scholarly journals A Single Base Insertion in F9 Causing Hemophilia B in a Family of Newfoundland–Parti Standard Poodle Hybrid Dogs

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1491
Author(s):  
Henrike Kuder ◽  
Liubov Sandzhieva-Vuzzo ◽  
Alexandra Kehl ◽  
Jonathan M. Rappaport ◽  
Elisabeth Müller ◽  
...  
Keyword(s):  
Stop Codon ◽  
Molecular Genetic ◽  
Genetic Defect ◽  
Clinical Manifestations ◽  
Premature Stop Codon ◽  
Factor Ix ◽  
Hemophilia B ◽  
Surgical Removal ◽  
Standard Poodle ◽  
Plasma Factor

Hemophilia B is an x-linked recessive hereditary coagulopathy that has been reported in various species. We describe a male Newfoundland–Parti Standard Poodle hybrid puppy and its family with hemophilia B from clinical manifestations to the molecular genetic defect. The index case presented for dyspnea was found to have a mediastinal hematoma, while surgical removal and transfusion support brought some relief, progressive hematoma formations led to humane euthanasia. Sequencing the F9 exons revealed a single nucleotide insertion resulting in a frameshift in the last exon (NM_001003323.2:c.821_822insA), predicted to result in a premature stop codon (NP_001003323.1:p.Asn274LysfsTer23) with a loss of 178 of 459 amino acids. The unexpected high residual plasma factor IX activity (3% to 11% of control) was likely erroneous, but no further studies were performed. Both the purebred Newfoundland dam and her sister were heterozygous for the insertion. Five additional male offspring developed severe hemorrhage and were hemizygous for the F9 variant and/or had a prolonged aPTT. In contrast, other male littermates had normal aPTTs and no evidence of bleeding. While they are related to a common Newfoundland granddam, the prevalence of the pathogenic variant in the Newfoundland breed is currently unknown. These clinical to molecular genetic studies illustrate that precision medicine is achievable in clinical companion animal practice.

Two Distinct Mutations Cause Severe Hemophilia B in Two Unrelated Canine Pedigrees

1999 ◽  
Vol 82 (10) ◽  
pp. 1270-1275 ◽  
Author(s):  
Weikuan Gu ◽  
James Catalfamo ◽  
Jharna Ray ◽  
Kunal Ray ◽  
Marjory Brooks
Keyword(s):  
Catalytic Domain ◽  
Stop Codon ◽  
Spontaneous Mutation ◽  
Mammalian Species ◽  
Donor Site ◽  
Splice Junction ◽  
Factor Ix ◽  
Hemophilia B ◽  
Acceptor Site ◽  
Plasma Factor

SummaryThe molecular defects causing severe factor IX deficiency were identified in two distinct canine breed-variants. Both defects were associated with an absence of plasma factor IX coagulant activity and antigen. A large deletion mutation was found in 1 breed variant, spanning the entire 5’ region of the factor IX gene extending to exon 6. An approximately 5 kb insertion disrupted exon 8 of the second breed-variant. This insertion was associated with alternative splicing between a donor site 5’ and acceptor site 3’ to the normal exon 8 splice junction, with introduction of a new stop codon. The resultant transcript lacked most of the factor IX catalytic domain and 3’ untranslated region. Molecular analyses of canine hemophilia B define an experimental model for study of inhibitor formation and gene therapy strategies, and provide insight into spontaneous mutation mechanisms in the factor IX gene and on the X chromosome of mammalian species.

Point Mutations in Four Hemophilia B Patients from China

1990 ◽  
Vol 64 (02) ◽  
pp. 302-306 ◽  
Author(s):  
N S Wang ◽  
S H Chen ◽  
A R Thompson
Keyword(s):  
Dna Sequences ◽  
Genomic Dna ◽  
Stop Codon ◽  
Direct Sequencing ◽  
Point Mutations ◽  
Factor Ix ◽  
Hemophilia B ◽  
Chinese Patients ◽  
Severe Hemophilia ◽  
Plasma Factor

