ABSTRACT
Afibrinogenemia represents the rarest form of fibrinogen deficiency. Causative missense mutations occur rarely and may improve the understanding of fibrinogen structure and function. PATIENTS AND METHODS: The propositus was a 26-year-old Argentinian with afibrinogenemia. FGA, FGB and FGG exons and flanking regions were screened by sequencing and the mutant protein was analyzed in silico. RESULTS: A novel missense mutation in the FGB gene (Bbeta Gly272Arg, p.Gly302Arg) was identified. In silico analysis revealed its location in a highly conserved region, which preserves the core fold of the C-terminal beta-chain and is important for proper secretion. A substitution by a positively charged large Arg residue in this area would most likely disturb the core fold by additional interactions with adjacent residues (p.Asp291, p.Asp297, p.Asp311), or by forming of non-native interactions with other proteins, thereby hindering the action of molecular chaperones. Both alternatives would disturb the regular secretion of the beta-chain. CONCLUSIONS: The novel missense mutation in the FGB gene causes afibrinogenemia most probably by affecting the secretion of the fibrinogen beta-chain.
Subject(s)
Afibrinogenemia/diagnosis , Afibrinogenemia/genetics , Codon, Nonsense/genetics , Fibrinogen/genetics , Hemorrhage/diagnosis , Hemorrhage/genetics , Adult , Afibrinogenemia/complications , Base Sequence , Diagnosis, Differential , Fibrinogen/chemistry , Fibrinogen/ultrastructure , Genetic Predisposition to Disease/genetics , Genetic Testing/methods , Hemorrhage/complications , Humans , Male , Molecular Sequence Data , Rare Diseases/diagnosis , Rare Diseases/genetics , Structure-Activity RelationshipABSTRACT
Hematological parameters in newborn umbilical cord blood samples (n = 476), collected at the Hospital Provincial del Centenario, Rosario, were studied. They were divided into 3 groups: (I) full term newborns with weight according to gestational age; (II) low weight and normal gestational age; (III) preterm newborns. The results were as follows: group (I) Hb: 15.5 +/- 1.1 g/dl; RBC; 4.66 +/- 0.33 x 10(12)/l; PCV: 49% +/- 4.3%, MCV 105.1 +/- 5.3 fl; MHC: 33.2 +/- 1.2 pg. Decreased Hb concentration (p < 0.05) and increased MCV (p < 0.01) were observed in preterm newborns in comparison with normal ones, and a slight PCV increase and RBC values in low weight newborns compared to the control group (p < 0.05). Erythrocyte morphology was normal as well as reticulocyte values in these samples. The electrophoretic pattern was (FA) with the following Hb F values 66.3 +/- 6.8%, and Hb A2 0.45 +/- 0.3% in group (I), with a significant increase of Hb F in 30-35 weeks preterm newborns. Group (I) values are considered as normal hematological parameters in newborns in our country, whereas MCV < 94.7 fl is considered as a neonatal microcytosis marker, consequently an alert to investigate alpha-thalassemia. There was no influence on Hb concentration due to maternal smoking habit. The present work could be of relevance for our region since up to the present time there are no similar records.
Subject(s)
Fetal Blood/chemistry , Erythrocyte Indices , Erythrocytes , Female , Fetal Hemoglobin/analysis , Hematocrit , Hemoglobin A2/analysis , Hemoglobins/analysis , Humans , Infant, Newborn , Infant, Premature/blood , Prospective StudiesABSTRACT
Two lines of mice divergently selected from the control strain (CBi) against the positive phenotypic correlation between body weight (b.w.) and tail (skeletal) length were obtained (CBi/C: high weight, short tail; CBi/L: low weight, long tail). The selected animals showed a different relationship between body and skeletal masses. To compare the adequacy between biomass and load-bearing ability of the skeleton, and to describe the eventual role of bone mechanostat in the production of these changes, cross-sectional and bending properties of both femur diaphyses were determined in CBi, CBi/C, and CBi/L adult mice of both genders. Cortical bone material quality (elastic modulus) was reduced in the selected lines (p < 0.001), significantly less in CBi/C than in CBi/L. In contrast, cross-sectional design (b.w.-adjusted values of moment of inertia, CSMI) was largely improved (p < 0.001), significantly more in CBi/C than in CBi/L. These effects determined a greater stiffness and strength in CBi/C than in CBi/L or CBi weight-paired mice. The elevations of the negative regression lines between elastic modulus and CSMI ("distribution/quality" curves) decreased in the order CBi/C > CBi/L > CBi. Data show that selection improved diaphyseal stiffness and strength in CBi/C animals because of an architectural overcompensation for the reduced bone material quality. Therefore, an inadequate control of long-bone architectural design as a function of the mechanical quality of cortical bone and b.w. bearing could have been induced in that line. Assuming bone mechanostatic regulation to be genetically programmed, some of the corresponding biological determinants should be transmitted independently, because artificial selection separately affected material quality and architectural design. The possibility of transmission of an inadequate mechanostatic function (inability to adapt bone modeling to bone material quality as a function of the biomass to be supported) was also shown, as some genotypes could express architectural modifications that largely exceed bone material quality deterioration.
