scholarly journals Identification of ATP2C1 mutations in the patients of Hailey-Hailey disease

2020 ◽  
Author(s):  
xiaoli li ◽  
dingwei zhang ◽  
jiahui ding ◽  
li li ◽  
zhenghui wang
Keyword(s):  
Nonsense Mutation ◽  
Polypeptide Chain ◽  
Stop Codon ◽  
Skin Lesions ◽  
Signaling Proteins ◽  
Missense Mutations ◽  
Functional Region ◽  
Bullous Dermatosis ◽  
Normal Human ◽  
Regulatory Effects

Abstract Background: Familial benign chronic pemphigus, also known as Hailey-Hailey disease (HHD), is a clinically rare bullous Dermatosis. However the mechanism has not been clarified. The study aim to detect novel mutations in exons of ATP2C1 gene in HHD patients; to explore the possible mechnism of HHD pathogenesis by examining the expression profile of hSPCA1, miR-203, p63, Notch1 and HKⅡ proteins in the skin lesions of HHD patients. Methods: Genomic DNA was extracted from peripheral blood of HHD patients. All exons of ATP2C1 gene in HHD patients were amplified by PCR and the products were purified and sequenced. All related signaling proteins of interest were stained by using skin lesion tissues from HHD patients and miR-203 levels were also determined. Results: One synonymous mutation c.G2598A (in exon 26), one nonsense mutation c.C635A and two missense mutations c.C1286A (p.A429D) and c. A1931G (p. D644G) were identified. The nonsense mutation changed codon UCG to stop codon UAG, causing a premature polypeptide chain of the functional region A. The two missense mutations were located in the region P (phosphorylation region) and the Mn binding site of hSPCA1. The level of hSPCA1 was significantly decreased in HHD patients compared to the normal human controls, accompanied by an increase of miR-203 level and a decrease of p63 and HKⅡ levels. Conclusion: In our study, we found four mutations in HHD. Meanwhile we found increase of miR-203 level and a decrease of p63 and HKⅡ levels. In addition, Notch1, which was negatively regulated p63, is downregulated. These factors may be involved in the signaling pathways of HHD pathogenesis. Our data showed that both p63 and miR-203 may have significant regulatory effects on Notch1 in the skin.

scholarly journals Identification of ATP2C1 mutations in the patients of Hailey-Hailey disease

2020 ◽  
Author(s):  
xiaoli li ◽  
dingwei zhang ◽  
jiahui ding ◽  
li li ◽  
zhenghui wang
Keyword(s):  
Nonsense Mutation ◽  
Polypeptide Chain ◽  
Stop Codon ◽  
Skin Lesions ◽  
Signaling Proteins ◽  
Missense Mutations ◽  
Functional Region ◽  
Bullous Dermatosis ◽  
Normal Human ◽  
Regulatory Effects

Abstract Background: Familial benign chronic pemphigus, also known as Hailey-Hailey disease (HHD), is a clinically rare bullous Dermatosis. However the mechanism has not been clarified. The study aim to detect novel mutations in exons of ATP2C1 gene in HHD patients; to explore the possible mechnism of HHD pathogenesis by examining the expression profile of hSPCA1, miR-203, p63, Notch1 and HKⅡ proteins in the skin lesions of HHD patients. Methods: Genomic DNA was extracted from peripheral blood of HHD patients. All exons of ATP2C1 gene in HHD patients were amplified by PCR and the products were purified and sequenced. All related signaling proteins of interest were stained by using skin lesion tissues from HHD patients and miR-203 levels were also determined. Results: One synonymous mutation c.G2598A (in exon 26), one nonsense mutation c.C635A and two missense mutations c.C1286A (p.A429D) and c. A1931G (p. D644G) were identified. The nonsense mutation changed codon UCG to stop codon UAG, causing a premature polypeptide chain of the functional region A. The two missense mutations were located in the region P (phosphorylation region) and the Mn binding site of hSPCA1. The level of hSPCA1 was significantly decreased in HHD patients compared to the normal human controls, accompanied by an increase of miR-203 level and a decrease of p63 and HKⅡ levels. Conclusion: In our study, we found four mutations in HHD. Meanwhile we found increase of miR-203 level and a decrease of p63 and HKⅡ levels. In addition, Notch1, which was negatively regulated p63, is downregulated. These factors may be involved in the signaling pathways of HHD pathogenesis. Our data showed that both p63 and miR-203 may have significant regulatory effects on Notch1 in the skin.

