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.

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 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.

Idiopathic infantile hypercalcemia: mutations in SLC34A1 and CYP24A1 in two siblings and fathers

2020 ◽  
Vol 33 (10) ◽  
pp. 1353-1358
Author(s):  
Ayla Güven ◽  
Martin Konrad ◽  
Karl P. Schlingmann
Keyword(s):  
Vitamin D ◽  
Stop Codon ◽  
Gene Mutations ◽  
Splice Site Mutation ◽  
Heterozygous Mutation ◽  
High Dose ◽  
Loss Of Function ◽  
Site Mutation ◽  
Medullary Nephrocalcinosis ◽  
Idiopathic Infantile Hypercalcemia

AbstractObjectivesBoth CYP24A1 and SLC34A1 gene mutations are responsible for idiopathic infantile hypercalcemia, whereas loss-of-function mutations in CYP24A1 (25-OH-vitamin D-24-hydroxylase) lead to a defect in the inactivation of active 1.25(OH)2D; mutations in SLC34A1 encoding renal sodium phosphate cotransporter NaPi-IIa lead to primary renal phosphate wasting combined with an inappropriate activation of vitamin D. The presence of mutations in both genes has not been reported in the same patient until today.Case presentationHypercalcemia was incidentally detected when a 13-month-old boy was being examined for urinary tract infection. After 21 months, hypercalcemia was detected in his six-month-old sister. High dose of vitamin D was not given to both siblings. Both of them also had hypophosphatemia and decreased tubular phosphate reabsorption. Intensive hydration, furosemide and oral phosphorus treatment were given. Bilateral medullary nephrocalcinosis was detected in both siblings and their father. Serum Ca and P levels were within normal limits at follow-up in both siblings. Siblings and their parents all carry a homozygous stop codon mutation (p.R466*) in CYP24A1. Interestingly, both siblings and the father also have a heterozygous splice-site mutation (IVS6(+1)G>A) in SLC34A1. The father has nephrocalcinosis.ConclusionsA biallelic loss-of-function mutation in the CYP24A1 gene was identified as responsible for hypercalcemia, hypercalciuria and nephrocalcinosis. In addition, a heterozygous mutation in the SLC34A1 gene, although not being the main pathogenic factor, might contribute to the severe phenotype of both patients.

scholarly journals A 5′-Splice Site Mutation in the Cytochrome P450 Steroid 17α-Hydroxylase Gene in 17α-Hydroxylase Deficiency

1997 ◽  
Vol 82 (6) ◽  
pp. 1934-1938
Author(s):  
Hideki Yamaguchi ◽  
Masamitsu Nakazato ◽  
Mikiya Miyazato ◽  
Kenji Kangawa ◽  
Shigeru Matsukura
Keyword(s):  
Cytochrome P450 ◽  
Splice Site ◽  
Splice Site Mutation ◽  
Site Mutation ◽  
Hydroxylase Deficiency ◽  
Hydroxylase Gene

scholarly journals Detecting RB1 gene mutations in retinoblastoma tumour of patients in Northern Vietnam in 2020

2021 ◽  
Vol 63 (9) ◽  
pp. 10-13
Author(s):  
Thi Phuong Le ◽  
◽  
Nguyen Ha Linh Dao ◽  
Minh Ngoc Nguyen ◽  
Huy Thinh Tran ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
Splice Site Mutation ◽  
Large Deletion ◽  
Site Mutation ◽  
Nonsense Mutations ◽  
Rb1 Gene ◽  
Cancer In Children ◽  
Inactivating Mutations

Retinoblastoma, a type of eye cancer in children, is mostly caused by inactivating mutations of both copies of the RB1gene. Early diagnosis and identification ofRB1 gene mutations would improve treatment outcomes and patients’ management. This study was performed on 10 tumour samples of retinoblastoma patients using the direct sequencing technique. 11 different mutations were found in 9 out of 10 tumour samples, including 6 nonsense mutations, 1 missense mutation, 1 splice site mutation, and 3 frameshift mutations with 1 novel mutation that has not been reported before. The MLPA method was required to identify large deletion mutations in the RB1gene and the study on more samples to provide a picture of RB1 gene mutations in Vietnamese retinoblastoma patients

scholarly journals Application of Biotechnology in Detection ATP7B Gene Mutation in Vietnamese Children with Wilson Disease and Screening Target Mutation for Their Family Members

2020 ◽  
Vol 4 (5) ◽  
Author(s):  
Mai Huong Nguyen ◽  
Pham Anh Hoa Nguyen ◽  
Diem Ngoc Ngo
Keyword(s):  
Gene Mutation ◽  
Direct Sequencing ◽  
Family Members ◽  
Gene Mutations ◽  
Copper Metabolism ◽  
Autosomal Recessive Disorder ◽  
Clinical Feature ◽  
Atp7b Gene ◽  
Exon 2 ◽  
P Type

