Identification of a novel frameshift mutation causing a premature stop codon in a young Nigerian man with type I antithrombin deficiency

SummaryNonsense mutations, deletions and splice site mutations are a common cause of type I protein C deficiency. Either directly or indirectly by altering the reading frame, these' lesions generate or may generate premature stop codons and could therefore be expected to result in premature termination of translation. In this study, the possibility that such mutations could instead exert their pathological effects at an earlier stage in the expression pathway, through “allelic exclusion” at the RNA level, was investigated. Protein C (PROC) mRNA was analysed in seven Spanish type I protein C deficient patients heterozygous for two nonsense mutations, a 7bp deletion, a 2bp insertion and three splice site mutations. Ectopic RNA transcripts from patient and control lymphocytes were analysed by RT-PCR and direct sequencing of amplified PROC cDNA fragments. The nonsense mutations and the deletion were absent from the cDNAs indicating that only mRNA derived from the normal allele had been expressed. Similarly for the splice site mutations, only normal PROC cDNAs were obtained. In one case, exclusion of the mutated allele could be confirmed by polymorphism analysis. In contrast to these six mutations, the 2 bp insertion was not associated with loss of mRNA from the mutated allele. In this case, cDNA analysis revealed the absence of 19 bases from the PROC mRNA consistent with the generation and utilization of a cryptic splice site 3’ to the site of mutation, which would result in a frameshift and a premature stop codon. It is concluded that allelic exclusion is a common causative mechanism in those cases of type I protein C deficiency which result from mutations that introduce premature stop codons

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Aminoglycoside-Induced Premature Stop Codon Read-Through of Mucopolysaccharidosis Type I Patient Q70X and W402X Mutations in Cultured Cells

JIMD Reports - JIMD Reports - Case and Research Reports, Volume 13 ◽

10.1007/8904_2013_270 ◽

2013 ◽

pp. 139-147 ◽

Cited By ~ 14

Author(s):

Makoto Kamei ◽

Karissa Kasperski ◽

Maria Fuller ◽

Emma J. Parkinson-Lawrence ◽

Litsa Karageorgos ◽

...

Keyword(s):

Cultured Cells ◽

Stop Codon ◽

Premature Stop Codon ◽

Type I ◽

Mucopolysaccharidosis Type ◽

Mucopolysaccharidosis Type I

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

Thrombosis and Haemostasis ◽

10.1160/th11-09-0671 ◽

2012 ◽

Vol 107 (04) ◽

pp. 673-680 ◽

Cited By ~ 11

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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A Novel Frameshift Mutation of SCNN1G Causing Liddle Syndrome with Normokalemia

American Journal of Hypertension ◽

10.1093/ajh/hpz053 ◽

2019 ◽

Vol 32 (8) ◽

pp. 752-758

Author(s):

Peng Fan ◽

Yu-Mo Zhao ◽

Di Zhang ◽

Ying Liao ◽

Kun-Qi Yang ◽

...

Keyword(s):

Genetic Testing ◽

Frameshift Mutation ◽

Stop Codon ◽

Single Gene ◽

Family Members ◽

Premature Stop Codon ◽

Chinese Family ◽

Autosomal Dominant Disorder ◽

Liddle Syndrome ◽

Genetic Sequencing

Abstract BACKGROUND Liddle syndrome (LS) is an autosomal dominant disorder caused by single-gene mutations of the epithelial sodium channel (ENaC). It is characterized by early-onset hypertension, spontaneous hypokalemia and low plasma renin and aldosterone concentrations. In this study, we reported an LS pedigree with normokalemia resulting from a novel SCNN1G frameshift mutation. METHODS Peripheral blood samples were collected from the proband and eight family members for DNA extraction. Next-generation sequencing and Sanger sequencing were performed to identify the SCNN1G mutation. Clinical examinations were used to comprehensively evaluate the phenotypes of two patients. RESULTS Genetic analysis identified a novel SCNN1G frameshift mutation, p.Arg586Valfs*598, in the proband with LS. This heterozygous frameshift mutation generated a premature stop codon and deleted the vital PY motif of ENaC. The same mutation was present in his elder brother with LS, and his mother without any LS symptoms. Biochemical examination showed normokalemia in the three mutation carriers. The mutation identified was not found in any other family members, 100 hypertensives, or 100 healthy controls. CONCLUSIONS Our study identified a novel SCNN1G frameshift mutation in a Chinese family with LS, expanding the genetic spectrum of SCNN1G. Genetic testing helped us identify LS with a pathogenic mutation when the genotypes and phenotype were not completely consistent because of the hypokalemia. This case emphasizes that once a proband is diagnosed with LS by genetic testing, family genetic sequencing is necessary for early diagnosis and intervention for other family members, to protect against severe cardiovascular complications.

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Noval Mutation in Four Saudi Families with Glanzmann Thrombasthenia

Blood ◽

10.1182/blood.v118.21.1136.1136 ◽

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.

