Mutations of ATP7B gene in two Thai siblings with Wilson disease

Abstract Background: Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by mutations in ATP7B gene. Objective: Report the clinical data and mutation analysis of two Thai siblings suspected of WD. Subject and methods: A 13-year-old boy who presented with cirrhosis, arthralgia, hypoalbuminemia, and coagulopathy, and his 11-year-old sister who was asymptomatic but had hepatomegaly with elevation of transaminases, were studied. Mutation analysis of ATP7B gene and mRNA analysis was performed in both patients and their parents. Results: Investigations were consistent with WD, and their liver diseases improved after standard treatment for WD. DNA analyses in these two patients revealed two novel mutations, which were a deletion of the first 2bp of exon 6 (c.1870_1871delGA), and a single base substitution from A to G at nucleotide 4075 (c.4075A>G) in the exon 20 (p.M1359V). PCR-restriction digestion with NcoI restriction enzyme was employed as the second method for confirmation of the c.4075A>G mutation and for rapid screening in 100 chromosomes from unrelated healthy controls, and this variant was not present in the controls. The c.1870_1871delGA deletion caused a frameshift effect, which results in a premature stop codon (p.E624fsX753), and the p.M1359V mutation is a substitution of methionine with valine, which may have effects upon its orientation and interaction with other adjacent amino acids. Conclusion: Two novel mutations of ATP7B gene were identified in two Thai siblings with WD.

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Mutation analysis of ATP7B gene in Turkish Wilson disease patients: Identification of five novel mutations

European Journal of Medical Genetics ◽

10.1016/j.ejmg.2013.01.003 ◽

2013 ◽

Vol 56 (4) ◽

pp. 175-179 ◽

Cited By ~ 9

Author(s):

Ozlenen Simsek Papur ◽

Sezin Asik Akman ◽

Raif Cakmur ◽

Orhan Terzioglu

Keyword(s):

Mutation Analysis ◽

Wilson Disease ◽

Atp7b Gene ◽

Novel Mutations

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Mutation analysis of Wilson disease in the Spanish population - identification of a prevalent substitution and eight novel mutations in the ATP7B gene

Clinical Genetics ◽

10.1111/j.1399-0004.2005.00439.x ◽

2005 ◽

Vol 68 (1) ◽

pp. 61-68 ◽

Cited By ~ 58

Author(s):

E Margarit ◽

V Bach ◽

D Gómez ◽

M Bruguera ◽

P Jara ◽

...

Keyword(s):

Mutation Analysis ◽

Wilson Disease ◽

Spanish Population ◽

Atp7b Gene ◽

Novel Mutations

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Mutational analysis of ATP7B gene in Egyptian children with Wilson disease: 12 novel mutations

Journal of Human Genetics ◽

10.1007/s10038-008-0298-7 ◽

2008 ◽

Vol 53 (8) ◽

pp. 681-687 ◽

Cited By ~ 29

Author(s):

Tawhida Y. Abdelghaffar ◽

Solaf M. Elsayed ◽

Ezzat Elsobky ◽

Bettina Bochow ◽

Janine Büttner ◽

...

Keyword(s):

Wilson Disease ◽

Mutational Analysis ◽

Atp7b Gene ◽

Novel Mutations ◽

Egyptian Children

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A G-to-A mutation in IVS-3 of the human gamma fibrinogen gene causing afibrinogenemia due to abnormal RNA splicing

Blood ◽

10.1182/blood.v96.7.2501 ◽

2000 ◽

Vol 96 (7) ◽

pp. 2501-2505 ◽

Cited By ~ 22

Author(s):

Maurizio Margaglione ◽

Rosa Santacroce ◽

Donatella Colaizzo ◽

Davide Seripa ◽

Gennaro Vecchione ◽

...

Keyword(s):

Amino Acid ◽

Rna Splicing ◽

Messenger Rna ◽

Stop Codon ◽

Premature Stop Codon ◽

Autosomal Recessive Disorder ◽

Chain Gene ◽

Hemorrhagic Diathesis ◽

Reading Frame ◽

Congenital Afibrinogenemia

Abstract Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by a hemorrhagic diathesis of variable severity. Although more than 100 families with this disorder have been described, genetic defects have been characterized in few cases. An investigation of a young propositus, offspring of a consanguineous marriage, with undetectable levels of functional and quantitative fibrinogen, was conducted. Sequence analysis of the fibrinogen genes showed a homozygous G-to-A mutation at the fifth nucleotide (nt 2395) of the third intervening sequence (IVS) of the γ-chain gene. Her first-degree relatives, who had approximately half the normal fibrinogen values and showed concordance between functional and immunologic levels, were heterozygtes. The G-to-A change predicts the disappearance of a donor splice site. After transfection with a construct, containing either the wild-type or the mutated sequence, cells with the mutant construct showed an aberrant messenger RNA (mRNA), consistent with skipping of exon 3, but not the expected mRNA. Sequencing of the abnormal mRNA showed the complete absence of exon 3. Skipping of exon 3 predicts the deletion of amino acid sequence from residue 16 to residue 75 and shifting of reading frame at amino acid 76 with a premature stop codon within exon 4 at position 77. Thus, the truncated γ-chain gene product would not interact with other chains to form the mature fibrinogen molecule. The current findings show that mutations within highly conserved IVS regions of fibrinogen genes could affect the efficiency of normal splicing, giving rise to congenital afibrinogenemia.