Background/Purpose: Wilson’s disease (WD) is an autosomal recessive disorder of the copper metabolism, which is caused by a mutation in the copper-transporting P-type ATPase (ATP7B). The mechanism of this disease is the failure of hepatic excretion of copper to bile, and leads to copper deposits in the liver and other organs. The ATP7B gene is located on the long arm of chromosome 13 (13q14.3). This study aimed to investigate the gene mutation in the Vietnamese patients with WD, and make a asymptomatic diagnosis for their familial members. Methods: Forty-three WD patients and their 67 siblings were identified as having ATP7B gene mutations. Genomic DNA was extracted from peripheral blood samples; 21 exons and exon-intron boundaries of the ATP7B gene were analyzed by direct sequencing. Results: A total of 27 different mutations were detected in this study, which accounted for 96.8%. Of which, S105* was the most prevalent mutation, accounting for 37.1%. Following was the five other mutations, including I1148T (7.3%), IVS14-2A>G (6.6%), L1371P (6.0%), T850I and V176SfsX28 (5.3%). Among 47 genotypes, ratio of compound heterozygote was 62.8%. Most of the mutations in the study occurred in exon 2 (43.0%), exon 16 (9.9%), exon 8 (8.6%), exon 14 and intron 14 (6.6%). A total of 13 affected siblings were identified by target mutation on ATP7B gene which was identified in the proband. Among them, 5 cases were asymptomatic that would be treated soon to prevent clinical feature. This study also discoved 65 carriers in their family members. Conclusion: The findings’ highest diagnostic importance for patients and their family members is in prognosis and the prevention of morbidity and mortality.

Novel vitamin D 1α-hydroxylase gene mutations in a Chinese vitamin-D-dependent rickets type I patient

2011 ◽  
Vol 90 (2) ◽  
pp. 339-342 ◽  
Author(s):  
LIHUA CAO ◽  
FANG LIU ◽  
YU WANG ◽  
JIAN MA ◽  
SHUSEN WANG ◽  
...  
Keyword(s):  
Vitamin D ◽  
Gene Mutations ◽  
Type I ◽  
Hydroxylase Gene

scholarly journals Characterization of a Putative Founder Mutation that Accounts for the High Incidence of Cystinosis in Brittany

2001 ◽  
Vol 12 (10) ◽  
pp. 2170-2174
Author(s):  
VASILIKI KALATZIS ◽  
STÉPHANIE CHERQUI ◽  
GENEVIÈVE JEAN ◽  
BÉATRICE CORDIER ◽  
PIERRE COCHAT ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Founder Mutation ◽  
Pcr Amplification ◽  
Splice Site Mutation ◽  
Autosomal Recessive Disorder ◽  
Site Mutation ◽  
Live Births ◽  
Reverse Transcription Pcr ◽  
High Incidence

Abstract. Cystinosis is an autosomal recessive disorder, characterized by an accumulation of intralysosomal cystine, with an incidence of 1 in 100,000 to 200,000 live births. A higher incidence of cystinosis, 1 in 26,000 live births, has been reported in the western French province of Brittany. PCR amplification and sequencing has identified a 27-bp deletion starting 3 bp before the end of exon 8 and continuing into intron 8, 898-900+24del27, which has only been detected in families from this region. Reverse transcription—PCR amplification of RNA from an affected individual has shown that this mutation is indeed a splice-site mutation and results in the production of aberrant transcripts. These transcripts are predicted to either severely truncate cystinosin or alter its topology, thus accounting for the severe phenotype of these individuals. The mutation 898-900+24del27 has been identified in 7 of 18 alleles studied. This mutation is likely to be a founder mutation and would account for the higher incidence of cystinosis in Brittany.1

scholarly journals Prevalence of CYP17A1 gene mutations in 17α-hydroxylase deficiency in the Chinese Han population

2019 ◽  
Vol 25 (1) ◽  
Author(s):  
Menglin Wang ◽  
Hao Wang ◽  
Haiying Zhao ◽  
Ling Li ◽  
Min Liu ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Gene Mutations ◽  
Autosomal Recessive Disorder ◽  
Chinese Han ◽  
Hydroxylase Deficiency ◽  
Case Presentation ◽  
Chinese Populations ◽  
Pathogenic Variants ◽  
Cytochrome P450 Family ◽  
Chinese Girls

Abstract Background 17α-hydroxylase deficiency is a rare autosomal recessive disorder caused by mutations in the cytochrome P450 family 17 subfamily A member 1 gene. The major clinical presentation includes hypertension, hypokalemia, male pseudohermaphroditism and female gonadal dysplasia. Hundreds of pathogenic variants have been reported in this disorder, and some common mutations were found to be race-specific. Case presentation In this study, we reported 5 Chinese girls with 17α-hydroxylase deficiency from Henan Province. The patients all came to the hospital for hypertension, and they also presented with sexual infantilism. The average age of the patients was 14 years old, ranging from 12 to 17 years old. They all had reduced blood cortisol, estradiol (E2), and testosterone (TESTO) and increased adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). They all had the appearance of females; however, three of the chromosome karyotypes were 46XX, and two were 46XY. Conclusions All of the patients carried a mutation on the 329 amino acid of CYP17A1 exon 6. By summarizing the currently known pathogenic mutations of 17α-hydroxylase deficiency, we demonstrated the prevalence of these gene mutations in Chinese Han and non-Chinese populations.

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