scholarly journals Identification of ATP2C1 mutations in the patients of Hailey-Hailey disease

2020 ◽  
Author(s):  
xiaoli li ◽  
dingwei zhang ◽  
jiahui ding ◽  
li li ◽  
zhenghui wang
Keyword(s):  
Nonsense Mutation ◽  
Polypeptide Chain ◽  
Stop Codon ◽  
Skin Lesions ◽  
Signaling Proteins ◽  
Missense Mutations ◽  
Functional Region ◽  
Bullous Dermatosis ◽  
Normal Human ◽  
Regulatory Effects

Abstract Background: Familial benign chronic pemphigus, also known as Hailey-Hailey disease (HHD), is a clinically rare bullous Dermatosis. However the mechanism has not been clarified. The study aim to detect novel mutations in exons of ATP2C1 gene in HHD patients; to explore the possible mechnism of HHD pathogenesis by examining the expression profile of hSPCA1, miR-203, p63, Notch1 and HKⅡ proteins in the skin lesions of HHD patients. Methods: Genomic DNA was extracted from peripheral blood of HHD patients. All exons of ATP2C1 gene in HHD patients were amplified by PCR and the products were purified and sequenced. All related signaling proteins of interest were stained by using skin lesion tissues from HHD patients and miR-203 levels were also determined. Results: One synonymous mutation c.G2598A (in exon 26), one nonsense mutation c.C635A and two missense mutations c.C1286A (p.A429D) and c. A1931G (p. D644G) were identified. The nonsense mutation changed codon UCG to stop codon UAG, causing a premature polypeptide chain of the functional region A. The two missense mutations were located in the region P (phosphorylation region) and the Mn binding site of hSPCA1. The level of hSPCA1 was significantly decreased in HHD patients compared to the normal human controls, accompanied by an increase of miR-203 level and a decrease of p63 and HKⅡ levels. Conclusion: In our study, we found four mutations in HHD. Meanwhile we found increase of miR-203 level and a decrease of p63 and HKⅡ levels. In addition, Notch1, which was negatively regulated p63, is downregulated. These factors may be involved in the signaling pathways of HHD pathogenesis. Our data showed that both p63 and miR-203 may have significant regulatory effects on Notch1 in the skin.

scholarly journals Identification of ATP2C1 mutations in the patients of Hailey-Hailey disease

2020 ◽  
Author(s):  
xiaoli li ◽  
dingwei zhang ◽  
jiahui ding ◽  
li li ◽  
zhenghui wang
Keyword(s):  
Nonsense Mutation ◽  
Polypeptide Chain ◽  
Stop Codon ◽  
Skin Lesions ◽  
Signaling Proteins ◽  
Missense Mutations ◽  
Functional Region ◽  
Bullous Dermatosis ◽  
Normal Human ◽  
Regulatory Effects

Abstract Background: Familial benign chronic pemphigus, also known as Hailey-Hailey disease (HHD), is a clinically rare bullous Dermatosis. However the mechanism has not been clarified. The study aim to detect novel mutations in exons of ATP2C1 gene in HHD patients; to explore the possible mechnism of HHD pathogenesis by examining the expression profile of hSPCA1, miR-203, p63, Notch1 and HKⅡ proteins in the skin lesions of HHD patients. Methods: Genomic DNA was extracted from peripheral blood of HHD patients. All exons of ATP2C1 gene in HHD patients were amplified by PCR and the products were purified and sequenced. All related signaling proteins of interest were stained by using skin lesion tissues from HHD patients and miR-203 levels were also determined. Results: One synonymous mutation c.G2598A (in exon 26), one nonsense mutation c.C635A and two missense mutations c.C1286A (p.A429D) and c. A1931G (p. D644G) were identified. The nonsense mutation changed codon UCG to stop codon UAG, causing a premature polypeptide chain of the functional region A. The two missense mutations were located in the region P (phosphorylation region) and the Mn binding site of hSPCA1. The level of hSPCA1 was significantly decreased in HHD patients compared to the normal human controls, accompanied by an increase of miR-203 level and a decrease of p63 and HKⅡ levels. Conclusion: In our study, we found four mutations in HHD. Meanwhile we found increase of miR-203 level and a decrease of p63 and HKⅡ levels. In addition, Notch1, which was negatively regulated p63, is downregulated. These factors may be involved in the signaling pathways of HHD pathogenesis. Our data showed that both p63 and miR-203 may have significant regulatory effects on Notch1 in the skin.

scholarly journals Identification of ATP2C1 mutations in the patients of Hailey-Hailey disease

