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Vetro A.,Biotechnology Research Laboratories | Iascone M.,Ussd Laboratorio Of Genetica Medica | Limongelli I.,Fondazione IRCCS Policlinico San Matteo | Ameziane N.,VU University Amsterdam | And 16 more authors.
Human Mutation | Year: 2015

The diagnosis of VACTERL syndrome can be elusive, especially in the prenatal life, due to the presence of malformations that overlap those present in other genetic conditions, including the Fanconi anemia (FA). We report on three VACTERL cases within two families, where the two who arrived to be born died shortly after birth due to severe organs' malformations. The suspicion of VACTERL association was based on prenatal ultrasound assessment and postnatal features. Subsequent chromosome breakage analysis suggested the diagnosis of FA. Finally, by next-generation sequencing based on the analysis of the exome in one family and of a panel of Fanconi genes in the second one, we identified novel FANCL truncating mutations in both families. We used ectopic expression of wild-type FANCL to functionally correct the cellular FA phenotype for both mutations. Our study emphasizes that the diagnosis of FA should be considered when VACTERL association is suspected. Furthermore, we show that loss-of-function mutations in FANCL result in a severe clinical phenotype characterized by early postnatal death. © 2015 WILEY PERIODICALS, INC. Source


Caccia S.,University of Milan | Ricagno S.,University of Pavia | Ricagno S.,Biotechnology Research Laboratories | Ricagno S.,University of Milan | Bolognesi M.,University of Milan
Biomolecular Concepts | Year: 2010

Serpins build a large and evolutionary widespread protein superfamily, hosting members that are mainly Ser-protease inhibitors. Typically, serpins display a conserved core domain composed of three main β-sheets and 9-10 α-helices, for a total of approximately 350 amino acids. Neuroserpin (NS) is mostly expressed in neurons and in the central and peripheral nervous systems, where it targets tissue-type plasminogen activator. NS activity is relevant for axogenesis, synaptogenesis and synaptic plasticity. Five (single amino acid) NS mutations are associated with severe neurodegenerative disease in man, leading to early onset dementia, epilepsy and neuronal death. The functional aspects of NS protease inhibition are linked to the presence of a long exposed loop (reactive center loop, RCL) that acts as bait for the incoming partner protease. Large NS conformational changes, associated with the cleavage of the RCL, trap the protease in an acyl-enzyme complex. Contrary to other serpins, this complex has a half-life of approximately 10 min. Conformational flexibility is held to be at the bases of NS polymerization leading to Collins bodies intracellular deposition and neuronal damage in the pathological NS variants. Two main general mechanisms of serpin polymerization are currently discussed. Both models require the swapping of the RCL among neighboring serpin molecules. Specific differences in the size of swapped regions, as well as differences in the folding stage at which polymerization can occur, distinguish the two models. The results provided by recent crystallographic and biophysical studies allow rationalization of the functional and pathological roles played by NS based on the analysis of four three-dimensional structures. © Walter de Gruyter Berlin New York 2010. Source


Rossi E.,University of Pavia | Radi O.,University of Pavia | De Lorenzi L.,University of Milan | Vetro A.,Biotechnology Research Laboratories | And 7 more authors.
PLoS ONE | Year: 2014

Sexual development in mammals is based on a complicated and delicate network of genes and hormones that have to collaborate in a precise manner. The dark side of this pathway is represented by pathological conditions, wherein sexual development does not occur properly either in the XX and the XY background. Among them a conundrum is represented by the XX individuals with at least a partial testis differentiation even in absence of SRY. This particular condition is present in various mammals including the dog. Seven dogs characterized by XX karyotype, absence of SRY gene, and testicular tissue development were analysed by Array-CGH. In two cases the array-CGH analysis detected an interstitial heterozygous duplication of chromosome 9. The duplication contained the SOX9 coding region. In this work we provide for the first time a causative mutation for the XXSR condition in the dog. Moreover this report supports the idea that the dog represents a good animal model for the study of XXSR condition caused by abnormalities in the SOX9 locus. © 2014 Rossi et al. Source


Barnidge D.R.,Mayo Medical School | Dispenzieri A.,Mayo Medical School | Merlini G.,Biotechnology Research Laboratories | Katzmann J.A.,Mayo Medical School | Murray D.L.,Mayo Medical School
Clinical Chemistry and Laboratory Medicine | Year: 2016

Background: Serum immunoglobulin free light chains (FLC) are secreted into circulation by plasma cells as a by-product of immunoglobulin production. In a healthy individual the population of FLC is polyclonal as no single cell is secreting more FLC than the total immunoglobulin secreting cell population. In a person with a plasma cell dyscrasia, such as multiple myeloma (MM) or light chain amyloidosis (AL), a clonal population of plasma cells secretes a monoclonal light chain at a concentration above the normal polyclonal background. Methods: We recently showed that monoclonal immunoglobulin rapid accurate mass measurement (miRAMM) can be used to identify and quantify a monoclonal light chain (LC) in serum and urine above the polyclonal background. This was accomplished by reducing immunoglobulin disulfide bonds releasing the LC to be analyzed by microLC-ESI-Q-TOF mass spectrometry. Here we demonstrate that the methodology can also be applied to the detection and quantification of FLC by analyzing a non-reduced sample. Results: Proof of concept experiments were performed using purified FLC spiked into normal serum to assess linearity and precision. In addition, a cohort of 27 patients with AL was analyzed and miRAMM was able to detect a monoclonal FLC in 23 of the 27 patients that had abnormal FLC values by immunonephelometry. Conclusions: The high resolution and high mass measurement accuracy provided by the mass spectrometry based methodology eliminates the need for κ/λ ratios as the method can quantitatively monitor the abundance of the κ and λ polyclonal background at the same time it measures the monoclonal FLC. © 2016 by De Gruyter 2016. Source


Balduini A.,University of Pavia | Balduini A.,Biotechnology Research Laboratories | Balduini A.,Tufts University | Di Buduo C.A.,University of Pavia | And 2 more authors.
Thrombosis and Haemostasis | Year: 2016

Platelets, which are released by megakaryocytes, play key roles in haemostasis, angiogenesis, immunity, tissue regeneration and wound healing. The scarcity of clinical cures for life threatening platelet diseases is in a large part due to limited insight into the mechanisms that control the developmental process of megakaryocytes and the mechanisms that govern the production of platelets within the bone marrow. To overcome these limitations, functional human tissue models have been developed and studied to extrapolate ex vivo outcomes for new insight on bone marrow functions in vivo. There are many challenges that these models must overcome, from faithfully mimicking the physiological composition and functions of bone marrow, to the collection of the platelets generated and validation of their viability and function for human use. The overall goal is to identify innovative instruments to study mechanisms of platelet release, diseases related to platelet production and new therapeutic targets starting from human progenitor cells. © Schattauer 2016. Source

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