Bothnia dystrophy is caused by domino-like rearrangements in cellular retinaldehyde-binding protein mutant R234W

Cellular retinaldehyde-binding protein (CRALBP) is essential for mammalian vision by routing 11-cis-retinoids for the conversion of photobleached opsin molecules into photosensitive visual pigments. The arginine-to-tryptophan missense mutation in position 234 (R234W) in the human gene RLBP1 encoding CRALBP compromises visual pigment regeneration and is associated with Bothnia dystrophy. Here we report the crystal structures of both wild-type human CRALBP and of its mutant R234W as binary complexes complemented with the endogenous ligand 11-cis-retinal, at 3.0 and 1.7 A resolution, respectively. Our structural model of wild-type CRALBP locates R234 to a positively charged cleft at a distance of 15 A from the hydrophobic core sequestering 11-cis-retinal. The R234W structural model reveals burial of W234 and loss of dianion-binding interactions within the cleft with physiological implications for membrane docking. The burial of W234 is accompanied by a cascade of side-chain flips that effect the intrusion of the side-chain of I238 into the ligand-binding cavity. As consequence of the intrusion, R234W displays 5-fold increased resistance to light-induced photoisomerization relative to wild-type CRALBP, indicating tighter binding to 11-cis-retinal. Overall, our results reveal an unanticipated domino-like structural transition causing Bothnia-type retinal dystrophy by the impaired release of 11-cis-retinal from R234W.

Early renal failure after domino hepatic transplantation using the liver from a compound heterozygous patient with primary hyperoxaluria.

BACKGROUND To cover the shortage of cadaveric organs, new approaches to expand the donor pool are needed. Here we report on a case of domino liver transplantation (DLT) using an organ harvested from a compound heterozygous patient with primary hyperoxaluria (PHO), who underwent combined liver and kidney transplantation. The DLT recipient developed early renal failure with oxaluria. The time to the progression to oxalosis with renal failure in such situations is unknown, but, based on animal data, we hypothesize that calcineurin inhibitors may play a detrimental role. METHODS A cadaveric liver and kidney transplantation was performed in a 52-year-old male with PHO. His liver was used for a 64-year-old patient with a non-resectable, but limited cholangiocarcinoma. RESULTS While the course of the PHO donor was uneventful, in the DLT recipient early post-operative, dialysis-dependent renal failure with hyperoxaluria developed. Histology of a kidney biopsy revealed massive calcium oxalate crystal deposition as the leading aetiological cause. CONCLUSIONS DLT using PHO organs for marginal recipients represents a possible therapeutic approach regarding graft function of the liver. However, it may negatively alter the renal outcome of the recipient in an unpredictable manner, especially with concomitant use of cyclosporin. Therefore, we suggest that, although DLT should be promoted, PHO organs are better excluded from such procedures.

Decreta Concilii Prouincialis Treuerensis : pr[a]esidente Reuere[n]dissimo in Christo Patre ac domino, D. Ioanne Archiepiscopo Treuerensi, sacri Romani Imperij ... celebrati ; Anno Iesu Christi M.D.XLIX ; Vna cum Decretis Synodi Episcopalis, celebratae Anno M.D.XLVIII

Fingerprint nach Ex. der UB Frankfurt

Da pacem Domine, & c. : X. vox, Deo ter opt. maximo, regi regum, Domino exercituum, principi pacis, devotum

Andreas Berger composuit

Der schwarze Domino : Oper in 3 Akten

Musik von Auber. [Text] nach dem Franz. des Scribe vom ... von Lichtenstein

Der schwarze Domino : komische Oper in 3 Akten

Musik von D. F. E. Auber. [Text] von Eugen Scribe. Neu rev. dt. Text der Gesänge, mit Angabe des Inhalts der Oper und einer Einf. in dieselbe von Hermann Mendel

Der schwarze Domino : komische Oper in drei Akten

von Auber

Geraldine Farrar, Rollenbild, Kniestück, in: D. F. E. Auber: Le domino noir

Signatur des Originals: S 36/F03619

Frieda Hempel, Rollenbild, Kniestück, in: D. F. E. Auber: Schwarzer Domino

Signatur des Originals: S 36/F04427

Bianca Bianchi als Angela, Rollenbild, in: Daniel-Françoise-Esprit Auber: Le Domino noir

Signatur des Originals: S 36/F08212

Tractatus de anima / editus ac castigatus de nouo, a domino Petro de Alliaco.

Marca tip. en port. (Silvestre. Marques, 104)

Sacra Rituum Congregatione Emo & Rmo Domino Card. Antonio ab Auria valentina beatificationis [et] canonizationis Ven. Servi Dei Joannis de Ribera Patriarchae Antiocheni & Archiepiscopi Valentini Nova positio super miraculis [Texto impreso]

Marca tip. en port.

Sacra Rituum Congregatione Emo & Rmo Domino Card. Antonio ab Auria Valentina Beatificationis [et] Canonizationis Ven. Servi Dei Joannis de Ribera ... [Texto impreso] Positio super miraculis

Marca tip. en port

Prima Synodus Oriolana [Texto impreso] : sub sanctissimo domino nostro Pio V pontif. max. ... : a Gregorio Gallo, Episcopo Oriolensi habita : XIX maii, anno MDLXIX

Apéndices en español

Analysis of the Drosophila host defense in domino mutant larvae, which are devoid of hemocytes

We have analyzed the Drosophila immune response in domino mutant larvae, which are devoid of blood cells. The domino mutants have a good larval viability, but they die as prepupae. We show that, on immune challenge, induction of the genes encoding antimicrobial peptides in the fat body is not affected significantly in the mutant larvae, indicating that hemocytes are not essential in this process. The hemocoele of domino larvae contains numerous live microorganisms, the presence of which induces a weak antimicrobial response in the fat body. A full response is observed only after septic injury. We propose that the fat body cells are activated both by the presence of microorganisms and by injury and that injury potentiates the effect of microorganisms. Survival experiments after an immune challenge showed that domino mutants devoid of blood cells maintain a wild-type resistance to septic injury. This resistance was also observed in mutant larvae in which the synthesis of antibacterial peptides is impaired (immune deficiency larvae) and in mutants that are deficient for humoral melanization (Black cells larvae). However, if domino was combined with either the immune deficiency or the Black cell mutation, the resistance to septic injury was reduced severely. These results establish the relevance of the three immune reactions: phagocytosis, synthesis of antibacterial peptides, and melanization. By working in synergy, they provide Drosophila a highly effective defense against injury and/or infection.