Molecular analysis of multiple genetic variants in Spanish FXII-deficient families

Mordillo, Carolina; Martínez-Marchán, Elisabeth; Fontcuberta, Jordi; Soria, José Manuel Nieto

doi:10.3324/haematol.11388

Cited by 7 publications

(6 citation statements)

References 16 publications

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“…They are detected by chance through a prolonged activated partial thromboplastin time (APTT). Several cases in the literature show bleeding, thrombosis or spontaneous abortion [9,10]. Hereby, the variable clinical phenotype of FXII deficiency is observed.…”

Section: Introductionmentioning

confidence: 98%

Identification of Genetic Defects Underlying FXII Deficiency in Four Unrelated Chinese Patients

et al. 2016

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Congenital factor XII (FXII) deﬁciency is a rare autosomal recessive disorder, characterized by a great variability in its clinical manifestations. In this study, we screened for mutations in the F12 gene of 4 unrelated patients with FXII coagulant activity <10% of that of normal human plasma. To investigate the molecular defects in these FXII-deficient patients, we performed FXII mutation screening. By sequencing all coding exons as well as flanking intronic regions of the F12 gene, 6 different mutations, including 3 missense mutations (Gly341Arg, Glu502Lys and Gly542 Ser), 1 insertion (7142insertC) and 2 deletions (5741-5742 delCA and 6753-6755delACA), were identiﬁed on the F12 gene. Three of them (Gly341Arg, 5741-5742delCA and 6753-6755delACA) are reported here for the first time. Computer-based algorithms predicted these missense mutations to be deleterious. This study has increased our knowledge of the mutational spectrum underlying FXII deficiency.

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Section: Introductionmentioning

confidence: 98%

Identification of Genetic Defects Underlying FXII Deficiency in Four Unrelated Chinese Patients

et al. 2016

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“…In addition, she was homozygous for the T allele at the 46C/T polymorphism, both in the F12 gene. Familiar segregation of the different allelic variants in the family was described in [13]. Patient 2 was heterozygous for the – 13C/T mutation and was also heterozygous for the 46C/T polymorphism.…”

Section: Resultsmentioning

confidence: 99%

“…We recruited also her 2 sisters, who were 60 and 51 years old, a 32 year old daughter, and 2 nieces 25 and 15 years of age respectively. No consanguinity was reported [13]. Patient 2 was a 6 year old girl with FXII deficiency (22% level).…”

Section: Design and Methodsmentioning

confidence: 99%

“…We analyzed the whole F12 gene (including the promoter, exons, introns and the 3′-UTR) by PCR and direct sequencing of 4 overlapping fragments as previously described [13]. Numbering refers to +1 position corresponding to the initiation of transcription, i.e, 49bp prior to the ATG codon.…”

Section: Design and Methodsmentioning

confidence: 99%

“…Our study examined the functional effect of two naturally-occurring mutations, located in a putative HNF4 binding site of the F12 promoter region in 2 subjects with FXII deficiency. One is a C/G substitution at position – 8 identified in a homozygous patient with severe FXII deficiency (<1%) [13], and another is a C/T substitution located at position – 13, located in a heterozygous 6-year old girl with mild FXII deficiency (22%) without any personal or familiar history of thrombotic disease. Both mutations have also been described in asymptomatic patients with congenital factor XII deficiency from Northern Italy [14].…”

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confidence: 99%

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Combined cis-regulator elements as important mechanism affecting FXII plasma levels

Sabater‐Lleal

Chillón

Mordillo

et al. 2010

Thrombosis Research

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Genetic analysis of a novel missense mutation (Gly542Ser) with factor XII deficiency in a Chinese patient of consanguineous marriage

et al. 2018

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Coagulation factor XII deficiency is a rare autosomal recessive disorder, which could be found in a consanguineous family. We studied a Chinese family in which the activated partial thromboplastin time (APTT) of the proband had clearly prolonged up to 101.7 s, associated with low FXII activity of 3% and FXII antigen < 1%. To analyze the gene mutation in this FXII-deficient patient, we performed FXII mutation screening, and analyzed the DNA sequence of the F12 gene. A ClustalX-2.1-win and four online bioinformatics software services were used to study the conservatism and effects of the mutation. A transient in vitro expression study was performed to elucidate the possible pathological mechanism. Sequence analysis revealed a homozygous c.1681 G > A point mutation in exon 14, causing a novel Gly542Ser mutation in the catalytic domain. The results of the conservatism and bioinformatics analyses both indicated that the mutation likely affects the function of the protein. Additional expression studies in COS-7 cells showed that the antigen level of mutant FXII (FXII-Gly542Ser) was lower than wild type in culture medium, whereas the corresponding level of FXII antigen in cell lysates was equivalent. These results suggest that the Gly542Ser mutation causes FXII deficiency through intracellular degradation.

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Molecular analysis of multiple genetic variants in Spanish FXII-deficient families

Cited by 7 publications

References 16 publications

Identification of Genetic Defects Underlying FXII Deficiency in Four Unrelated Chinese Patients

Identification of Genetic Defects Underlying FXII Deficiency in Four Unrelated Chinese Patients

Combined cis-regulator elements as important mechanism affecting FXII plasma levels

Genetic analysis of a novel missense mutation (Gly542Ser) with factor XII deficiency in a Chinese patient of consanguineous marriage

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