SummaryPoint mutations in factor IX genes of four unrelated Chinese patients with hemophilia B have been identified by direct sequencing of amplified genomic DNA fragments. These four mutations occur in exon 8 of the factor IX gene. A C to T transition at nucleotide 30,863 changes codon 248 from Arg (CGA) to a new Stop codon (TGA), described in a previous family as factor IXMalmo3 (Green P M et al., EMBO J 1989; 8: 1067). A G to A transition, at nucleotide 31,051 changes codon 310 from Trp (TGG) to a nonsense or Stop codon (TGA; factor IXchongqing2)- A G to A transition at nucleotide 31,119 changes codon 333 which is for Arg (CGA) in normal factor IX, to one for Gin (CAA) in the variant previously described as factor IXLondon2 (Tsang T C et al., EMBO J 1988; 7: 3009) in a patient with moderately severe hemophilia B. The fourth patient has a novel C to A transversion at nucleotide 31,290, which corresponds to replacement of codon 390 which is for Ala (GCA) in normal factor IX, to one for Glu (GAA) in a patient with moderately severe hemophilia B (factor IXChongqing3)- DNA sequences of amplified fragments from mothers of three showed both their son’s variant and a normal nucleotide at the appropriate position, indicating that they are carriers. The fourth patient’s (factor IXMalmo3) mother, whose DNA was not evaluable, was most probably a carrier because of her low plasma factor IX levels.

scholarly journals A novel nonsense PTH1R variant shows incomplete penetrance of primary failure of eruption: a case report

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Cristina Grippaudo ◽  
Concetta Cafiero ◽  
Isabella D’Apolito ◽  
Agnese Re ◽  
Maurizio Genuardi ◽  
...  
Keyword(s):  
Stop Codon ◽  
Clinical Manifestations ◽  
Premature Stop Codon ◽  
Diagnostic Value ◽  
Open Bite ◽  
Incomplete Penetrance ◽  
Functional Protein ◽  
Case Presentation ◽  
Primary Failure Of Eruption ◽  
Buccal Swabs

Abstract Background Aim of this work was to describe a rare inheritance pattern of Primary Failure of Eruption (PFE) in a small family with incomplete penetrance of PFE and a novel nonsense PTH1R variant. Case presentation The proband, a 26 year-old man with a significant bilateral open-bite, was diagnosed with PFE using clinical and radiographic characteristics. DNA was extracted from the proband and his immediate family using buccal swabs and the entire PTH1R coding sequence was analyzed, revealing a novel heterozygous nonsense variant in exon 7 of PTH1R (c.505G > T). This variant introduces a premature stop codon in position 169, predicted to result in the production of a truncated and non-functional protein. This variant has never been reported in association with PFE and is not present in the Genome Aggregation Database (gnomAD). Interestingly, the c.505G > T variant has also been identified in the unaffected mother of our proband, suggesting incomplete penetrance of PFE. Conclusions In this study, we report a new PTH1R variant that segregates in an autosomal dominant pattern and causes PFE with incomplete penetrance. This underlines the diagnostic value of a thorough clinical and genetic analysis of all family members in order to estimate accurate recurrence risks, identify subtle clinical manifestations and provide proper management of PFE patients.

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

1998 ◽  
pp. 96-100 ◽  
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.

scholarly journals Christmas disease in a Hovawart family resembling human hemophilia B Leyden is caused by a single nucleotide deletion in a highly conserved transcription factor binding site of the F9 gene promoter

2018 ◽  
Author(s):  
Bertram Brenig ◽  
Lilith Steingräber ◽  
Shuwen Shan ◽  
Fangzheng Xu ◽  
Marc Hirschfeld ◽  
...  
Keyword(s):  
Coagulation Factor ◽  
Bleeding Disorder ◽  
Factor Ix ◽  
Hemophilia B ◽  
Start Codon ◽  
Luciferase Reporter ◽  
Single Nucleotide ◽  
Single Nucleotide Deletion ◽  
Nucleotide Deletion ◽  
Plasma Factor