2020 ◽  
Author(s):  
xiaoli li ◽  
dingwei zhang ◽  
jiahui ding ◽  
li li ◽  
zhenghui wang
Keyword(s):  
Nonsense Mutation ◽  
Polypeptide Chain ◽  
Stop Codon ◽  
Skin Lesions ◽  
Signaling Proteins ◽  
Missense Mutations ◽  
Functional Region ◽  
Bullous Dermatosis ◽  
Normal Human ◽  
Regulatory Effects

Abstract Background: Familial benign chronic pemphigus, also known as Hailey-Hailey disease (HHD), is a clinically rare bullous Dermatosis. However the mechanism has not been clarified. The study aim to detect novel mutations in exons of ATP2C1 gene in HHD patients; to explore the possible mechnism of HHD pathogenesis by examining the expression profile of hSPCA1, miR-203, p63, Notch1 and HKⅡ proteins in the skin lesions of HHD patients. Methods: Genomic DNA was extracted from peripheral blood of HHD patients. All exons of ATP2C1 gene in HHD patients were amplified by PCR and the products were purified and sequenced. All related signaling proteins of interest were stained by using skin lesion tissues from HHD patients and miR-203 levels were also determined. Results: One synonymous mutation c.G2598A (in exon 26), one nonsense mutation c.C635A and two missense mutations c.C1286A (p.A429D) and c. A1931G (p. D644G) were identified. The nonsense mutation changed codon UCG to stop codon UAG, causing a premature polypeptide chain of the functional region A. The two missense mutations were located in the region P (phosphorylation region) and the Mn binding site of hSPCA1. The level of hSPCA1 was significantly decreased in HHD patients compared to the normal human controls, accompanied by an increase of miR-203 level and a decrease of p63 and HKⅡ levels. Conclusion: In our study, we found four mutations in HHD. Meanwhile we found increase of miR-203 level and a decrease of p63 and HKⅡ levels. In addition, Notch1, which was negatively regulated p63, is downregulated. These factors may be involved in the signaling pathways of HHD pathogenesis. Our data showed that both p63 and miR-203 may have significant regulatory effects on Notch1 in the skin.

scholarly journals Identification of ATP2C1 mutations in the patients of Hailey-Hailey disease

2020 ◽  
Author(s):  
xiaoli li ◽  
dingwei zhang ◽  
jiahui ding ◽  
li li ◽  
zhenghui wang
Keyword(s):  
Nonsense Mutation ◽  
Stop Codon ◽  
Protein Structures ◽  
Skin Lesions ◽  
Signaling Proteins ◽  
Missense Mutations ◽  
Functional Region ◽  
Bullous Dermatosis ◽  
Normal Human ◽  
Regulatory Effects

Abstract Background: Familial benign chronic pemphigus (OMIM 169600), also known as Hailey-Hailey disease (HHD), is a clinically rare bullous Dermatosis. However the mechanism has not been clarified. Objective: To detect novel mutations in exons of ATP2C1 gene in HHD patients; to explore the mechnism of HHD pathogenesis by examining the expression profile of hSPCA1, Mir-203, p63, Notch1 and HKⅡ proteins in the skin lesions of HHD patients. Methods: Genomic DNA was extracted from peripheral blood of HHD patients. All exons of ATP2C1 gene in HHD patients were amplified by PCR and the products were purified and sequenced. All related signaling proteins of interest were stained by using skin lesion tissues from HHD patients and Mir-203 levels were also determined. Results: In this study, one synonymous mutation c.G2598A (in exon 26), one nonsense mutation c.C635A and two missense mutations c.C1286A (p.A429D) and c. A1931G (p. D644G) were identified. The nonsense mutation changed codon UCG to stop codon UAG, causing a premature polypeptide chain of the functional region A. The two missense mutations were located in the region P (phosphorylation region) and the Mn binding site of hSPCA1. The calcium pump was not no longer functional due to impaired protein structures. The level of hSPCA1 was significantly decreased in HHD patients compared to the normal human controls, accompanied by an increase of Mir-203 level and a decrease of p63 and HKⅡ levels. Conclusion: In HHD patients, these factors may be involved in the signaling pathways of HHD pathogenesis. In addition, Notch1, which was negatively regulated p63, is downregulated. Our data showed that both p63 and Mir-203 may have significant regulatory effects on Notch1 in the skin.

scholarly journals ID: 1048 A novel nonsense mutation in the CYP21A2 gene of a Vietnamese patient with congenital adrenal hyperplasia

