scholarly journals A de-novo large deletion of 2.8 kb produced in the ABCD1 gene causing adrenoleukodystrophy disease

2016 ◽  
Vol 94 (3) ◽  
pp. 265-269
Author(s):  
Fakhri Kallabi ◽  
Ghada Ben Salah ◽  
Amel Ben Chehida ◽  
Mouna Tabebi ◽  
Rahma Felhi ◽  
...  
Keyword(s):  
Long Range ◽  
De Novo ◽  
Neurodegenerative Disorder ◽  
Stop Codon ◽  
Direct Sequencing ◽  
Premature Stop Codon ◽  
Large Deletion ◽  
Exon 2 ◽  
Abcd1 Gene ◽  
Long Range Pcr

X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder caused by mutations in the ABCD1 gene, which encodes an ATP-binding cassette transporter protein, ALDP. The disease is characterized by increased concentrations of very long chain fatty acids (VLCFAs) in plasma, adrenal, testicular, and nerve tissues. For this study, our objective was to conduct clinical, molecular, and genetic studies of a Tunisian patient with X-ALD. The diagnosis was based on clinical indications, biochemical analyses, typical brain-scan patterns, and molecular biology; the molecular analyses were based on PCR, long-range PCR, and sequencing. The molecular analysis by long-range PCR and direct sequencing of the ABCD1 gene showed the presence of a de-novo 2794 bp deletion covering the whole of exon 2. Using bioinformatics tools, we demonstrate that the large deletion is located in a region rich with Alu sequences. Furthermore, we suggest that the AluJb sequence could be the cause of the large deletion of intron 1, exon 2, and intron 2, and the creation of a premature stop codon within exon 3. This report is the first report in which we demonstrate the breakpoints and the size of a large deletion in a Tunisian with X-ALD.

De Novo Mutated TUBB2B Associated Pachygyria Diagnosed by Medical Exome Sequencing and Long-Range PCR

2018 ◽  
Vol 38 (1) ◽  
pp. 63-71 ◽  
Author(s):  
Hui Wang ◽  
Shaoyuan Li ◽  
Shengli Li ◽  
Niping Jiang ◽  
Jimin Guo ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Long Range ◽  
De Novo ◽  
Long Range Pcr

Noval Mutation in Four Saudi Families with Glanzmann Thrombasthenia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1136-1136
Author(s):  
Tarek Owaidah ◽  
Hala Abalkhail ◽  
Abdulrahman Al Musa ◽  
Hasan Mosmali ◽  
Albanyan Abdulmajeed ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Stop Codon ◽  
Direct Sequencing ◽  
Family Members ◽  
Premature Stop Codon ◽  
Type I ◽  
Bleeding Tendency ◽  
Coding Region ◽  
Glanzmann Thrombasthenia ◽  
Exon 1

Abstract Abstract 1136 Introduction: Glanzmann thrombasthenia (GT) is a rare autosomal recessive inherited bleeding disorder characterized by an impaired platelet aggregation and variable bleeding tendency. Inherited genetic mutations in integrin alpha IIb and beta3 (ITGA2B, ITGB3) result in a heterogeneity of the thrombasthenia phenotypes. It is phenotypically expressed in homozygotes or compound heterozygotes, given that 50% of normal aIIbb3 is sufficient to guarantee unimpaired platelet function that result in asymptomatic carriers. Defects in ITGB3 result in failure of binding of B3 and alpha IIb. These defects had been reported in Arabs (Iraqi Jews). We are reporting some results of Saudi GT genotype project. Materials & Methods: In this study, we analyzed the entire coding region ITGB3 gene using polymerase chain reaction (PCR) and direct sequencing with primers specifically designed to amplify the coding region of exon 1–15 and exon /Intron boundaries in a cohort of 51 GT patients diagnosed and treated in our institute. Results: Out of 51 cases from 20 families had mutational screening of the ITGB3 gene with the aim to detect the causative pathogenic mutations to enable the pre-symptomatic diagnosis in at risk family members. In this study we detect 1 novel germline mutation c.2190delC (p.Ser703fs) in exon 13. The mutation is predicted to result in premature stop codon and protein truncation. The mutation was detected in 6 patients in homozygous stat (3 males and 3 females). Three tested samples from the patients family members detected the mutation in heterozygous state and all of them were asymptomatic with normal PFA and Intact expression of Platelet Glycoprotiens CD41(Gpllb), CD42a(GPIX), CD42b(GPlb), and CD61(Gpllla). All the GT patients with this mutation were type I GT with Prolonged PFA and complete absence of CD41(Gpllb) and CD61(Gpllla) glycoprotein. Conclusion: The result of this study represents the first Molecular analysis of ITGB3 gene in Saudi Arabia and displays the existence of novel pathogenic and possibly a founder effect in Saudi families. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Hereditary Multiple Exostoses: Clinical, Molecular and Radiologic Survey in 9 Families

