True Congenital Prothrombin Deficiency Due to a ‘New’ Mutation in the Pre-Propeptide (ARG-39 GLN)

Girolami, Antonio; Santarossa, Liliana; Scarparo, Pamela; Candeo, Nicole; Girolami, Bruno

doi:10.1159/000162281

Cited by 10 publications

(6 citation statements)

References 31 publications

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“…13 For an unclear reason, prothrombin mutations are more prevalent in patients from a Latin/Hispanic origin (Puerto Rico, Spain, France, etc.). 2,11 Prothrombin deficiency is classified into severe (when factor level <5%), moderate (factor level 5%-10%), and mild (factor level >10%). 1 In patients with severe deficiency, the condition is always associated with a significant bleeding tendency, usually with prolonged postinjury bleeding and subcutaneous and muscle hematomas.…”

Section: Discussionmentioning

confidence: 99%

“…Prothrombin (factor II) is a vitamin K–dependent glycoprotein encoded by a gene on chromosome 11p11‐q1212 in the centromere region, and it contains 14 coding exons 1,11 . Prothrombin is synthesized in the liver and is usually present in plasma at concentrations of 1 to 2 μM.…”

Section: Discussionmentioning

confidence: 99%

“…Prothrombin is synthesized in the liver and is usually present in plasma at concentrations of 1 to 2 μM. The protein contains five functional domains: the propeptide leader sequence, the γ ‐carboxyglutamic acid (Gla) domain, two Kringle areas, and the serine protease catalytic domain 11 . Prothrombin is activated by factor Xa in the presence of phospholipids, calcium, and factor Va to form active α‐thrombin, which cleaves fibrinogen into fibrin to form a blood clot.…”

Section: Discussionmentioning

confidence: 99%

“…For an unclear reason, prothrombin mutations are more prevalent in patients from a Latin/Hispanic origin (Puerto Rico, Spain, France, etc.) 2,11 . Prothrombin deficiency is classified into severe (when factor level <5%), moderate (factor level 5%‐10%), and mild (factor level >10%) 1 .…”

Section: Discussionmentioning

confidence: 99%

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A case of congenital prothrombin deficiency with two concurrent mutations in the prothrombin gene

Mansory¹,

Bhai²,

Stuart³

et al. 2021

Research and Practice in Thrombosis and Haemostasis

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Congenital prothrombin deficiency is an extremely rare, autosomal recessive bleeding disorder with a prevalence of 1 in 2 million individuals. Here, we report a case of congenital prothrombin deficiency with two concurrent mutations in the prothrombin gene (F2), affecting the heavy B chain. The patient presented with a history of multiple bleeding events in his youth that are mostly trauma associated, with a family history of prothrombin deficiency. Laboratory analysis showed a prolonged activated partial thromboplastin time and a prothrombin activity level of 5%. Genetic analysis of the F2 gene identified two heterozygous variants; one is a previously reported pathogenic deletion (c.1814_1815del; p.His605Argfs*13), and the other is a novel missense variant (c.1147C>T; p.Arg383Trp). In silico analysis predicted that p.Arg383Trp is likely to be disease causing, as it affects one of the anion‐binding exosites‐I of the B chain. This case highlights the significance of molecular findings in confirming the diagnosis of patients with congenital prothrombin deficiency.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

A case of congenital prothrombin deficiency with two concurrent mutations in the prothrombin gene

Mansory¹,

Bhai²,

Stuart³

et al. 2021

Research and Practice in Thrombosis and Haemostasis

View full text Add to dashboard Cite

show abstract

“…If we discovered a significant cis-eQTL for the gene of interest (that is, a locus on chromosome 6 with an LRS greater than or equal to the “significant LRS” genome-wide threshold), we then performed a second genome-wide association test for the trait of interest using GEMMA [82] with the following parameters: WGS-based marker genotypes, a minor allele frequency threshold of 0.05, and leave-one-chromosome-out (LOCO). By using both Haley-Knott regression and GEMMA, we could first discover loci that exceeded a genome-wide LRS threshold, and then more precisely estimate the effect of those loci on gene expression [83].…”

Section: Methodsmentioning

confidence: 99%

Epistasis between mutator alleles contributes to germline mutation spectra variability in laboratory mice

Sasani

Quinlan

Harris

2023

Preprint

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Maintaining germline genome integrity is essential and enormously complex. Hundreds of proteins are involved in DNA replication and proofreading, and hundreds more are mobilized to repair DNA damage. While loss-of-function mutations in any of the genes encoding these proteins might lead to elevated mutation rates, mutator alleles have largely eluded detection in mammals. DNA replication and repair proteins often recognize particular sequence motifs or excise lesions at specific nucleotides. Thus, we might expect that the spectrum of de novo mutations - that is, the frequency of each individual mutation type (C>T, A>G, etc.) - will differ between genomes that harbor either a mutator or wild-type allele at a given locus. Previously, we used quantitative trait locus mapping to discover candidate mutator alleles in the DNA repair gene Mutyh that increased the C>A germline mutation rate in a family of inbred mice known as the BXDs. In this study we developed a new method, called "inter-haplotype distance," to detect alleles associated with mutation spectrum variation. By applying this approach to mutation data from the BXDs, we confirmed the presence of the germline mutator locus near Mutyh and discovered an additional C>A mutator locus on chromosome 6 that overlaps Ogg1 and Mbd4, two DNA glycosylases involved in base-excision repair. The effect of a chromosome 6 mutator allele depended on the presence of a mutator allele near Mutyh, and BXDs with mutator alleles at both loci had even greater numbers of C>A mutations than those with mutator alleles at either locus alone. Our new methods for analyzing mutation spectra reveal evidence of epistasis between germline mutator alleles, and may be applicable to mutation data from humans and other model organisms.

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Factor II

Astermark

2014

Textbook of Hemophilia

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True Congenital Prothrombin Deficiency Due to a ‘New’ Mutation in the Pre-Propeptide (ARG-39 GLN)

Cited by 10 publications

References 31 publications

A case of congenital prothrombin deficiency with two concurrent mutations in the prothrombin gene

A case of congenital prothrombin deficiency with two concurrent mutations in the prothrombin gene

Epistasis between mutator alleles contributes to germline mutation spectra variability in laboratory mice

Factor II

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