2017 ◽  
Vol 4 (S) ◽  
pp. 129
Author(s):  
Vu Chi Dung ◽  
Ngoc Lan Nguyen ◽  
Huy Hoang Nguyen ◽  
Thi Kim Lien Nguyen ◽  
Thinh Huy Tran ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Nonsense Mutation ◽  
Stop Codon ◽  
Large Deletion ◽  
Heterozygous Mutation ◽  
Normal Allele ◽  
Adrenal Hyperplasia ◽  
Steroid Synthesis ◽  
Cyp21a2 Gene ◽  
Exon 1

Inactivating mutations in the CYP21A2 gene which encodes the protein involved in steroid synthesis have been reported in the patients with congenital adrenal hyperplasia (CAH). An infant who diagnosed with the severe phenotype of CAH such as increasing testicular volume, elevating of 17-hydroxyprogesteron, testosterone and progesterone and his family were subjected for genetic studies. Initially, we used PCR and direct sequencing to screen mutations in the CYP21 gene in the proband and his family. We identified a novel nonsense mutation c.374C>G predicts a substitution of serine for a stop codon at codon 125 (p.S125*) within exon 3 in the proband. However, the inheritance pattern of the mutation was not consistent with disease causation because of a heterozygous mutation carrier in father and sibling, wild-type alleles in mother but mutant alleles in proband. This inspired us to find deletions of exon using multiplex ligation-dependent probe amplification (MLPA) assay. In the profiles of MLPA electropherogram, the proband had a large deletion in exon 3, but his mother did not have. It means that the proband inherited a normal allele from his mother and a mutant allele from his father, but the deletion of a normal allele occurred in the proband. Therefore, mutation c.374C>G (p.S125*) in exon 3 in the proband is considered as a heterozygous deletion mutation. In addition, a large deletion in exon 1 in the maternal allele in the proband is observed. Taking together, the proband carried a nonsense mutation accompanied with two deletions in exon 1 and exon 3 in the CYP21A2 gene affect the CAH phenotype severity. These mutations also expand the CYP21A2 mutation spectrum in CAH disorder. This case also highlights the need of caution when interpreting results of molecular genetics and biochemical testing during genetic counseling.

scholarly journals Interferon-Lambda 1 Inhibits Staphylococcus aureus Colonization in Human Primary Keratinocytes

2021 ◽  
Vol 12 ◽  
Author(s):  
Xia Wu ◽  
Yan Zhao ◽  
Ying Gu ◽  
Kun Li ◽  
Xiaojie Wang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Mrna Expression ◽  
Human Keratinocytes ◽  
Skin Lesions ◽  
Inhibitory Effect ◽  
Oxidase Inhibitor ◽  
Primary Keratinocytes ◽  
Intracellular Ros ◽  
Normal Human ◽  
Human Primary Keratinocytes

Atopic dermatitis (AD) is a common inflammatory skin disease. Staphylococcus aureus (S. aureus) colonization in skin lesions occurs in approximately 70% of AD patients. It has been found that IFN-λ1 can inhibit the colonization of S. aureus in normal human nasal mucosa. IFN-λ1 can increase IL-28RA in infected human keratinocytes. In this study, we found that IFN-λ1 can increase mRNA expression of FLG and antimicrobial peptides (AMPs) and inhibit TSLP mRNA expression in infected human keratinocytes. IFN-λ1 can increase intracellular ROS level, decrease STAT1 phosphorylation, and inhibit the colonization of S. aureus in human primary keratinocytes. These effects were attenuated by knocking-down IL-28R and NADPH oxidase inhibitor, suggesting that this function was mediated by JAK-STAT1 signaling pathway. These results suggest that IFN-λ1 might have an inhibitory effect on S. aureus colonization in AD lesions. Our findings might have potential value in the treatment for AD.

scholarly journals Four novel mutations in deficiency of coagulation factor XIII: consequences to expression and structure of the A-subunit

Blood ◽  
1996 ◽  
Vol 87 (1) ◽  
pp. 141-151 ◽  
Author(s):  
H Mikkola ◽  
VC Yee ◽  
M Syrjala ◽  
R Seitz ◽  
R Egbring ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Nonsense Mutation ◽  
Factor Xiii ◽  
Three Dimensional ◽  
Factor Xiiia ◽  
Missense Mutations ◽  
Dimensional Model ◽  
Three Dimensional Model ◽  
Core Domain ◽  
A Subunit

