TB5

The critical role of the TB5 domain of fibrillin-1 in endochondral ossification

Mutations in the fibrillin-1 (FBN1) gene are responsible for the autosomal dominant form of geleophysic dysplasia (GD), which is characterized by short stature and extremities, thick skin and cardiovascular disease. All known FBN1 mutations in patients with GD are localized within the region encoding the transforming growth factor-β binding protein-like 5 (TB5) domain of this protein. Herein, we generated a knock-in mouse model, Fbn1Y1698C by introducing the p.Tyr1696Cys mutation from a patient with GD into the TB5 domain of murine Fbn1 to elucidate the specific role of this domain in endochondral ossification. We found that both Fbn1Y1698C/+ and Fbn1Y1698C/Y1698C mice exhibited a reduced stature reminiscent of the human GD phenotype. The Fbn1 point mutation introduced in these mice affected the growth plate formation owing to abnormal chondrocyte differentiation such that mutant chondrocytes failed to establish a dense microfibrillar network composed of FBN1. This original Fbn1 mutant mouse model offers new insight into the pathogenic events underlying GD. Our findings suggest that the etiology of GD involves the dysregulation of the extracellular matrix composed of an abnormal FBN1 microfibril network impacting the differentiation of the chondrocytes.

Separation in genetic pathogenesis of mutations in FBN1-TB5 region between autosomal dominant acromelic dysplasia and Marfan syndrome

Mutations in the transforming growth factor β-binding protein-like domain 5 (TB5) region of FBN1 can lead to autosomal acromelic dysplasia and Marfan syndrome, which are two diseases with apparently opposite phenotypes. We identified six patients with acromelic dysplasia carrying either the previously reported mutations c.5284G > A (p.Gly1762Ser) and c.5096A > G (p.Tyr1699Cys) or the novel mutation c.5260G > A (p.Gly1754Ser). A systematic review of patients with mutations in the FBN1-TB5 region showed that acromelic dysplasia is caused only by in-frame amino acid substitutions. In contrast, truncating mutations in the FBN1-TB5 have been reported only in Marfan syndrome. Acromelic dysplasia subtypes that share symptoms with Marfan syndrome are associated with FBN1-TB5 disulfide disruptions, which are also commonly found in Marfan syndrome. These results suggest that the type and location of mutations in the FBN1-TB5 region determine the clinical spectrum of fibrillinopathy.

Draft Genome Sequence of the Termite-Associated "Cuckoo Fungus," Athelia ( Fibularhizoctonia) sp. TMB Strain TB5

Atheliales is a diverse order of crust-forming Basidiomycota fungi. Here, we report the draft genome of the "cuckoo fungus," Athelia (Fibularhizoctonia) sp. TMB strain TB5 (Atheliales), which forms termite-egg-mimicking sclerotia that termites tend. We further compare its repertoire of psilocybin gene homologs to homologs previously reported for Fibularhizoctonia psychrophila.

Phenological, morpho-physiological and proteomic responses of Triticum boeoticum to drought stress

Drought is the most important abiotic stress limiting wheat production worldwide. Triticum boeoticum, as wild wheat, is a rich gene pool for breeding for drought stress tolerance. In this study, to identify the most drought-tolerant and susceptible genotypes, ten T. boeoticum accessions were evaluated under non-stress and drought-stress conditions for two years. Among the studied traits, water-use efficiency (WUE) was suggested as the most important trait to identify drought-tolerant genotypes. According to the desirable and undesirable areas of the bi-plot, Tb5 and Tb6 genotypes were less and more affected by drought stress, respectively. Therefore, their flag-leaves proteins were used for two-dimensional gel electrophoresis. While, Tb5 contained a high amount of yield, yield components, and WUE, Tb6 had higher levels of water use, phenological related traits, and root related characters. Of the 235 spots found in the studied accessions, 14 spots (11 and 3 spots of Tb5 and Tb6, respectively) were selected for sequencing. Of these 14 spots, 9 and 5 spots were upregulated and downregulated, respectively. The identified proteins were grouped into six functional protein clusters, which were mainly involved in photosynthesis (36%), carbohydrate metabolism (29%), chaperone (7%), oxidation and reduction (7%), lipid metabolism and biological properties of the membrane (7%) and unknown function (14%). We report for the first time that MICP, in the group of lipid metabolism proteins, was significantly changed into wild wheat in response to drought stress. Maybe, the present-identified proteins could play an important role to understand the molecular pathways of wheat drought tolerance. We believe comparing and evaluating the similarity-identified proteins of T. boeoticum with the previously identified proteins of Aegilops tauschii, can provide a new direction to improve wheat tolerance to drought stress.

Fibrillin-1 mutations causing Weill-Marchesani syndrome and acromicric and geleophysic dysplasias disrupt heparan sulfate interactions

The extracellular glycoprotein fibrillin-1 forms microfibrils that act as the template for elastic fibers. Most mutations in fibrillin-1 cause Marfan syndrome with severe cardiovascular and ocular symptoms, and tall stature. This is in contrast to mutations within a heparin-binding TB domain (TB5), which is downstream of the arg-gly-asp cell adhesion domain, which can cause Weill-Marchesani syndrome (WMS) or Acromicric (AD) and Geleophysic Dysplasias (GD). WMS is characterized by short limbs, joint stiffness and ocular defects, whilst fibrillin-1 AD and GD have severe short stature, joint defects and thickened skin. We previously showed that TB5 binds heparin. Here, we show that the corresponding region of fibrillin-2 binds heparin very poorly, highlighting a novel functional difference between the two isoforms. This finding enabled us to map heparin/heparan sulfate binding to two sites on fibrillin-1 TB5 using a mutagenesis approach. Once these sites were mapped, we were able to investigate whether disease-causing mutations in this domain disrupt binding to HS. We show that a WMS deletion mutant, and five AD and GD point mutants all have disrupted heparin binding to TB5. These data provide insights into the biology of fibrillins and the pathologies of WMS, AD and GD.