scholarly journals The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene

Blood ◽  
1995 ◽  
Vol 86 (10) ◽  
pp. 3797-3804 ◽  
Author(s):  
Q Zhu ◽  
M Zhang ◽  
RM Blaese ◽  
JM Derry ◽  
A Junker ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Point Mutations ◽  
Gene Mutations ◽  
Exon Skipping ◽  
Splice Site Mutation ◽  
Missense Mutations ◽  
Site Mutation ◽  
Exon 2 ◽  
Wiskott Aldrich Syndrome ◽  
Was Gene

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia, small platelets, eczema, recurrent infections, and immunodeficiency. Besides the classic WAS phenotype, there is a group of patients with congenital X-linked thrombocytopenia (XLT) who have small platelets but only transient eczema, if any, and minimal immune deficiency. Because the gene responsible for WAS has been sequenced, it was possible to correlate the WAS phenotypes with WAS gene mutations. Using a fingerprinting screening technique, we determined the approximate location of the mutation in 13 unrelated WAS patients with mild to severe clinical symptoms. Direct sequence analysis of cDNA and genomic DNA obtained from patient-derived cell lines showed 12 unique mutations distributed throughout the WAS gene, including insertions, deletions, and point mutations resulting in amino acid substitutions, termination, exon skipping, or splicing defects. Of 4 unrelated patients with the XLT phenotype, 3 had missense mutations affecting exon 2 and 1 had a splice-site mutation affecting exon 9. Patients with classic WAS had more complex mutations, resulting in termination codons, frameshift, and early termination. These findings provide direct evidence that XLT and WAS are caused by mutations of the same gene and suggest that severe clinical phenotypes are associated with complex mutations.

scholarly journals Clinical characteristics and prenatal diagnosis in 22 families in Henan Province of China with X-linked agammaglobulinemia (XLA) related with Bruton’s tyrosine kinase (BTK) gene mutations.

2020 ◽  
Author(s):  
shanshan gao ◽  
Shuang Hu ◽  
Huikun Duan ◽  
Li Wang ◽  
Xiangdong Kong
Keyword(s):  
Prenatal Diagnosis ◽  
Clinical Symptoms ◽  
Genetic Diagnosis ◽  
Splice Site Mutation ◽  
Large Deletion ◽  
Missense Mutations ◽  
Male Fetus ◽  
Site Mutation ◽  
Female Fetus ◽  
Exon 2

Abstract Background: X-linked agammaglobulinaemia (XLA) is a rare immunodeficiency disease, and the main clinical symptoms is recurrent severe infections. BTK is the main disease-causing gene, and the genetic mode is X chromosome recessive inheritance. But the current mutations do not fully explain this disorder. Methods: We detected the percentage of CD19+ B cells and serum immunoglobulin (IgG, IgA, and IgM) levels by Flow cytometer and rate scatter immunoturbidimetry, and investigated the mutation profile of BTK gene through Sanger sequencing and Real- Time PCR in 22 XLA patients. Results: We described the clinical symptoms and investigated the genetic mutations in 22 XLA patients, and then identified six novel mutations of BTK gene, which included 2 missense mutations (c.23G>T and c.112T>C), 2 frameshift mutations (c.522_523insC and c.1060delA), 1 large deletion (deletion of exon 2 to 5), and 1 splice-site mutation (c.1631+2T>C). Prenatal diagnosis were performed in six families (F10, F11, F15, F18, F20 and F21). F10 was a male fetus without c.922_923delGA mutation; F15 was a male fetus without c.1631+1G>T splicing mutation; F20 was a female fetus without c.1931T>C mutation; and F21 was a male fetus without large deletion mutation. All four fetuses were less likely to become XLA patients in the future. Family 11 and Family 18 were male fetuses with c.1060delA and c.1684C>T mutations, respectively. The pregnant women in F18 chose to terminate the pregnancy, and the F11 chose to continue the pregnancy. Conclusion: It is noticeable that we confirmed the diagnosis of 22 XLA patients from 22 unrelated families and found six new pathogenic mutations. Prenatal diagnosis was performed in six families. Early genetic diagnosis and routine lifelong immunoglobulin replacement therapy can prevent and treat the infections of the XLA children and save their lives.

scholarly journals A novel splice site mutation in WAS gene in patient with Wiskott-Aldrich syndrome and chronic colitis: a case report

2018 ◽  
Vol 19 (1) ◽  
Author(s):  
Hossein Esmaeilzadeh ◽  
Mohammad Reza Bordbar ◽  
Hassan Dastsooz ◽  
Mohammad Silawi ◽  
Mohammad Ali Farazi Fard ◽  
...  
Keyword(s):  
Case Report ◽  
Splice Site ◽  
Splice Site Mutation ◽  
Chronic Colitis ◽  
Site Mutation ◽  
Wiskott Aldrich Syndrome ◽  
Was Gene

