An International Classification of Inherited Metabolic Disorders (ICIMD)

Several initiatives at establishing a classification of inherited metabolic disorders have been published previously, some focusing on pathomechanisms, others on clinical manifestations, while yet another attempted a simplified approach of a comprehensive nosology. Some of these classifications suffered from shortcomings, such as lack of a mechanism for continuous update in light of a rapidly‐evolving field, or lack of widespread input from the metabolic community at large. Our classification – the International Classification of Inherited Metabolic Disorders, or ICIMD – includes 1,450 disorders, and differs from prior approaches in that it benefited from input by a large number of experts in the field, and was endorsed by major metabolic societies around the globe. Several criteria such as pathway involvement and pathomechanisms were considered. The main purpose of the hierarchical, group‐based approach of the ICIMD is an improved understanding of the interconnections between many individual conditions that may share functional, clinical and diagnostic features. The ICIMD aims to include any primary genetic condition in which alteration of a biochemical pathway is intrinsic to specific biochemical, clinical and/or pathophysiological features. As new disorders are discovered, we will seek the opinion of experts in the advisory board prior to inclusion in the appropriate group of the ICIMD, thus guaranteeing the continuing relevance of this classification via regular curation and expert advice

Hsp70 Cochaperones HspBP1 and BAG-1M Differentially Regulate Steroid Hormone Receptor Function

Hsp70 binding protein 1 (HspBP1) and Bcl2-associated athanogene 1 (BAG-1), the functional orthologous nucleotide exchange factors of the heat shock protein 70 kilodalton (Hsc70/Hsp70) chaperones, catalyze the release of ADP from Hsp70 while inducing different conformational changes of the ATPase domain of Hsp70. An appropriate exchange rate of ADP/ATP is crucial for chaperone-dependent protein folding processes. Among Hsp70 client proteins are steroid receptors such as the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), and the androgen receptor (AR). BAG-1 diversely affects steroid receptor activity, while to date the influence of HspBP1 on steroid receptor function is mostly unknown. Here, we compared the influence of HspBP1 and BAG-1M on Hsp70-mediated steroid receptor folding complexes and steroid receptor activity. Coimmunoprecipitation studies indicated preferential binding of Hsp40 and the steroid receptors to BAG-1M as compared to HspBP1. Furthermore, Hsp70 binding to the ligand-binding domain of GR was reduced in the presence of HspBP1 but not in the presence of BAG-1M as shown by pull-down assays. Reporter gene experiments revealed an inhibitory effect on GR, MR, and AR at a wide range of HspBP1 protein levels and at hormone concentrations at or approaching saturation. BAG-1M exhibited a transition from stimulatory effects at low BAG-1M levels to inhibitory effects at higher BAG-1M levels. Overall, BAG-1M and HspBP1 had differential impacts on the dynamic composition of steroid receptor folding complexes and on receptor function with important implications for steroid receptor physiology

Impact of Nucleon Mass Shift on the Freeze Out Process

The freeze out of a massive nucleon gas through a finite layer with time-like normal is studied. The impact of in-medium nucleon mass shift on the freeze out process is investigated. A considerable modification of the thermodynamical variables temperature, flow-velocity, energy density and particle density has been found. Due to the nucleon mass shift the freeze out particle distribution functions are changed noticeably in comparison with evaluations, which use vacuum nucleon mass.Comment: submitted to Physical Review

Disturbed cofactor binding by a novel mutation in UDP-galactose 4 '-epimerase results in a type III galactosemia phenotype at birth

The p.A89V variant of UDP-galactose 4′-epimerase (GALE) is less stable and has lower affinity for the NAD+cofactor than the wild-type enzyme.</p

