Congenital Analbuminemia in Unrelated Algerian and Turkish Families is Caused by the Same Molecular Defect in the Albumin Gene

SummaryWe have prospectively evaluated the biologic response to desmopressin (DDAVP) in 28 children with type 2 von Willebrand disease (VWD) in correlation with the phenotype and the molecular defect of VWF. The diagnosis of VWD type 2 was mainly based on VWF functional parameters and/or an aberrant VWF multimer pattern. Seventeen different mutations were identified (6 of them novel). No response with respect to the functional parameters VWF:RCo and/or VWF:CB was seen in patients with severe abnormality of the VWF multimer pattern. One patient with VWD type 2A phenotype IIC Miami did not respond with respect to VWF:CB, but showed a good response of VWF:Ag and FVIII:C as expected. Interestingly he showed a persistently high level of VWF:Ag and FVIII:C up to 4 hours after DDAVP infusion. Patients with minor alterations of multimer structure and particular mutations responded well to DDAVP, whereas patients with normal multimer structure but a defect in platelet dependent functional parameters did not respond with VWF:RCo. Conclusion: Children with VWD type 2 show a variable response to desmopressin depending on the mutation that correlates with the functional defect and the presence or absence as well as the half-life of large VWF multimers. Our data emphasize the usefulness of DDAVP testing even in patients with VWD type 2, possibly with the exception of VWD type 2B.

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Paris I Dysfibrinogenemia: A Point Mutation in Intron 8 Results in Insertion of a 15 Amino Acid Sequence in the Fibrinogen γ-Chain

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651583 ◽

1993 ◽

Vol 69 (03) ◽

pp. 217-220 ◽

Cited By ~ 12

Author(s):

Jonathan B Rosenberg ◽

Peter J Newman ◽

Michael W Mosesson ◽

Marie-Claude Guillin ◽

David L Amrani

Keyword(s):

Amino Acid ◽

Amino Acid Sequence ◽

Point Mutation ◽

Genomic Dna ◽

Comparative Sequence Analysis ◽

Chain Gene ◽

Molecular Defect ◽

Nucleotide Position ◽

Normal Individuals ◽

Polymerase Chain

SummaryParis I dysfibrinogenemia results in the production of a fibrinogen molecule containing a functionally abnormal γ-chain. We determined the basis of the molecular defect using polymerase chain reaction (PCR) to amplify the γ-chain region of the Paris I subject’s genomic DNA. Comparative sequence analysis of cloned PCR segments of normal and Paris I genomic DNA revealed only an A→G point mutation occurring at nucleotide position 6588 within intron 8 of the Paris I γ-chain gene. We examined six normal individuals and found only normal sequence in this region, indicating that this change is not likely to represent a normal polymorphism. This nucleotide change leads to a 45 bp fragment being inserted between exons 8 and 9 in the mature γparis I chain mRNA, and encodes a 15 amino acid insert after γ350 [M-C-G-E-A-L-P-M-L-K-D-P-C-Y]. Alternative splicing of this region from intron 8 into the mature Paris I γ-chain mRNA also results after translation into a substitution of S for G at position γ351. Biochemical studies of 14C-iodoacetamide incorporation into disulfide-reduced Paris I and normal fibrinogen corroborated the molecular biologic predictions that two additional cysteine residues exist within the γpariS I chain. We conclude that the insertion of this amino acid sequence leads to a conformationallyaltered, and dysfunctional γ-chain in Paris I fibrinogen.

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The Immunological Properties of Factor VIII

Thrombosis and Haemostasis ◽

10.1055/s-0038-1655645 ◽

1966 ◽

Vol 16 (03/04) ◽

pp. 559-573 ◽

Cited By ~ 1

Author(s):

L Uszyński

Keyword(s):

Factor Viii ◽

Inhibitory Activity ◽

Hemophilia A ◽

Severe Form ◽

Molecular Defect ◽

Bovine Plasma ◽

Human Factor Viii ◽

Antigenic Properties ◽

Coagulation Tests ◽

Normal Human

SummaryRabbits immunized against human AHG fibrinogen-free preparations, were shown to produce anti-AHG antibodies. The inhibitory activity of these antibodies was tested by thromboplastin generation test, thrombelastography, and the specific anti-AHG antibodies neutralization test. The latter test permitted quantitative determination of antigenic form of factor VIII. The inhibitory activity of anti-FI-O-Ta serum resulted exclusively from the anti-AHG antibodies which in coagulation tests behaved like circulating anticoagulants directed against factor VIII.The anti-AHG antibodies were neutralizable by normal human serum or plasma even contained only trace of AHG activity after storage. There was no antigenic form of factor VIII in the severely affected patients with hemophilia A, von Willebrand’s disease nor in the normal plasma adsorbed on bentonite. The presented results suggest a molecular defect of factor VIII in patients with hemophilia A. The severe form of this disease depends, probably, on a major impairment of AHG biosynthesis, leading to changes in the antigenic properties of the molecule. The AHG from rabbit, porcine and bovine plasma respectively did not neutralize the anti-AHG antibodies formed in rabbits immunized against human factor VIII preparations.