Hemophilia B is a classical monogenic X-chromosomal recessively transmitted bleeding disorder caused by genetic variants within the coagulation factor IX gene (F9). Although hemophilia B has been described in 32 dog breeds hitherto, it has not yet been reported in the Hovawart. Here we describe the identification of a Hovawart family transmitting typical signs of an X-linked bleeding disorder. Five males had been reported to suffer from recurrent hemorrhagic episodes, four of them had to be euthanized finally and one died due to severe blood loss. A blood sample of one of these males with only 2% of the normal concentration of plasma factor IX (FIX) together with samples of seven relatives including the mother and grandmother were provided for further analysis. Next generation sequencing of DNA of the mother and grandmother revealed a single nucleotide deletion in the F9 promoter (NC_006621.3:g.109,501,492delC; CanFam3.1). Genotyping of the deletion in 1,298 dog specimens (83 different breeds) including 720 Hovawarts revealed that the mutation was only present in the aforementioned Hovawart family. The deletion is located 73 bp upstream of the F9 start codon in the highly conserved overlapping DNA binding sites of hepatocyte nuclear factor 4α (HNF4α) and androgen receptor (AR). The deletion only abolishes binding of HNF4α as demonstrated by electrophoretic mobility shift assay (EMSA) using purified recombinant human HNF4α and a transient overexpression lysate of human AR with double-stranded DNA probes encompassing the mutated promoter region. Luciferase reporter assays using wild type and mutated promoter fragment constructs transfected into Hep G2 cells showed a 65.3% reduction in expression of the mutated promoter. The data presented here provide evidence that the deletion identified in the Hovawart family caused a rare type of hemophilia B resembling human hemophilia B Leyden.

scholarly journals Factor IXAlabama: a point mutation in a clotting protein results in hemophilia B

Blood ◽  
1987 ◽  
Vol 69 (1) ◽  
pp. 140-143
Author(s):  
LM Davis ◽  
RA McGraw ◽  
JL Ware ◽  
HR Roberts ◽  
DW Stafford
Keyword(s):  
Point Mutation ◽  
Genetic Defect ◽  
Factor Ix ◽  
Hemophilia B ◽  
Single Amino Acid ◽  
Structural Protein ◽  
Coding Regions ◽  
Normal Gene ◽  
Clotting Protein ◽  
Single Base Pair

Factor IXAlabama is a variant factor IX molecule responsible for a clinically moderate form of hemophilia B. Twenty-five kilobases (kb) of the variant gene, including seven exons coding for the structural protein, were cloned and characterized. The restriction map and the arrangement of coding regions are identical to those of the normal gene. DNA sequence analysis of the coding regions revealed a single base-pair difference between the gene for factor IXAlabama and the normal factor IX gene. An adenine to guanine transition in the first nucleotide of exon d causes the substitution of a glycine codon (GGT) for the normal aspartic acid codon (GAT). This point mutation results in a single amino acid substitution at residue 47 of the zymogen and represents the genetic defect in factor IXAlabama.

scholarly journals LAD-1/variant syndrome is caused by mutations in FERMT3

Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4740-4746 ◽  
Author(s):  
Taco W. Kuijpers ◽  
Edith van de Vijver ◽  
Marian A. J. Weterman ◽  
Martin de Boer ◽  
Anton T. J. Tool ◽  
...  
Keyword(s):  
Stop Codon ◽  
Leukocyte Adhesion ◽  
Genetic Defect ◽  
Premature Stop Codon ◽  
Focal Adhesions ◽  
Splice Site Mutation ◽  
Homozygosity Mapping ◽  
Convincing Evidence ◽  
Chromosome 11 ◽  
Site Mutation

Abstract Leukocyte adhesion deficiency-1/variant (LAD1v) syndrome presents early in life and manifests by infections without pus formation in the presence of a leukocytosis combined with a Glanzmann-type bleeding disorder, resulting from a hematopoietic defect in integrin activation. In 7 consanguineous families, we previously established that this defect was not the result of defective Rap1 activation, as proposed by other investigators. In search of the genetic defect, we carried out homozygosity mapping in 3 of these patients, and a 13-Mb region on chromosome 11 was identified. All 7 LAD1v families share the same haplotype, in which 3 disease-associated sequence variants were identified: a putative splice site mutation in CALDAGGEF1 (encoding an exchange factor for Rap1), an intronic 1.8-kb deletion in NRXN2, and a premature stop codon (p.Arg509X) in FERMT3. Two other LAD1v patients were found to carry different stop codons in FERMT3 (p.Arg573X and p.Trp229X) and lacked the CALDAGGEF1 and NRXN2 mutations, providing convincing evidence that FERMT3 is the gene responsible for LAD1v. FERMT3 encodes kindlin-3 in hematopoietic cells, a protein present together with integrins in focal adhesions. Kindlin-3 protein expression was undetectable in the leukocytes and platelets of all patients tested. These results indicate that the LAD1v syndrome is caused by truncating mutations in FERMT3.

