A Systemic Approach to Multi-Party Relationship Modeling

Socio-economic systems exist in a wide variety of activity domains and are composed of multiple stakeholder groups. These groups pursue objectives which are often entirely motivated from within their local context. Domain specificities in the form of institutional design, for example the deregulation of Public Utility systems, can further fragment this context. Nevertheless, for these systems to be viable, a management subsystem that maintains a holistic view of the system is required. From a Systems perspective, this highlights the need to invest in methods that capture the interactions between the different stakeholders of the system. It is the understanding of the individual interactions that can help piece together a holistic view of the system thereby enabling system level discourse. In this paper we present a modeling technique that models industry interactions as a multi-party value realization process and takes a Systems approach in analyzing them. Every interaction is analyzed both from outside – system as a black box and from within – system as a white box. The design patterns that emerge from this whole/composite view of value realization provide the necessary foundation to analyze the working of multi-stakeholder systems. An explicit specification of these concepts is presented as Regulation Enabling Ontology, REGENT. As an example, we instantiate REGENT for the urban residential electricity market and demonstrate its effectiveness in identifying the requirements for time-based electricity supply systems

Missense mutations in the copper transporter gene ATP7A cause X-Linked distal hereditary motor neuropathy

Distal hereditary motor neuropathies comprise a clinically and genetically heterogeneous group of disorders. We recently mapped an X-linked form of this condition to chromosome Xq13.1-q21 in two large unrelated families. The region of genetic linkage included ATP7A, which encodes a copper-transporting P-type ATPase mutated in patients with Menkes disease, a severe infantile-onset neurodegenerative condition. We identified two unique ATP7A missense mutations (p.P1386S and p.T994I) in males with distal motor neuropathy in two families. These molecular alterations impact highly conserved amino acids in the carboxyl half of ATP7A and do not directly involve the copper transporter's known critical functional domains. Studies of p.P1386S revealed normal ATP7A mRNA and protein levels, a defect in ATP7A trafficking, and partial rescue of a S. cerevisiae copper transport knockout. Although ATP7A mutations are typically associated with severe Menkes disease or its milder allelic variant, occipital horn syndrome, we demonstrate here that certain missense mutations at this locus can cause a syndrome restricted to progressive distal motor neuropathy without overt signs of systemic copper deficiency. This previously unrecognized genotype-phenotype correlation suggests an important role of the ATP7A copper transporter in motor-neuron maintenance and function

Absence of Dystrophin Related Protein-2 disrupts Cajal bands in a patient with Charcot-Marie-Tooth disease

Using exome sequencing in an individual with Charcot-Marie-Tooth disease (CMT) we have identified a mutation in the X-linked dystrophin-related protein 2 (DRP2) gene. A 60-year-old gentleman presented to our clinic and underwent clinical, electrophysiological and skin biopsy studies. The patient had clinical features of a length dependent sensorimotor neuropathy with an age of onset of 50 years. Neurophysiology revealed prolonged latencies with intermediate conduction velocities but no conduction block or temporal dispersion. A panel of 23 disease causing genes was sequenced and ultimately was uninformative. Whole exome sequencing revealed a stop mutation in DRP2, c.805C>T (Q269*). DRP2 interacts with periaxin and dystroglycan to form the periaxin-DRP2-dystroglycan complex which plays a role in the maintenance of the well-characterized Cajal bands of myelinating Schwann cells. Skin biopsies from our patient revealed a lack of DRP2 in myelinated dermal nerves by immunofluorescence. Furthermore electron microscopy failed to identify Cajal bands in the patient's dermal myelinated axons in keeping with ultrastructural pathology seen in the Drp2 knockout mouse. Both the electrophysiologic and dermal nerve twig pathology support the interpretation that this patient's DRP2 mutation causes characteristic morphological abnormalities recapitulating the Drp2 knockout model and potentially represents a novel genetic cause of CMT