A novel splice site mutation in the WAS gene causes Wiskott???Aldrich syndrome in two siblings of a Saudi family

2004 ◽  
Vol 15 (7) ◽  
pp. 599-603
Author(s):  
Khaled K Abu-Amero ◽  
Tarek M Owaidah ◽  
Abduallah Al Jefri ◽  
Abdulaziz Al-Ghonaium ◽  
Ibrahim M Fawaz ◽  
...  
Keyword(s):  
Splice Site ◽  
Splice Site Mutation ◽  
Site Mutation ◽  
Wiskott Aldrich Syndrome ◽  
Saudi Family ◽  
Was Gene

scholarly journals Vitamin D 1α-Hydroxylase Gene Mutations in Patients with 1α-Hydroxylase Deficiency

2007 ◽  
Vol 92 (8) ◽  
pp. 3177-3182 ◽  
Author(s):  
Chan Jong Kim ◽  
Larry E. Kaplan ◽  
Farzana Perwad ◽  
Ningwu Huang ◽  
Amita Sharma ◽  
...  
Keyword(s):  
Vitamin D ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
Splice Site Mutation ◽  
Autosomal Recessive Disorder ◽  
The United States ◽  
Site Mutation ◽  
Hydroxylase Deficiency ◽  
Exon 2 ◽  
Hydroxylase Gene

Abstract Context: Vitamin D 1α-hydroxylase deficiency, also known as vitamin D-dependent rickets type 1, is an autosomal recessive disorder characterized by the early onset of rickets with hypocalcemia and is caused by mutations of the 25-hydroxyvitamin D 1α-hydroxylase (1α-hydroxylase, CYP27B1) gene. The human gene encoding the 1α-hydroxylase is 5 kb in length, located on chromosome 12, and comprises nine exons and eight introns. We previously isolated the human 1α-hydroxylase cDNA and gene and identified 19 different mutations in 25 patients with 1α-hydroxylase deficiency. Objectives, Patients, and Methods: We analyzed the 1α-hydroxylase gene of 10 patients, five from Korea, two from the United States, and one each from Argentina, Denmark, and Morocco, all from nonconsanguineous families. Each had clinical and radiographic features of rickets, hypocalcemia, and low serum concentrations of 1,25-dihydroxyvitamin D3. Results: Direct sequencing identified the responsible 1α-hydroxylase gene mutations in 19 of 20 alleles. Four novel and four known mutations were identified. The new mutations included a nonsense mutation in exon 6, substitution of adenine for guanine (2561G→A) creating a stop signal at codon 328; deletion of adenine in exon 9 (3922delA) causing a frameshift; substitution of thymine for cytosine in exon 2 (1031C→T) causing the amino acid change P112L; and a splice site mutation, substitution of adenine for guanine in the first nucleotide of intron 7 (IVS7+1 G→A) causing a frameshift. Conclusions: Mutations in the 1α-hydroxylase gene previously were identified in 44 patients, to which we add 10 more. The studies show a strong correlation between 1α-hydroxylase mutations and the clinical findings of 1α-hydroxylase deficiency.

Detection of Ten New Mutations by Screening the Gene Encoding Factor IX of Danish Hemophilia B Patients

1995 ◽  
Vol 73 (05) ◽  
pp. 774-778 ◽  
Author(s):  
Marianne Schwartz ◽  
Jørgen Ingerslev ◽  
Elma Scheibel ◽  
Lise Rud Nielsen
Keyword(s):  
Point Mutations ◽  
Splice Site Mutation ◽  
Factor Ix ◽  
Hemophilia B ◽  
Missense Mutations ◽  
Coding Region ◽  
Site Mutation ◽  
Gene Encoding ◽  
Base Pair Deletion ◽  
Wide Range

SummaryHemophilia B is caused by a wide range of mutations. In order to characterize the mutations among patients in Denmark, we have systematically screened the entire coding region, the promoter region and exon flanking sequences of the gene encoding factor IX using single strand conformation and heteroduplex analyses. Patients from 32 different families were examined, and point mutations (23 different) were found in all of them. Ten of the mutations have not been reported by others; they include a splice site mutation, a single base pair deletion, and missense mutations. Notably, the study contains a female patient and a previously described Leyden mutation. In ten families with sporadic cases of hemophilia B, all 10 mothers were found to be carriers. The origin of two of these mutations was established.

scholarly journals SAMHD1Gene Mutations Are Associated with Cerebral Large-Artery Atherosclerosis