scholarly journals A clinical case of hereditary papillary thyroid carcinoma associated with a germline DICER1 gene mutation

2017 ◽  
Vol 63 (5) ◽  
pp. 320-324
Author(s):  
Svetlana A. Babinskaya ◽  
Natalia Yu. Kalinchenko ◽  
Alexey A. Ilyin ◽  
Natalia V. Severskaya ◽  
Irina V. Chebotareva ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Gene Mutation ◽  
Multinodular Goiter ◽  
Clinical Case ◽  
Stop Codon ◽  
Molecular Genetic ◽  
Premature Stop Codon ◽  
Papillary Thyroid ◽  
Reading Frame

Here, we report a clinical case of isolated papillary thyroid cancer associated with a germline DICER1 gene mutation in a boy and his father. The father underwent surgery for a euthyroid multinodular goiter at the age of 7 and 9 years. On examination at the age of 27 years, he was diagnosed with papillary thyroid cancer. At the age of 7 years, the boy was suspected of having a multinodular goiter (based on thyroid ultrasonography findings); he underwent total thyroidectomy. A histological examination of the surgical material revealed encapsulated papillary carcinoma. Neither boy nor his father had been exposed to radiation or chemotherapy before the diagnosis of papillary thyroid cancer. To clarify the etiology of disease, a molecular genetic testing was performed using next-generation sequencing (NGS). The proband and his parent had a heterozygous thymine deletion in the exon 4 at position 380, which led to a shift in the reading frame with the formation of a premature stop codon (c.380delT p.L127QfsX3).

A Homozygote Mutation in S-Antigen Visual Arrestin SAG Gene in an Iranian Patient with Oguchi Type One: A Case Report

2020 ◽  
Author(s):  
Hajar ARYAN ◽  
Atekeh BAHADORI ◽  
Dariush D. FARHUD ◽  
Marjan ZARIF YEGANEH ◽  
Haniyeh POURKALHOR
Keyword(s):  
Night Blindness ◽  
Stop Codon ◽  
Molecular Genetic ◽  
Premature Stop Codon ◽  
Molecular Evidence ◽  
Molecular Testing ◽  
Congenital Stationary Night Blindness ◽  
Full Field ◽  
Iranian Patient ◽  
Oguchi Disease

Oguchi disease is a rare autosomal recessive form of congenital stationary night blindness (CSNB) characterized by specific features such as golden-brown discoloration of the fundus called Mizuo-Nakamura phenomenon which is distinguishable by fundoscopy, and retinography. Clinical diagnosis is confirmed through genetic test. Two known genes in pathogenesis of Oguchi disease are SAG and GRK1. A 35-year-old Iranian male exhibiting the clinical features of congenital stationary night blindness, was referred to the genetic clinic of Dr. Farhud, Tehran, Iran in 2012 and examined. Ophthalmic examination including slit-lamp biomicroscopy, perimetry and funduscopy was performed. Additionally, the full-field electroretinography and molecular testing for congenital stationary night blindness were performed. Molecular genetic tests, including the analysis of GSK1 and SAG genes exon-intron boundaries were performed for this patient and his family. According to the sequencing results, we did not find any mutation in GSK1 gene. However, a new homozygote mutation at location chr2:233320735, c.517delC, p.P96LfsX28 was identified in exon four of SAG gene. This deletion causes a frame shift mutation, and premature stop codon that results in deletion of about 281 amino acid residues of S-antigen visual arrestin protein (from entire C-terminal). This mutation was also found in patient’s parents and one of his sister as heterozygote form. This is the first molecular evidence for SAG gene mutation in an Iranian family affected with Oguchi disease type 1. The identification of the new c.517delC, p.P96LfsX28 mutation in this family with Oguchi disease can confirm the pathogenicity of this variant.

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