Molecular analysis of the genotype-phenotype relationship in factor X deficiency

Millar, David; Elliston, Linda Anne; Deex, P.; Krawczak, Michael; Wacey, A. I.; Reynaud, J.; Nieuwenhuis, H. Karel; Bolton‐Maggs, Paula; Mannucci, P. M.; Reverter, Joan Carles; Cachia, P. G.; Pasi, K. J.; Layton, D. M.; Cooper, David Neil

doi:10.1007/s004390051035

Cited by 78 publications

(60 citation statements)

References 93 publications

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“…This paucity of nonsense mutations in the F7 mutational spectrum is highly unusual but mirrors the situation noted by Millar et al (2000) for the F10 gene. The ratio of nonsense to missense mutations is normally ~1:4 (Human Gene Mutation Database, http://www.uwcm.ac.uk/uwcm/ mg/hgmd0.html), suggesting that the DNA sequence architecture of the F7 gene might be responsible.…”

Section: Discussionmentioning

confidence: 84%

Molecular analysis of the genotype-phenotype relationship in factor VII deficiency

et al. 2000

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Factor VII (FVII) deficiency is a rare haemorrhagic condition, normally inherited as an autosomal recessive trait, in which clinical presentation is highly variable and correlates poorly with laboratory phenotype. The FVII (F7) gene was sequenced in 48 unrelated individuals with FVII deficiency, yielding a total of 23 novel lesions including 15 missense mutations, 2 micro-deletions, 5 splice junction mutations and a single base-pair substitution in the 5' untranslated region. Family studies were performed in order to distinguish the contributions of individual mutant F7 alleles to the clinical and laboratory phenotypes. Specific missense mutations were evaluated by molecular modelling in the context of the FVIIa-tissue factor crystal structure. Single base-pair substitutions in splice sites and the 5' untranslated region were studied by in vitro splicing assay and luciferase reporter gene assay, respectively. All probands were also typed for four previously reported F7 polymorphisms. In the majority of cases of FVII deficiency studied here, consideration of both mutational and polymorphism data permitted the derivation of plausible explanations for the FVII activity and antigen levels measured in the laboratory. Inter-familial variation in FVII activity and the antigen levels of heterozygous relatives of probands was found to be significantly higher than intra-familial variation, consistent with the view that the nature of the F7 gene lesion(s) segregating in a given family is a prime determinant of laboratory phenotype. Although no relationship could be discerned between laboratory phenotype and polymorphism genotype, the frequencies of the A2 and M2 polymorphic alleles were significantly higher in the FVII-deficient individuals tested than in controls. This suggests that the presence of these alleles may have served to increase the likelihood of pathological F7 gene lesions coming to clinical attention.

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Section: Discussionmentioning

confidence: 84%

Molecular analysis of the genotype-phenotype relationship in factor VII deficiency

et al. 2000

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“…It can be activated through either the contact-activated (intrinsic) pathway or the tissue-factor (extrinsic) pathway (23). F10 is composed of light and heavy chains held together by a disulfide bond (24) as well as synthesized in the liver as a single-chain molecule (25).…”

Section: Discussionmentioning

confidence: 99%

Association of gene polymorphisms with chronic kidney disease in Japanese individuals

Yamada¹

2009

Int J Mol Med

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Abstract. Chronic kidney disease (CKD) is recognized as a risk factor not only for end-stage renal disease but also for cardiovascular disease. Early detection and treatment of CKD is a likely key factor for prevention of its complications. Although genetic linkage analyses and association studies have implicated several loci and candidate genes in predisposition to CKD, the genes that underlie genetic susceptibility to this condition have remained largely unknown. The purpose of the present study was to identify genetic variants that confer susceptibility to CKD in Japanese individuals. The study population comprised 4,829 Japanese individuals (2,697 men, 2,132 women), including 757 subjects with CKD [464 men, 293 women; estimated glomerular filtration rate (eGFR) <50 ml min 1.73 m -2 ] and 4,072 controls (2,233 men, 1,839 women; eGFR ≥60 ml min 1.73 m -2 ). The genotypes for 40 polymorphisms of 39 candidate genes were determined. The chi-square test, multivariable logistic regression analysis with adjustment for covariates, as well as a stepwise forward selection procedure revealed that six polymorphisms of F10, PITRM1, PCSK2, JPH3, MYO7B, and AKAP12 were related (P<0.05) to the prevalence of CKD. Among these polymorphisms, the C→T polymorphism of F10 (rs5962) was most significantly associated with this condition. Determination of genotypes for the C→T polymorphism of F10 may prove informative for assessment of genetic risk for CKD in Japanese individuals.

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“…81 The Russell viper venom test is usually prolonged, although it can be normal in some variants. 53 A factor X assay is the definitive test, although it is important to compare results with normal levels for age and exclude vitamin K deficiency before confirming the diagnosis.…”

Section: Factor X Deficiencymentioning

confidence: 99%

Evaluating for Suspected Child Abuse: Conditions That Predispose to Bleeding

Carpenter¹,

Abshire²,

Anderst³

et al. 2013

Pediatrics

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Child abuse might be suspected when children present with cutaneous bruising, intracranial hemorrhage, or other manifestations of bleeding. In these cases, it is necessary to consider medical conditions that predispose to easy bleeding/bruising. When evaluating for the possibility of bleeding disorders and other conditions that predispose to hemorrhage, the pediatrician must consider the child’s presenting history, medical history, and physical examination findings before initiating a laboratory investigation. Many medical conditions can predispose to easy bleeding. Before ordering laboratory tests for a disease, it is useful to understand the biochemical basis and clinical presentation of the disorder, condition prevalence, and test characteristics. This technical report reviews the major medical conditions that predispose to bruising/bleeding and should be considered when evaluating for abusive injury.

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Molecular analysis of the genotype-phenotype relationship in factor X deficiency

Cited by 78 publications

References 93 publications

Molecular analysis of the genotype-phenotype relationship in factor VII deficiency

Molecular analysis of the genotype-phenotype relationship in factor VII deficiency

Association of gene polymorphisms with chronic kidney disease in Japanese individuals

Evaluating for Suspected Child Abuse: Conditions That Predispose to Bleeding

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