NR AEHA
AU Gabizon,R.; Halimi,M.; Meiner,Z.
TI Genetics and biochemistry of Creutzfeldt-Jakob disease in Libyan Jews
QU Biomedicine and Pharmacotherapy 1994; 48(8-9): 385-90
PT journal article
AB A focus of Creutzfeldt-Jakob disease (CJD) among Jews from Libyan origin was identified in Israel 20 years ago. The incidence of the disease in this ethnic group is about 100 times more than in the worldwide population. The consumption of lightly cooked sheep brain has been invoked to explain the high incidence of CJD in this community. The discovery of mutations in the PrP gene which segregates with other familial prion diseases such as Gerstmann-Sträussler syndrome (GSS) lead us to perform a molecular genetic study and compare it to an epidemiological survey among the Libyan community. The epidemiological data suggests a very high familial incidence of CJD in this population and a molecular genetic research elucidated that CJD segregates with a point mutation at codon 200 of the PrP gene resulting in the substitution of Lysine for Glutamate. This mutation was found in some 40 CJD patients of Libyan origin and was not found in one Moroccan Jew suffering from CJD. It was also absent in almost 100 healthy Libyan controls above the age of 60. This result strongly supports a genetic etiology for CJD pathogenesis in the Libyan Jewish community and disregards the previous culinary hypothesis. The disease is vertically transmitted in autosomal dominant inheritance with unknown penetrance. All our patients were heterozygote for the mutation except one homozygote patient. The course of the disease in this patient was identical to the heterozygote patients, strongly arguing that inherited CJD displays complete phenotypic dominance. We examined the presence of PrP in cerebrospinal fluid (CSF), fibroblasts and leukocytes derived from eight CJD patients with the codon 200 mutation. In patients' CSF, only negligible higher concentration of the normal protein was found as compared to normal CSF. In cultured fibroblasts as well as leukocytes, there was a significant increase in PrP as judged by immunoblotting. Most of the PrP present in fibroblasts and leukocytes could be released from the external surface by phosphatidylinositol-specific phospholipase C, a property characteristic of PrPc. In leukocytes only, part of the protein was protease resistant, resembling PrPcJD. The concentration of PrP mRNA was similar in fibroblast lines derived from controls and from CJD patients. These results suggest that in CJD patients carrying a mutation at codon 200 of the PrP gene, the metabolism of PrP, rather than PrP synthesis, is abnormal.
IN Unter lybischen Juden tritt die Creutzfeldt-Jakob-Krankheit etwa 100-fach häufiger als normal auf. Dafür scheint aber nicht der Genuß unzureichend gekochter Schafgehirne, sondern die bekannte Mutation des Codons 200 des Prionproteins verantwortlich zu sein. Die von den Autoren sogenannte Prion-Krankheit wird autosomal dominant vererbt. In der Gehirn- und Rückenmarksflüssigkeit ist die Konzentration normaler Prionproteine nur vernachlässigbar erhöht. Dagegen wurden auf den Membranen kultivierter Fibroblasten und Leukozyten aus Creutzfeldt-Jakob-Patienten deutlich mehr Prionproteine gefunden. Diese ließen sich überwiegend durch die phosphatidylinositolspezifische Phospholipase C ins Medium freisetzen, was charakteristisch für normale Prionproteine ist. Auf Leukozyten war nur ein Teil der Prionproteine proteaseresistent. Die Fibroblasten aus Creutzfeldt-Jakob-Patienten enthielten aber nicht wesentlich mehr mRNA für das Prionprotein. Die Akkumulation der Prionproteine scheint demnach nicht auf einer gesteigerten Produktion zu beruhen.
MH Blotting, Northern; Blotting, Western; Creutzfeldt-Jakob Syndrome/ethnology/*genetics; Fibroblasts/chemistry; Human; *Jews; Leukocytes/chemistry; Libya/ethnology; Mutation; Prions/analysis/cerebrospinal fluid/genetics
AD Department of Neurology, Hadassah University Hospital, Jerusalem, Israel.
SP englisch
PO Frankreich
ZF kritische Zusammenfassung von Roland Heynkes