Mutations in the fibrinogen aalpha gene account for the majority of cases of congenital afibrinogenemia.

Congenital afibrinogenemia is a rare, autosomal, recessive disorder characterized by the complete absence of detectable fibrinogen. We previously identified the first causative mutations in a nonconsanguineous Swiss family; the 4 affected persons have homozygous deletions of approximately 11 kb of the fibrinogen alpha (FGA) gene. Haplotype data implied that these deletions occurred on distinct ancestral chromosomes, suggesting that this region may be susceptible to deletion by a common mechanism. We subsequently showed that all the deletions were identical to the base pair and probably resulted from a nonhomologous recombination mediated by 7-bp direct repeats. In this study, we have collected data on 13 additional unrelated patients to identify the causative mutations and to determine the prevalence of the 11-kb deletion. A common recurrent mutation, at the donor splice site of FGA intron 4 (IVS4 + 1 G > T), accounted for 14 of the 26 (54%) alleles. One patient was heterozygous for the previously identified deletion. Three more frameshift mutations, 2 nonsense mutations, and a second splice site mutation were also identified. Consequently, 86% of afibrinogenemia alleles analyzed to date have truncating mutations of FGA, though mutations in all 3 fibrinogen genes, FGG, FGA, and FGB, might be predicted to cause congenital afibrinogenemia.

The fine structure of calcified Mandl's corpuscles in teleost fish scales.

Calcified Mandl's corpuscles present in the internal layer (or fibrillary plate) of the teleost fish scale were studied by transmission and scanning electron microscopy for a better understanding of this special type of mineralization process. The corpuscles show a great variability in their structure, form and surface features depending on the arrangement of the collagen fibrils in the internal layer of the different fish species studied, on the localization of the corpuscles in the scale and on the technical treatment to which the scale is subjected.

Ultrastructural and cytochemical aspects of the initial phases of an experimental cutaneous calcinosis (calcergy) in the rat.

In rats a subcutaneous injection of KMnO4 leads to the calcification of the connective tissue. During mineral deposition, both intra- and extracellular changes are observed in the connective tissue. The intracellular phase is characterized by the formation of intramitochondrial granules and cytoplasmic vesicles, both in fibroblastic and extrinsic cells. In the extracellular phase, numerous heterogeneous matrix vesicles appear in the extracellular matrix. At the same time, globular particles which are resistant to microincineration, are observed between the collagen fibrils. The mineralization of the extracellular matrix takes place in two stages. The first stage comprises the appearance of needle-like structures and round aggregates. The needle-like structures are observed occasionally in the matrix vesicles and often in the extracellular matrix where they appear isolated or diverging from a central point. The round aggregates, composed of dense particles, are seen in the ground substance between the collagen fibrils. The second stage is characterized by a progressive mineralization of the collagen fibrils and the elastic fibers, without formation of extended calcified plaques.

The mineralization processes in teleost fish scales.

In Teleost fish scales, growth and mineralization are continuous. Different mineralization processes can be distinguished. The external layer of the scale is the first to be mineralized and may be classified as the initial calcifying structure of the scale. The initial calcification loci are matrix vesicles of cellular origin always observed during the formation of this layer. This mineralization process takes place progressively, closely following the elaboration of the organic matrix in the scale periphery. The outer limiting and internal layers of the scale are developed after the external layer has been formed. A mineral substance is deposited without the mediation of matrix vesicles, but in contact with the previously mineralized external layer. This type of mineralization is called subsequential. However, the mineralization of the outer limiting layer closely follows the secretion of a collagen-free organic matrix and is thus different from the mineralization of the internal layer in which the calcification front remains remote from the collagen matrix surface and corresponds to a delayed mineralization process. The isolated calcifications (Mandl's corpuscles) which develop in the unmineralized laminae of the internal layer are mineralized in the absence of matrix vesicles and without making contact with a pre-existing calcified tissue, probably by a heterogeneous nucleation of the collagen fibrils.