Fbn1 Gene

The gene encoding type 1 fibrillin (FBN1) is very large (over 230 kb) and is highly fragmented into 65 exons, transcribed in a 10-kb mRNA that encodes a 2871-amino acid protein.[7,9] Three additional alternatively spliced exons, most likely untranslated and well conserved between humans, mice, and porcine, were found upstream of exon 1. This region is GC-rich, contains a CpG island, and lacks conventional TATA or CCAAT boxes.[10]

The deduced primary structure reveals a highly repetitive protein that contains essentially three repeated modules:

• EGF-like module, which is homologous to the one found in the epidermal growth factor. These modules contain six cysteine residues that form three intradomain disulfide bonds. There are 47 of these throughout the fibrillin-1 protein. Among these, 43 contain a conserved consensus sequence for calcium binding and are called cb EGF-like modules. The presence of calcium ions significantly protects full-length or recombinant fragments of fibrillin-1 from proteolysis by trypsin, elastase, endoproteinase Glu-C, plasmin, and matrix metalloproteinases.[11]

• Transforming growth factor (TGF) b1-binding protein-like module (TGF p1-BP-like module), which is found seven times interspaced with cb EGF-like in the protein and is homologous to modules found in the TGF-p1 binding protein. This domain appears to be limited to proteins that localize to matrix fibrils [fibrillins and latent TGF p-binding proteins (LTBPs)]. These modules contain eight cysteine residues. No specific function has yet been ascribed to these modules. However, some evidence suggest that these domains mediate specific protein-protein interactions.1-12-1 • Hybrid module, which combines features of the former two. This consists of approximately 65 amino acids, and is found twice in the protein. This module is also found in LTBPs, which have a single hybrid domain.

Finally, the protein contains three unique regions: a proline-rich region that may act as a ''hingelike'' region[13] and the amino and carboxy terminal domains. The N-terminal and C-terminal domains of fibrillin display two prominent features: the presence of an even number of cysteine residues (four in the N-terminal and two in the C-terminal domains) and the presence of the basic consensus sequence for processing by furin-type enzymes BXBB (B=basic amino acid residue, K or R) in each domain. The four-cysteine domain in the N-terminus of fibrillin is homologous to similar four-cysteine domains in the N-terminal extended forms of the LTBPs. The C-terminal domain of fibrillin is homologous to the C-terminal domain of all four members of the fibulin family; thus a new type of extracellular module of approximately 120 amino acid residues in length has been proposed.1-14-1 This type of homology is not shared by LTBPs.

Other members of the fibrillin family were identified: FBN2 gene in 5q23-q31 (fibrillin-2 protein) carrying mutations in congenital contractural arachnodactyly (CCA) (OMIM no. 120150); and FBNL gene (or EFEMP1 gene) in 2p16 (fibrillin-like protein) carrying mutations in Doyne honeycomb retinal dystrophy (DHRD; OMIM no. 126600) or malattia Leventinese (MLVT).

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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