MFN2 mutations cause severe phenotypes in most patients with CMT2A

Background: Charcot-Marie-Tooth disease type 2A (CMT2A), the most common form of CMT2, is caused by mutations in the mitofusin 2 gene (MFN2), a nuclear encoded gene essential for mitochondrial fusion and tethering the endoplasmic reticulum to mitochondria. Published CMT2A phenotypes have differed widely in severity.Methods: To determine the prevalence and phenotypes of CMT2A within our clinics we performed genetic testing on 99 patients with CMT2 evaluated at Wayne State University in Detroit and on 27 patients with CMT2 evaluated in the National Hospital for Neurology and Neurosurgery in London. We then preformed a cross-sectional analysis on our patients with CMT2A.Results: Twenty-one percent of patients had MFN2 mutations. Most of 27 patients evaluated with CMT2A had an earlier onset and more severe impairment than patients without CMT2A. CMT2A accounted for 91% of all our severely impaired patients with CMT2 but only 11% of mildly or moderately impaired patients. Twenty-three of 27 patients with CMT2A were nonambulatory prior to age 20 whereas just one of 78 non-CMT2A patients was nonambulatory after this age. Eleven patients with CMT2A had a pure motor neuropathy while another 5 also had profound proprioception loss. MFN2 mutations were in the GTPase domain, the coiled-coil domains, or the highly conserved R3 domain of the protein.Conclusions: We find MFN2 mutations particularly likely to cause severe neuropathy that may be primarily motor or motor accompanied by prominent proprioception loss. Disruption of functional domains of the protein was particularly likely to cause neuropathy. Neurology (R) 2011;76:1690-169

Genotype-Phenotype correlations of MPZ mutations

Background: Myelin protein zero (MPZ) is the mai structural protein of peripheral myelin, costituiting approximately the 50% of total myelin proteins. MPZ is a single transmembrane glycoprotein, belonging to the immunoglobulin superfamily and is supposed to play an important role in myelin compaction, actins as an adhesion molecule. Missense mutations in MPZ cause inherited neuropathies charachterized by different grades of severity. Recently MPZ mutations were classified in two main groups: mutations causing an early onset phenotype with motor development delay and severe demyelinating neuropathy and the late onset mutations associated with weakness and sensory loss appearing in the third or fouth decade of life and with electrophysiological signs consistent with a mixed demyelinationg and axonal neuropathy. Aim of the project: To study how mutations associated to an early and late onset phenotype interfere with protein trafficking and adhesion. Material and Methods The human cDNA coding for the human MPZwt was cloned in a mammalian expression vector: pDsRed1-N1 (Clontech) in frame with DsRed. Five MPZ mutations associated with early onset (H52R), R69C, Deletion 22-28) and late onset phenotype (T95M, H10P) were cloned in another vector: pEGFP-N1 (Clonetech) in frame with EGFP. Chinese ovary cells (CHO) were transiently transfected with the plasmids coding for the MPZ mutations, both singularly or in double with MPZwt and the cellular localization of the proteins was visualized using a fluorescence microscope. An aggregation assay (M.Filbin 1990) was performed comparing the adhesive proprieties of MPZwt, T95M (late onset phenotype), deletion 22-28 (early onset) and pEGF-N1 control trasfected cells. Results Both the mutations associated to a late onset phenotype reached the cell membrane in a comparable way with the MPZwt. The early onset mutations behaved in a variable way, reaching (H52R), reaching only in a limited amount (deletion 22-28) or not reaching at all (R69C) the plasma membrane. In all cases, when the mutated MPZ was co-trasfected with the wild type protein, the latter was normally expressed on the plasma membrane. The aggregation test demonstrated that MPZwt expressing cells are more adhesive than cells transfected with pEGFP-Nl or Deletion 22-28, while T95M expressing cells perform the aggregation assay in a comparable way to MPZwt cells. Conc!usions These data suggest a more disruptive effect, on the protein structure, of MPZ early onset mutations, compared with MPZ late onset ones. A clear dominant negative effect was not demonstrated for any of the studied mutations, since the co-transfected MPZwt was never prevented from reaching the cellular membrane