2015 ◽  
Vol 2015 ◽  
pp. 1-8
Author(s):  
Wei Li ◽  
Baozhong Xin ◽  
Junpeng Yan ◽  
Ying Wu ◽  
Bo Hu ◽  
...  
Keyword(s):  
Small Vessel Disease ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
Splice Site Mutation ◽  
Large Artery ◽  
Missense Mutations ◽  
Site Mutation ◽  
Chinese Han ◽  
Functionally Impaired

Background. To investigate whether one or moreSAMHD1gene mutations are associated with cerebrovascular disease in the general population using a Chinese stroke cohort.Methods. Patients with a Chinese Han background (N=300) diagnosed with either cerebral large-artery atherosclerosis (LAA,n=100), cerebral small vessel disease (SVD,n=100), or other stroke-free neurological disorders (control,n=100) were recruited. Genomic DNA from the whole blood of each patient was isolated, and direct sequencing of theSAMHD1gene was performed. Both wild type and mutant SAMHD1 proteins identified from the patients were expressed inE. coliand purified; then their dNTPase activities and ability to form stable tetramers were analysedin vitro.Results. Three heterozygous mutations, including two missense mutations c.64C>T (P22S) and c.841G>A (p.E281K) and one splice site mutation c.696+2T>A, were identified in the LAA group with a prevalence of 3%. No mutations were found in the patients with SVD or the controls (p=0.05). The mutant SAMHD1 proteins were functionally impaired in terms of their catalytic activity as a dNTPase and ability to assemble stable tetramers.Conclusions. HeterozygousSAMHD1gene mutations might cause genetic predispositions that interact with other risk factors, resulting in increased vulnerability to stroke.

IGF2 Mutations

2019 ◽  
Vol 105 (1) ◽  
pp. 116-125 ◽  
Author(s):  
Yohei Masunaga ◽  
Takanobu Inoue ◽  
Kaori Yamoto ◽  
Yasuko Fujisawa ◽  
Yasuhiro Sato ◽  
...  
Keyword(s):  
High Frequency ◽  
Low Frequency ◽  
Splice Site Mutation ◽  
Missense Mutations ◽  
Site Mutation ◽  
Exon 2 ◽  
Mild Degree ◽  
Reduced Body ◽  
Limb Malformations ◽  
Silver Russell Syndrome

Abstract Objective IGF2 is a paternally expressed growth-promoting gene. Here, we report five cases with IGF2 mutations and review IGF2 mutation-positive patients described in the literature. We also compare clinical features between patients with IGF2 mutations and those with H19/IGF2:IG-DMR epimutations. Results We recruited five cases with IGF2 mutations: case 1 with a splice site mutation (c.–6–1G>C) leading to skipping of exon 2 and cases 2–5 with different missense mutations (p.(Cys70Tyr), p.(Cys71Arg), p.(Cys33Ser), and p.(Cys45Ser)) affecting cysteine residues involved in the S-S bindings. All the mutations resided on the paternally inherited allele, and the mutation of case 5 was present in a mosaic condition. Clinical assessment revealed Silver–Russell syndrome (SRS) phenotype with Netchine–Harbison scores of ≥5/6 in all the apparently nonmosaic 14 patients with IGF2 mutations (cases 1–4 described in this study and 10 patients reported in the literature). Furthermore, compared with H19/IGF2:IG-DMR epimutations, IGF2 mutations were associated with low frequency of hemihypoplasia, high frequency of feeding difficulty and/or reduced body mass index, and mild degree of relative macrocephaly, together with occasional development of severe limb malformations, high frequency of cardiovascular anomalies and developmental delay, and low serum IGF-II values. Conclusions This study indicates that IGF2 mutations constitute a rare but important cause of SRS. Furthermore, while both IGF2 mutations and H19/IGF2:IG-DMR epimutations lead to SRS, a certain degree of phenotypic difference is observed between the two groups, probably due to the different IGF2 expression pattern in target tissues.

Identification of Molecular Mutations Causing Haemophilia B From China: A Single-Center Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4627-4627
Author(s):  
Rong-Fu Zhou ◽  
Xian Zhang ◽  
Jian Ouyang ◽  
Yonggong Yang ◽  
Xiao-Yan Shao ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Cpg Islands ◽  
Gene Mutations ◽  
Splice Site Mutation ◽  
Hemophilia B ◽  
Missense Mutations ◽  
Site Mutation ◽  
Haemophilia B ◽  
Single Center Experience ◽  
Normal Plasma