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Characterization of an Abnormal Antithrombin (Milano 2) with Defective Thrombin Binding

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661681 ◽

1986 ◽

Vol 56 (03) ◽

pp. 349-352 ◽

Cited By ~ 2

Author(s):

A Tripodi ◽

A Krachmalnicoff ◽

P M Mannucci

Keyword(s):

Venous Thromboembolism ◽

Active Site ◽

Inhibitory Activity ◽

Antithrombin Iii ◽

Factor Xa ◽

Molecular Defect ◽

Affinity Adsorption ◽

Italian Family ◽

Crossed Immunoelectrophoresis

SummaryFour members of an Italian family (two with histories of venous thromboembolism) had a qualitative defect of antithrombin III reflected by normal antigen concentrations and halfnormal antithrombin activity with or without heparin. Anti-factor Xa activities were consistently borderline low (about 70% of normal). For the propositus’ plasma and serum the patterns of antithrombin III in crossed-immunoelectrophoresis with or without heparin were indistinguishable from those of normal plasma or serum. A normal affinity of antithrombin III for heparin was documented by heparin-sepharose chromatography. Affinity adsorption of the propositus’ plasma to human α-thrombin immobilized on sepharose beads revealed defective binding of the anti thrombin III to thrombin-sepharose. Hence the molecular defect of this variant appears to be at the active site responsible for binding and neutralizing thrombin, thus accounting for the low thrombin inhibitory activity.

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Residual catalase and molecular defect in the catalase gene examined by electrophoresis.

SEIBUTSU BUTSURI KAGAKU ◽

10.2198/sbk.35.159 ◽

1991 ◽

Vol 35 (3) ◽

pp. 159-168

Author(s):

Masana Ogata

Keyword(s):

Molecular Defect ◽

Catalase Gene

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Selective block of albumin gene expression in chick embryo hepatocytes cultured without hormones and its partial reversal by insulin.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(17)43813-0 ◽

1983 ◽

Vol 258 (24) ◽

pp. 15355-15360 ◽

Cited By ~ 8

Author(s):

P W Plant ◽

R G Deeley ◽

G Grieninger

Keyword(s):

Gene Expression ◽

Chick Embryo ◽

Albumin Gene ◽

Partial Reversal

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Molecular defect of truncated beta-spectrin associated with hereditary elliptocytosis. Beta-spectrin Gottingen

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)93001-2 ◽

1991 ◽

Vol 266 (13) ◽

pp. 8490-8494 ◽

Cited By ~ 1

Author(s):

S.H. Yoon ◽

H. Yu ◽

S. Eber ◽

J.T. Prchal

Keyword(s):

Molecular Defect ◽

Hereditary Elliptocytosis

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Maternal Uniparental Disomy of Chromosome 20 (UPD(20)mat) as Differential Diagnosis of Silver Russell Syndrome: Identification of Three New Cases

Genes ◽

10.3390/genes12040588 ◽

2021 ◽

Vol 12 (4) ◽

pp. 588

Author(s):

Pierpaola Tannorella ◽

Daniele Minervino ◽

Sara Guzzetti ◽

Alessandro Vimercati ◽

Luciano Calzari ◽

...

Keyword(s):

Growth Retardation ◽

Molecular Mechanisms ◽

Uniparental Disomy ◽

Postnatal Growth ◽

Molecular Diagnostic ◽

Growth Delay ◽

Molecular Defect ◽

Maternal Uniparental Disomy ◽

Feeding Difficulties ◽

Silver Russell Syndrome

Silver Russell Syndrome (SRS, MIM #180860) is a rare growth retardation disorder in which clinical diagnosis is based on six features: pre- and postnatal growth failure, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties (Netchine–Harbison clinical scoring system (NH-CSS)). The molecular mechanisms consist in (epi)genetic deregulations at multiple loci: the loss of methylation (LOM) at the paternal H19/IGF2:IG-DMR (chr11p15.5) (50%) and the maternal uniparental disomy of chromosome 7 (UPD(7)mat) (10%) are the most frequent causes. Thus far, about 40% of SRS remains undiagnosed, pointing to the need to define the rare mechanisms in such a consistent fraction of unsolved patients. Within a cohort of 176 SRS with an NH-CSS ≥ 3, a molecular diagnosis was disclosed in about 45%. Among the remaining patients, we identified in 3 probands (1.7%) with UPD(20)mat (Mulchandani–Bhoj–Conlin syndrome, OMIM #617352), a molecular mechanism deregulating the GNAS locus and described in 21 cases, characterized by severe feeding difficulties associated with failure to thrive, preterm birth, and intrauterine/postnatal growth retardation. Our patients share prominent forehead, feeding difficulties, postnatal growth delay, and advanced maternal age. Their clinical assessment and molecular diagnostic flowchart contribute to better define the characteristics of this rare imprinting disorder and to rank UPD(20)mat as the fourth most common pathogenic molecular defect causative of SRS.

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