Abstract The characterization of naturally occurring mutations is one way to approach functionally significant domains of polypeptides. About 10 mutations have been reported in factor XIII (FXIII) A-subunit deficiency, but very little is known about the effects of the mutations on the expression or the structure of this enzyme. In this study, the recent crystallization of FXIII A-subunit and determination of the three-dimensional model were used for the first time to pursue the structural consequences of mutations in the A-subunit. The molecular analysis of four families from Sweden, Germany, and Denmark revealed four previously unreported point mutations. Three of the mutations were missense mutations, Arg326-->Gln, Arg252-->Ile, and Leu498-->Pro, and one was a nonsense mutation, a deletion of thymidine in codon for Phe8 resulting in early frameshift and premature termination of the polypeptide chain. In the case of the nonsense mutation, delT Phe8, the steady-state mRNA level of FXIII A-subunit was reduced, as quantitated by reverse transcriptase-polymerase chain reaction and solid-phase minisequencing. In contrast, none of the missense mutations affected mRNA levels, indicating the possible translation of the mutant polypeptides. However, by enzyme-linked immunosorbent analysis and immunofluorescence, all the patients demonstrated a complete lack of detectable factor XIIIA antigen in their platelets. In the structural analysis, we included the mutations described in this work and the Met242-->Thr mutation reported earlier by us. Interestingly, in the three-dimensional model, all four missense mutations are localized in the evolutionarily conserved catalytic core domain. The substitutions are at least 15 A away from the catalytic cleft and do not affect any of the residues known to be directly involved in the enzymatic reaction. The structural analyses suggest that the mutations are most likely interfering with proper folding and stability of the protein, which is in agreement with the observed absence of detectable FXIIIA antigen. Arg326, Arg252, and Met242 are all buried within the molecule. The Arg326-->Gln and Arg252-->Ile mutations are substitutions of smaller, neutral amino acids for large, charged residues. They disrupt the electrostatic balance and hydrogen-bonding interactions in structurally significant areas. The Met242-->Thr mutation is located in the same region of the core domain as the Arg252-->Ile site and is expected to have a destabilizing effect due to an introduction of a smaller, polar residue in a tightly packed hydrophobic pocket. The substitution of proline for Leu498 is predicted to cause unfavorable interatomic contacts and a disruption of the alpha-helix mainchain hydrogen-bonding pattern; it is likely to form a kink in the helix next to the dimer interface and is expected to impair proper dimerization of the A-subunits. In the case of all four missense mutations studied, the knowledge achieved from the three-dimensional model of crystallized FXIII A-subunit provides essential information about the structural significance of the specific residues and aids in understanding the biologic consequences of the mutations observed at the cellular level.

Molecular analysis and genotype-phenotype correlation in patients with antithrombin deficiency from Southern Italy

2012 ◽  
Vol 107 (04) ◽  
pp. 673-680 ◽  
Author(s):  
Giuseppe Castaldo ◽  
Anna Cerbone ◽  
Anna Guida ◽  
Igor Tandurella ◽  
Rosaria Ingino ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Southern Italy ◽  
Stop Codon ◽  
Type I ◽  
Missense Mutations ◽  
Type Ii ◽  
Clinical Expression ◽  
Antithrombin Deficiency ◽  
At Deficiency ◽  
Molecular Bases

SummaryWe sequenced the SERPINC1 gene in 26 patients (11 males) with antithrombin (AT) deficiency (22 type I, 4 type II), belonging to 18 unrelated families from Southern Italy. Heterozygous mutations were identified in 15/18 (83.3%) families. Of them, eight were novel mutations, each being identified in one family. Seven clearly cause impaired protein synthesis (four frameshift, one non-stop, one splicing and one 21bp deletion). One, present in a single patient, is a missense mutation thought to be causative because: a) it is absent in 100 chromosomes from controls; b) it involves a highly conserved amino acid, whose change is predicted to impair AT activity; c) no other mutation is present in the propositus. Severe mutations (i.e. nonsense, frameshift, deletions) were invariably identified in type I patients. In type II patients, 3/4 were missense mutations; the fourth leads to a 19 nucleotides shift in the stop codon. In addition to the type of mutation, the co-existence of other predisposing factors in most patients helps explain the severity of the present type I cases (age at first event, recurrence during prophylaxis). In the five families in which there was more than one member affected, the same genotype and a concordant clinical expression of the disease were found. We conclude that the molecular bases of AT deficiency in Southern Italy are different as compared to other geographic areas, and that molecular analysis and the study of the effect of the mutation may help predict the clinical expression of the disease.

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