Abstract Abstract 4627 Objective: To identify F9 gene mutations in patients with hemophilia B registered in Nanjing Drum Tower Hospital Hemophilia Registeration Center. Methods: One stage method was used to detect APTT, PT, TT, Fg and the activities of endogenous coagultation factors. Correction testing was employed to exclud the existence of inhibitor with mixed normal plasma. Genomic DNA was extracted from blood samples of 19 unrelated haemophilia B patients and their traceable family members. All exons and their flanking sequences of the F9 gene were amplificated by PCR and subsequently, the products were purified and sequenced directly. Results: APTT was significantly prolonged for all 19 cases of hemophilia B patients, but could be corrected by mixed normal plasma. According to the serial number, FIX:C was 3.7%, 3.5%, 1.9%, 1.9%, 2.2%, 2.0%, 1.9%, 3.2%, 3.5%, 10.8%, 7.8%, 2.2%, 3.8%, 2.3%, 1.6%, 1.4%, 3.7%, 7.8% and 3.5%, respectively. Thirteen different mutations of F9 gene were identified, including C 20518 T, T 6427 C, C 6460 T, C 31008 G, C 17761 T, A 17759 G, G 30150 A, G 31093 C, T 30930 C, G 20565 A, G 30987 A, A 6473 G and C 9 G, respectively. The mutations were composed of 10 missense mutations, one nonsense mutation, one a donor splice site mutation and one promoter mutation. Among them, mutations sites nt6460, nt17761, nt20518, nt30150 and nt31008 were located in CpG islands, belonging to mutation hot-spots. Mutations including C 9 G, C 31008 G and G 31093 C were firstly reported. Conclusions: No inhibitors are detected in the plasma of all patients. The F9 mutations are heterogenous and the missense mutations are the most prevalent gene defects in Chinese HB patients. Disclosures: No relevant conflicts of interest to declare.

A novel splice site mutation in the WAS gene causes Wiskott–Aldrich syndrome in two siblings of a Saudi family

2004 ◽  
Vol 15 (7) ◽  
pp. 599-603
Author(s):  
Khaled K Abu-Amero ◽  
Tarek M Owaidah ◽  
Abduallah Al Jefri ◽  
Abdulaziz Al-Ghonaium ◽  
Ibrahim M Fawaz ◽  
...  
Keyword(s):  
Splice Site ◽  
Splice Site Mutation ◽  
Site Mutation ◽  
Wiskott Aldrich Syndrome ◽  
Saudi Family ◽  
Was Gene

scholarly journals Identification of Missense Mutation Pro77Arg As A Founder Mutation in Morquio-A Syndrome in Indian Gujarati Patel Ethnicity

2020 ◽  
Author(s):  
Jayesh J Sheth ◽  
Riddhi Bhavsar ◽  
Aadhira Nair ◽  
Chandni Patel ◽  
Premal Naik ◽  
...  
Keyword(s):  
Splice Site ◽  
Haplotype Analysis ◽  
Founder Mutation ◽  
Splice Site Mutation ◽  
Missense Mutations ◽  
Site Mutation ◽  
Exon 2 ◽  
Morquio A ◽  
Healthy Control ◽  
Morquio A Syndrome

Abstract Background: Morquio A syndrome (MPS IVA) is a mucopolysaccharide group storage disorder caused due to the deficient activity of the lysosomal enzyme N-acetylgalactoseamine-6-sulfatase encoded by GALNS. The present study represents the mutation spectrum of GALNS in 25 Gujarati Patel patients of India clinically and biochemically confirmed with Morquio-A disorder.Methods: Urinary GAG quantitation and leucocyte enzyme assay was carried out in all 25 patients. This was followed by molecular characterization by amplification and sequencing of the exons and adjacent intronic regions of GALNS gene. Haplotype analysis was performed in patients showing p.P77R variant, using microsatellite markers D16S3121, D16S3026 and D16S3023 and SNPs.Results: We identified 11 mutations that include eight missense mutations: (p.L36R, p.D39G, p.P77R, p.C79R, pP125L, p.P151L, p.G255A and p.L350P), one splice site mutation: (c.121-7C>G), one small insertion: (c.1241_1242insA, p.I416HfsTer2) and one small deletion: (c.839_41delACA). Of these, three missense mutations (p.D39G, p.G255A and p.L350P), one splice site and the two indels mentioned above are novel. In the present study, we found maximum number of mutant alleles in exon 2, and of note, the variant p.P77R was seen in fourteen patients. Conclusion: p.P77R variant was predominantly found in Gujarati Patel community and the results of haplotype analysis indicated it to be the founder mutation in this community. Further, a study of 200 unrelated healthy control participants from Gujarat has identified this mutation in the heterozygous status in two individuals. Overall, our study suggests that p.P77R is likely to be a founder mutation for Morquio-A syndrome in Gujarati Patel ethnicity.

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