Transient trimethylaminuria related to menstruation

BACKGROUND: Trimethylaminuria, or fish odor syndrome, includes a transient or mild malodor caused by an excessive amount of malodorous trimethylamine as a result of body secretions. Herein, we describe data to support the proposal that menses can be an additional factor causing transient trimethylaminuria in self-reported subjects suffering from malodor and even in healthy women harboring functionally active flavin-containing monooxygenase 3 (FMO3). METHODS: FMO3 metabolic capacity (conversion of trimethylamine to trimethylamine N-oxide) was defined as the urinary ratio of trimethylamine N-oxide to total trimethylamine. RESULTS: Self-reported Case (A) that was homozygous for inactive Arg500stop FMO3, showed decreased metabolic capacity of FMO3 (i.e., ~10% the unaffected metabolic capacity) during 120 days of observation. For Case (B) that was homozygous for common [Glu158Lys; Glu308Gly] FMO3 polymorphisms, metabolic capacity of FMO3 was almost ~90%, except for a few days surrounding menstruation showing < 40% metabolic capacity. In comparison, three healthy control subjects that harbored heterozygous polymorphisms for [Glu158Lys; Glu308Gly] FMO3 or homozygous for wild FMO3 showed normal (> 90%) metabolic capacity, however, on days around menstruation the FMO3 metabolic capacity was decreased to ~60–70%. CONCLUSION: Together, these results indicate that abnormal FMO3 capacity is caused by menstruation particularly in the presence, in homozygous form, of mild genetic variants such as [Glu158Lys; Glu308Gly] that cause a reduced FMO3 function

ost in promiscuity? An evolutionary and biochemical evaluation of HSD10 function in cardiolipin metabolism

Multifunctional proteins are challenging as it can be difficult to confirm pathomechanisms associated with disease-causing genetic variants. The human 17β-hydroxysteroid dehydrogenase 10 (HSD10) is a moonlighting enzyme with at least two structurally and catalytically unrelated functions. HSD10 disease was originally described as a disorder of isoleucine metabolism, but the clinical manifestations were subsequently shown to be linked to impaired mtDNA transcript processing due to deficient function of HSD10 in the mtRNase P complex. A surprisingly large number of other, mostly enzymatic and potentially clinically relevant functions have been attributed to HSD10. Recently, HSD10 was reported to exhibit phospholipase C-like activity towards cardiolipins (CL), important mitochondrial phospholipids. To assess the physiological role of the proposed CL-cleaving function, we studied CL architectures in living cells and patient fibroblasts in different genetic backgrounds and lipid environments using our well-established LC–MS/MS cardiolipidomic pipeline. These experiments revealed no measurable effect on CLs, indicating that HSD10 does not have a physiologically relevant function towards CL metabolism. Evolutionary constraints could explain the broad range of reported substrates for HSD10 in vitro. The combination of an essential structural with a non-essential enzymatic function in the same protein could direct the evolutionary trajectory towards improvement of the former, thereby increasing the flexibility of the binding pocket, which is consistent with the results presented here

Evaluating chiral symmetry restoration through the use of sum rules

We pursue the idea of assessing chiral restoration via in-medium modifications of hadronic spectral functions of chiral partners. The usefulness of sum rules in this endeavor is illustrated, focusing on the vector and axial-vector channels. We first present an update on constructing quantitative results for pertinent vacuum spectral functions. These spectral functions serve as a basis upon which the in-medium spectral functions can be constructed. A striking feature of our analysis of the vacuum spectral functions is the need to include excited resonances, dictated by satisfying the Weinberg-type sum rules. This includes excited states in both the vector and axial-vector channels. Preliminary results for the finite temperature vector spectral function are presented. Based on a rho spectral function tested in dilepton data which develops a shoulder at low energies, we find that the rho' peak flattens off. The flattening may be a sign of chiral restoration, though a study of the finite temperature axial-vector spectral function remains to be carried out.Comment: 9 pages, conference proceedings from Resonance Workshop at UT Austin, March 5-7 201

Direction of light propagation to order G^2 in static, spherically symmetric spacetimes: a new derivation

A procedure avoiding any integration of the null geodesic equations is used to derive the direction of light propagation in a three-parameter family of static, spherically symmetric spacetimes within the post-post-Minkowskian approximation. Quasi-Cartesian isotropic coordinates adapted to the symmetries of spacetime are systematically used. It is found that the expression of the angle formed by two light rays as measured by a static observer staying at a given point is remarkably simple in these coordinates. The attention is mainly focused on the null geodesic paths that we call the "quasi-Minkowskian light rays". The vector-like functions characterizing the direction of propagation of such light rays at their points of emission and reception are firstly obtained in the generic case where these points are both located at a finite distance from the centre of symmetry. The direction of propagation of the quasi-Minkowskian light rays emitted at infinity is then straightforwardly deduced. An intrinsic definition of the gravitational deflection angle relative to a static observer located at a finite distance is proposed for these rays. The expression inferred from this definition extends the formula currently used in VLBI astrometry up to the second order in the gravitational constant G.Comment: 19 pages; revised introduction; added references for introduction; corrected typos; published in Class. Quantum Gra