FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair

Chronic kidney disease (CKD) represents a major health burden. Its central feature of renal fibrosis is not well understood. By exome sequencing, we identified mutations in FAN1 as a cause of karyomegalic interstitial nephritis (KIN), a disorder that serves as a model for renal fibrosis. Renal histology in KIN is indistinguishable from that of nephronophthisis, except for the presence of karyomegaly. The FAN1 protein has nuclease activity and acts in DNA interstrand cross-link (ICL) repair within the Fanconi anemia DNA damage response (DDR) pathway. We show that cells from individuals with FAN1 mutations have sensitivity to the ICL-inducing agent mitomycin C but do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from individuals with Fanconi anemia. We complemented ICL sensitivity with wild-type FAN1 but not with cDNA having mutations found in individuals with KIN. Depletion of fan1 in zebrafish caused increased DDR, apoptosis and kidney cysts. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms contributing to renal fibrosis and CKD.     

Synthesis of 6-deoxy-6-fluoro-L-ascorbic acid

Summary 6-Deoxy-6-fluoro-L-ascorbic acid has been synthesized in 5 steps starting from 2,3-4,6-di-O-isopropylidene-2-keto-L-gulonic acid.Dedicated to Professor Albert Szent-Györgyi, National Foundation for Cancer Research, Marine Biological Laboratory, Woods Hole, Massachusetts, on the occasion of his 85th birthday.     

Bildung eines ascorbigenähnlichen Produktes ausp-Hydroxybenzylalkohol und L-Ascorbinsäure

Summary l-Ascorbic acid reacts withp-hydroxybenzyl alcohol in a similar way as with 3-hydroxymethyl indole in the formation of ascorbigen (bound ascorbic acid). The crystalline reaction product was identified as a 2-C-(p-hydroxybenzyl)-3-keto-hexulosonic acid lactone.

---

Bildung eines ascorbigenähnlichen Produktes ausp-Hydroxybenzylalkohol und L-Ascorbinsäure

     

Inhibition of endotoxin-induced platelet agglutination,histamine and serotonine releasein vitro by thiol-compounds

Zusammenfassung Es wird festgestellt, dass gewisse Thiolverbindungen wie Cystein, Mercaptoethanol, Thioglycolsäure und AET die von Endotoxin ausgelöste Thrombocyten-Agglutination, die Freisetzung von Histamin und Serotonin im Kaninchen-Thrombocytenplasma hemmen.     

Die Synthese des Novobiocins

Summary The synthesis of the antibiotic novobiocin is described. First the essential carbohydrate, the 3-O-carbamoylnoviose was synthesized fromd-glucose. A number of steps (1–6) led to the 3,5,6-tri-O-benzyl-2-O-methyl-d-galactono--lactone (6) which is characterized by the correct array of carbon atoms inherent to the noviose. Further transformations (7–15) finally yielded the carbohydrate. The problem of glycosidation is discussed in some detail. Glycosidation of a suitable aglycon precursor (18) with 2,3-O-carbonyl--noviosyl-chloride (22) proved possible and led to the isolation of an-glycoside (23) which was further transformed (24–28) into novobiocin.

---

---

Chemische Forschungsabteilung der F. Hoffmann-La Roche & Co. AG, Basel.

---

Vortrag Dr.B. P. Vaterlaus, gehalten an der Gordon Research Conference on Steroids and other Natural Products, 16.–20. Juli 1962, New Hampton, N.H., USA, und vor der Basler Chemischen Gesellschaft, 8. November 1962. Im Auszug:H. Spiegelberg,Synthèse du 3-O-carbamoylnoviose, sucre de la novobiocine, Symposium international de chimie organique, Bruxelles, 15. Juni 1962;J. Kiss,The Synthesis of Noviose and Allied Compounds, Birkbeck College (Univ. London), 23. Oktober 1962. Der vorliegende Aufsatz ist Gegenstand von Detailpublikationen in den Helv. chim. Acta, in Vorbereitung (1963).     

Comparative studies on the125I uptake of the thyroid and thymus

Zusammenfassung Es wird gezeigt, dass an erwachsenen und neugeborenen Ratten die Jodaufnahme des Thymus bei den letzteren viel höher ist als die Jodaufnahme der Thyroidea. Dies unterstützt die These, wonach die Jodspeicherkapazität der Thyroidea das Resultat einer Differenzierung darstellt, indem auf früherer ontogenetischer Stufe für den ganzen Vorderdarm eine Jodspeicherkapazität besteht.     

Biological activity of precocene analogues onLocusta migratoria

Summary Structure-optimization studies of C-5-C-8-substituted precocene (P) analogues revealed that 1) compounds disubstituted asymmetrically at C-6, C-7 had an anti-allatal effect only if the C-6 side-group was shorter than that at C-7, 2) in the case of C-5, C-7 disubstitution, activity was enhanced by Me at C-5 whereas MeO caused inactivity. Effects of various other substitutions are also discussed.     

The effect of pinealectomy on the Ca and SO4 turnover of the lymphatic organs

Zusammenfassung Untersuchungen mit Na₂ ³⁵SO₄ zeigten, dass nach Exstirpation des Corpus pineale sich die Inkorporation von SO₄ in den lymphatischen Organen bedeutend vermehrt, gleichzeitig der³⁵SO₄-Spiegel des Blutes rasch abnimmt. Parallel dazu ist die⁴⁵CaCl₂-Aufnahme in der Milz und im Thymus herabgesetzt.