2017 ◽  
Vol 118 (2-3) ◽  
pp. 87-94
Author(s):  
Karel Medek ◽  
Jiří Zeman ◽  
Tomáš Honzík ◽  
Hana Hansíková ◽  
Štěpánka Švecová ◽  
...  
Keyword(s):  
Malignant Transformation ◽  
De Novo ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Gene Mutations ◽  
Nonsense Mutations ◽  
Hereditary Multiple Exostoses ◽  
Multiple Exostoses ◽  
The Mean

Hereditary multiple exostoses (HME) represents a heterogeneous group of diseases often associated with progressive skeletal deformities. Most frequently, mutations inEXT1andEXT2genes with autosomal dominant inheritance are responsible for HME. In our group of 9 families with HME we evaluated the clinical course of the disease and analysed molecular background using Sanger sequencing and MLPA inEXT1andEXT2genes. The mean age in our group of patients, when the first exostosis was recognised was 4.5 years (range 2–10 years) and the number of exostoses per one patient documented on X-ray ranged from 2 to 54. Most of the exostoses developed before the growth was completed and they were dominantly localised in the distal femurs, proximal tibia, proximal humerus and distal radius. In all patients, at least one to 8 surgeries were necessary due to complaints and local complications, but neither patient developed malignant transformation. In half of the patients, the disease resulted in short stature. DNA analyses were positive in 7 families. In five probands, differentEXT1gene mutations resulting in premature stop-codon (p.Gly124Argfs*65, p.Leu191*, p.Trp364Lysfs*11, p.Val371Glyfs*10, p.Leu490Profs*31) were found. In two probands, nonsense mutations were found inEXT2gene (p.Val187Profs*115, p.Cys319fs*46). Five mutations have been novel and two mutations have occurredde novoin probands. Although the risk for malignant transformation is usually low, especially in patients with low number of exostoses, early diagnostics and longitudinal follow up of patients is of a big importance, because early surgery can prevent progression of secondary bone deformities.

scholarly journals A new mutation at exon 2 of hprt1 locus causing Lesch-Nyhan Syndrome.

2015 ◽  
Vol 3 (1) ◽  
pp. 18-21
Author(s):  
Adriana María Gil Zapata ◽  
Adriana Castillo Pico ◽  
Leonor Gusmão ◽  
António Amorim ◽  
Fernando Rodríguez Sanabria
Keyword(s):  
Genetic Counseling ◽  
Inborn Error ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Dna Fragments ◽  
Hprt Gene ◽  
New Mutation ◽  
Exon 2 ◽  
The Family ◽  
Hypoxanthine Guanine Phosphoribosyl Transferase

Introduction: Lesch-Nyhan síndrome (LNS) is an X-linked recessive inborn error of metabolism, due to deficiency of the enzyme Hypoxanthine-guanine-phosphoribosyl transferase (HGPRT; EC.2.4.2.8) resulting in hyperuricemia, neurological and behavioural disturbances. In the present work, we report the results of the study of a Colombian family, where LNS was previously clinically and biochemically diagnosed. Material and Methods: The full HPRT gene, including 9 exons and 8 introns, was amplified on eight separate DNA fragments. Both strands, forward and reverse, of the amplified DNA fragments were analyzed and the obtained sequences were compared with those deposited at National Center for Biotechnology Information. Results and conclusions: Sequence analysis allowed the detection of new LNS causing mutation, an adenine deletion in exon 2 of HPRT1 gene resulting in a frameshift which determines a premature stop codon. This study, besides adding a new mutation to the already large spectrum of disease causing variation at HPRT, allows therefore providing genetic counseling for the family as well as prenatal diagnosis.