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Mutation analysis in patients with Wilson disease: Identification of 4 novel mutations

Human Mutation ◽

10.1002/(sici)1098-1004(1999)14:1<88::aid-humu15>3.0.co;2-h ◽

1999 ◽

Vol 14 (1) ◽

pp. 88-88 ◽

Cited By ~ 12

Author(s):

Regina Haas ◽

Bertha Gutierrez-Rivero ◽

Judith Knoche ◽

Klaus B�ker ◽

Michael P. Manns ◽

...

Keyword(s):

Mutation Analysis ◽

Wilson Disease ◽

Novel Mutations ◽

Disease Identification

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Molecular basis and clinical presentation of classic galactosemia in a Croatian population

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2017-0302 ◽

2018 ◽

Vol 31 (1) ◽

pp. 71-75 ◽

Cited By ~ 2

Author(s):

Danijela Petković Ramadža ◽

Vladimir Sarnavka ◽

Jurica Vuković ◽

Ksenija Fumić ◽

Vjekoslav Krželj ◽

...

Keyword(s):

Stop Codon ◽

Premature Stop Codon ◽

Dietary Treatment ◽

Autosomal Recessive Disorder ◽

Neurological Complications ◽

Galactose Metabolism ◽

Classic Galactosemia ◽

Number Of Patients ◽

Direct Sequence Analysis ◽

Single Allele

AbstractBackground:Classic galactosemia is an autosomal recessive disorder of galactose metabolism caused by severely decreased activity of galactose-1-phosphate uridylyltransferase (GALT) due to pathogenic mutations in theGALTgene. To date more than 330 mutations have been described, with p.Q188R and p.K285N being the most common in Caucasian populations. Although acute manifestations can be fully avoided by a galactose-restricted diet, chronic complications, such as neurological ones, cannot be prevented in a significant number of patients despite compliance with the dietary treatment.Methods:A cohort of 16 galactosemic Croatian patients, including one pair of siblings, was studied. Molecular characterization was performed by direct sequence analysis of theGALTgene.Results:Sixteen patients were analyzed and only four different mutations were detected. As expected, p.Q188R and p.K285N were common, accounting for 40% and 37% of unrelated alleles, respectively. The third mutation accounting for 20% of mutant alleles was p.R123X causing a premature stop codon, is thus considered to be severe, which is in accordance with the phenotype presented by the homozygous patient described here. The fourth mutation p.E271D was found in a single allele. More than half of our patients manifested some chronic neurological complications.Conclusions:This is the first report on mutational and phenotypic spectra of classic galactosemia in Croatia that expands the knowledge on the mutational map of theGALTgene across Europe and reveals the genetic homogeneity of the Croatian population.

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Band 3 Campinas: A Novel Splicing Mutation in the Band 3 Gene (AE1 ) Associated With Hereditary Spherocytosis, Hyperactivity of Na+/Li+ Countertransport and an Abnormal Renal Bicarbonate Handling

Blood ◽

10.1182/blood.v90.7.2810 ◽

1997 ◽

Vol 90 (7) ◽

pp. 2810-2818 ◽

Cited By ~ 18

Author(s):

Paulo R.M. Lima ◽

José A.R. Gontijo ◽

José B. Lopes de Faria ◽

Fernando F. Costa ◽

Sara T.O. Saad

Keyword(s):

Hereditary Spherocytosis ◽

Stop Codon ◽

Collecting Duct ◽

Direct Sequencing ◽

Donor Site ◽

Premature Stop Codon ◽

Band 3 ◽

Base Substitution ◽

Molecular Defect ◽

Urinary Acidification

Abstract We have studied the molecular defect underlying band 3 deficiency in one family with hereditary spherocytosis using nonradioactive single strand conformation polimorphism of polymerase chain reaction (PCR) amplified genomic DNA of the AE1 gene. By direct sequencing, a single base substitution in the splicing donor site of intron 8 (position + 1G → T) was identified. The study of the cDNA showed a skipping of exon 8. This exon skipping event is responsible for a frameshift leading to a premature stop codon 13 amino acids downstream. The distal urinary acidification test by furosemide was performed to verify the consequences of the band 3 deficiency in α intercalated cortical collecting duct cells (αICCDC). We found an increased basal urinary bicarbonate excretion, associated with an increased basal urinary pH and an efficient distal urinary acidification. We also tested the consequences of band 3 deficiency on the Na+/H+ exchanger, by the measurement of Na+/Li+ countertransport activity in red blood cells. The Na+/Li+ countertransport activity was increased threefold to sixfold in the patients compared with the controls. It is possible that band 3 deficiency in the kidney leads to a decrease in the reabsorption of HCO−3 in αICCDC and anion loss, which might be associated with an increased sodium-lithium countertransport activity.

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