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Molecular genetic study in two patients with congenital hypoaldosteronism (types I and II) in relation to previously published hormonal studies

Acta Endocrinologica ◽

10.1530/eje.0.1390096 ◽

1998 ◽

pp. 96-100 ◽

Cited By ~ 14

Author(s):

M Peter ◽

K Bunger ◽

SL Drop ◽

WG Sippell

Keyword(s):

Genetic Study ◽

Stop Codon ◽

Molecular Genetic ◽

Premature Stop Codon ◽

Type I ◽

Type Ii ◽

Loss Of Function ◽

Molecular Genetic Study ◽

Base Exchange ◽

Deficiency Type

We performed a molecular genetic study in two patients with congenital hypoaldosteronism. An original study of these patients was published in this Journal in 1982. Both index cases, a girl (patient 1) and a boy (patient 2). presented with salt-wasting and failure to thrive in the neonatal period. Parents of patient 1 were not related, whereas the parents of patient 2 were cousins. Endocrine studies had shown a defect in 18-oxidation of 18-OH-corticosterone in patient 1 and a defect in the 18-hydroxylation of corticosterone in patient 2. Plasma aldosterone was decreased in both patients, whereas 18-OH-corticosterone was elevated in patient 1 and decreased in patient 2. Plasma corticosterone and 11-deoxycorticosterone were elevated in both patients, whereas cortisol and its precursors were in the normal range. According to the nomenclature proposed by Ulick, the defects are termed corticosterone methyl oxidase (CMO) deficiency type II in patient 1, and type I in patient 2 respectively. Genetic defects in the gene CYP11B2 encoding aldosterone synthase have been described in a few cases. In patient 1, we identified only one heterozygous amino acid substitution (V386A) in exon 7, which has no deleterious effect on the enzyme activity. In patient 2 and his older brother, we identified a homozygous single base exchange (G to T) in codon 255 (GAG), causing a premature stop codon E255X (TAG). The mutant enzyme has lost the five terminal exons containing the haem binding site, and is thus a loss of function enzyme. This is only the second report of a patient with CMO deficiency type II without a mutation in the exons and exon-intron boundaries, whereas the biochemical phenotype of the two brothers with CMO deficiency type I can be explained by the patient's genotype.

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A novel frameshift mutation leading to inherited type I antithrombin deficiency

Blood Coagulation & Fibrinolysis ◽

10.1097/mbc.0000000000000555 ◽

2016 ◽

pp. 1

Author(s):

Saaya Mori ◽

Jun Yamanouchi ◽

Koji Okamoto ◽

Takaaki Hato ◽

Masaki Yasukawa

Keyword(s):

Frameshift Mutation ◽

Type I ◽

Antithrombin Deficiency

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Truncating Mutation in FOXC2 Gene in Familial Hemorrhoids and Varicose Veins

International Journal of Biology and Biomedical Engineering ◽

10.46300/91011.2020.14.5 ◽

2020 ◽

Vol 14 ◽

Keyword(s):

Frameshift Mutation ◽

Stop Codon ◽

Varicose Veins ◽

Premature Stop Codon ◽

Genetic Mutations ◽

Physiological Factors ◽

Vascular Integrity ◽

Truncating Mutation ◽

Two Samples

Hemorrhoids and varicose veins are conditions resulting from loss of vascular integrity and, despite being worldwide health concerns, their pathogenesis has not been clearly defined. Many risk factors have been linked to the development of these complications including diet, defecating habits, alcohol consumption and other physiological factors. There are limited studies involving the possible role of genetic mutations in the development of hemorrhoids and varicose veins. FoxC2 is an important transcription factor that plays many roles in a variety of embryonic developmental processes, including angiogenesis. In the current study, we aimed to investigate the role of the FOXC2 gene variations in the development of familial hemorrhoids and varicose veins in the Jordanian population. Thirty-two samples were collected from eight families manifested hemorrhoids and/or varicose veins conditions. DNA sequencing was performed to screen variation in the FOXC2 gene. Two individuals with severe and early onset of hemorrhoids and varicose veins from the same family showed a frameshift mutation (881'inT) in the coding exon of the FOXC2 gene resulting in a premature stop codon at position +1386 (294 residues truncated peptide). In conclusion, our results support a possible role of genetic predisposition in the development of hemorrhoids and varicose veins with a frequency of 6% in the selected population

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A novel homozygous frameshift mutation in the FUCA1 gene causes both severe and mild fucosidosis

Journal of Clinical Pathology ◽

10.1136/jclinpath-2018-205074 ◽

2018 ◽

Vol 71 (9) ◽

pp. 821-824 ◽

Cited By ~ 1

Author(s):

Nasrollah Saleh-Gohari ◽

Kolsoum Saeidi ◽

Roya Zeighaminejad

Keyword(s):

Next Generation Sequencing ◽

Frameshift Mutation ◽

Stop Codon ◽

Premature Stop Codon ◽

Gene Mutations ◽

Next Generation ◽

Lysosomal Storage ◽

Illumina Hiseq ◽

Almost All ◽

Generation Sequencing

AimsFucosidosis is a rare autosomal recessive lysosomal storage disorder caused by α-L-fucosidase deficiency as a result of FUCA1 gene mutations. Here, we studied clinical features and the molecular basis of fucosidosis in a family from Iran, including two probands and nine family members.MethodsDNA sample of two probands were screened for gene defects using a next generation sequencing technique. The sequencing processes were performed on an Illumina Hiseq 4000 platform. Sequence reads were analysed using BWA-GATK.ResultsNext generation sequencing revealed a frameshift mutation caused by 2 bp deletion (c.837_838 delTG; p.Cys279) in the FUCA1 gene. The identified mutation was tested in all participants. Homozygous patients had almost all the complications associated with fucosidosis, while heterozygous carriers were unaffected.ConclusionsThe variant c.837_838 delTG; p.Cys279 has not been reported previously and is predicted to be pathogenic due to a premature stop codon.

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