scholarly journals 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 ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2810-2818 ◽  
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.

scholarly journals A de novo synonymous variant in EFTUD2 disrupts normal splicing and causes mandibulofacial dysostosis with microcephaly: case report

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Arthur Jacob ◽  
Jennifer Pasquier ◽  
Raphael Carapito ◽  
Frédéric Auradé ◽  
Anne Molitor ◽  
...  
Keyword(s):  
Splice Site ◽  
De Novo ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Genetic Alterations ◽  
Donor Splice Site ◽  
Donor Splice ◽  
First Case ◽  
Synonymous Variant ◽  
Mandibulofacial Dysostosis

Abstract Background Mandibulofacial dysostosis with microcephaly (MFDM) is a rare autosomal dominant genetic disease characterized by intellectual and growth retardations, as well as major microcephaly, induced by missense and splice site variants or microdeletions in the EFTUD2 gene. Case presentation Here, we investigate the case of a young girl with symptoms of MFDM and a normal karyotype. Whole-exome sequencing of the family was performed to identify genetic alterations responsible for this phenotype. We identified a de novo synonymous variant in the EFTUD2 gene. We demonstrated that this synonymous variant disrupts the donor splice-site in intron 9 resulting in the skipping of exon 9 and a frameshift that leads to a premature stop codon. Conclusions We present the first case of MFDM caused by a synonymous variant disrupting the donor splice site, leading to exon skipping.

GATA1 Mutations in Clonal Disorders of Children with and without Down Syndrome.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4314-4314
Author(s):  
Isis Q. Magalhaes ◽  
Alessandra Splendore ◽  
Mariana Emerenciano ◽  
Iris Ferrari ◽  
Maria S. Pombo-de-Oliveira
Keyword(s):  
Down Syndrome ◽  
Trisomy 21 ◽  
Genomic Dna ◽  
Stop Codon ◽  
Pediatric Population ◽  
Premature Stop Codon ◽  
Genetic Changes ◽  
Exon 2 ◽  
Gata1 Mutation ◽  
Proliferative Advantage

Abstract Down Syndrome (DS) children are 10–20 times folder likely to develop acute leukemia (AL) within the first four years of life compared to general pediatric population. Recently acquired somatic mutations in GATA1 gene on chromosome X have been described in most cases of DS AML and congenital TMD of DS carry the same type of mutations in exon 2 of GATA1. Here we report the preliminary results of GATA1 mutation in AL with and without DS children. The aim of this study is to provide insights in the relationships of GATA1 mutations and trisomy 21 in leukemogenesis process. GATA1 mutations were assayed in genomic DNA in 34 children with DS and AL, 2 with transient myeloproliferative disorder (TMD), 3 with myelodisplastic syndrome. Sequential sample including 2 pre-diagnosis in neonate period and 1 year before diagnosis were available in two children and 40 randomly selected DS children without known hematological disorder. A rare case of a non-DS neonate with TMD and clonal trisomy 21 were also examined. Genomic DNA was extracted and the exon 2 of GATA1 was PCR amplified as described by Wechsler et al. PCR products were sequenced in both directions and analyzed in a MegaBACE 1000 automated sequencer. Presently, GATA 1 mutations were found in 7 cases of AL, in all TMD cases with DS and none MDS case of DS. Interesting, a neonate girl with no phenotypic features of DS, but TMD features whose karyotype revealed 47, XX, +21/46, XX mosaics. A G-to-T transversion was detected which is predicted to result in a premature stop codon (c.119G>T; p.Glu67X) at the time of onset of TMD. However this same mutation was not detcted at 5 years of age.To our knowledge, this is the first reported case of TMD without DS with a detected GATA1 mutation. The presence of both somatically acquired abnormalities probably confers a proliferative advantage to the cell, resulting in TMD. We postulated in this case that both genetic abnormalities were temporary because of the non self-renewing nature of the progenitor that first had a non-disjunction event and this progenitor and the proliferative clone eventually disappeared. Therefore, even the proliferative advantage that the combination of trisomy 21 and GATA1 mutation confer, maintenance of these genetic changes are necessary for full leukemic transformation and persistence.

