression. She has been free from the disease for 28 months (without hypercortisolism or hypopituitarism). The hormonal and imaging data suggested that silent apoplexy of pituitary tumor led to spontaneous remission of CS. However, recurrence of CS was described in cases following pituitary apoplexy. Therefore, careful long-term follow-up is required.

scholarly journals Effects of modifications of α-crystallin on its chaperone and other properties

2002 ◽  
Vol 364 (3) ◽  
pp. 711-717 ◽  
Author(s):  
Barry K. DERHAM ◽  
John J. HARDING
Keyword(s):  
Congenital Cataract ◽  
Point Mutations ◽  
Small Heat Shock Protein ◽  
High Molecular Mass ◽  
Lens Crystallins ◽  
Post Translational Modifications ◽  
Chaperone Function ◽  
Arginine Residues

The role of α-crystallin, a small heat-shock protein and chaperone, may explain how the lens stays transparent for so long. α-Crystallin prevents the aggregation of other lens crystallins and proteins that have become unfolded by ‘trapping’ the protein in a high-molecular-mass complex. However, during aging, the chaperone function of α-crystallin becomes compromised, allowing the formation of light-scattering aggregates that can proceed to form cataracts. Within the central part of the lens there is no turnover of damaged protein, and therefore post-translational modifications of α-crystallin accumulate that can reduce chaperone function; this is compounded in cataract lenses. Extensive in vitro glycation, carbamylation and oxidation all decrease chaperone ability. In the present study, we report the effect of the modifiers malondialdehyde, acetaldehyde and methylglyoxal, all of which are pertinent to cataract. Also modification by aspirin, which is known to delay cataract and other diseases, has been investigated. Recently, two point mutations of arginine residues were shown to cause congenital cataract. 1,2-Cyclohexanedione modifies arginine residues, and the extent of modification needed for a change in chaperone function was investigated. Only methylglyoxal and extensive modification by 1,2-cyclohexanedione caused a decrease in chaperone function. This highlights the robust nature of α-crystallin.

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