scholarly journals Adrenocorticotropin-Dependent Precocious Puberty of Testicular Origin in a Boy with X-Linked Adrenal Hypoplasia Congenita Due to a Novel Mutation in the DAX1 Gene

2001 ◽  
Vol 86 (9) ◽  
pp. 4068-4071 ◽  
Author(s):  
Sorahia Domenice ◽  
Ana Claudia Latronico ◽  
Vinicius Nahime Brito ◽  
Ivo Jorge Prado Arnhold ◽  
Fernando Kok ◽  
...  
Keyword(s):  
Adrenal Insufficiency ◽  
Precocious Puberty ◽  
Stop Codon ◽  
Novel Mutation ◽  
Direct Sequencing ◽  
Receptor Gene ◽  
Premature Stop Codon ◽  
Rare Condition ◽  
Coding Region ◽  
Primary Adrenal Insufficiency

Primary adrenal insufficiency is a rare condition in pediatric age, and its association with precocious sexual development is very uncommon. We report a 2-yr-old Brazilian boy with DAX1 gene mutation whose first clinical manifestation was isosexual gonadotropin-independent precocious puberty. He presented with pubic hair, enlarged penis and testes, and advanced bone age. T levels were elevated, whereas basal and GnRH-stimulated LH levels were compatible with a prepubertal pattern. Chronic GnRH agonist therapy did not reduce T levels, supporting the diagnosis of gonadotropin-independent precocious puberty. Testotoxicosis was ruled out after normal sequencing of exon 11 of the LH receptor gene. At age 3 yr he developed clinical and hormonal features of severe primary adrenal insufficiency. The entire coding region of the DAX1 gene was analyzed through direct sequencing. A nucleotide G insertion between nucleotides 430 and 431 in exon 1, resulting in a novel frameshift mutation and a premature stop codon at position 71 of DAX-1, was identified. Surprisingly, steroid replacement therapy induced a clear decrease in testicular size and T levels to the prepubertal range. These findings suggest that chronic excessive ACTH levels resulting from adrenal insufficiency may stimulate Leydig cells and lead to gonadotropin-independent precocious puberty in some boys with DAX1 gene mutations.

scholarly journals Repurposing tRNAs for nonsense suppression

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Suki Albers ◽  
Bertrand Beckert ◽  
Marco C. Matthies ◽  
Chandra Sekhar Mandava ◽  
Raphael Schuster ◽  
...  
Keyword(s):  
De Novo ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Nonsense Suppression ◽  
Potent Effect ◽  
Systematic Analysis ◽  
Stop Codons ◽  
Release Factors ◽  
A Site ◽  
Sense Codon

AbstractThree stop codons (UAA, UAG and UGA) terminate protein synthesis and are almost exclusively recognized by release factors. Here, we design de novo transfer RNAs (tRNAs) that efficiently decode UGA stop codons in Escherichia coli. The tRNA designs harness various functionally conserved aspects of sense-codon decoding tRNAs. Optimization within the TΨC-stem to stabilize binding to the elongation factor, displays the most potent effect in enhancing suppression activity. We determine the structure of the ribosome in a complex with the designed tRNA bound to a UGA stop codon in the A site at 2.9 Å resolution. In the context of the suppressor tRNA, the conformation of the UGA codon resembles that of a sense-codon rather than when canonical translation termination release factors are bound, suggesting conformational flexibility of the stop codons dependent on the nature of the A-site ligand. The systematic analysis, combined with structural insights, provides a rationale for targeted repurposing of tRNAs to correct devastating nonsense mutations that introduce a premature stop codon.

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