title: The histidine-loop is essential for transport activity of human MDR3. A novel mutation of MDR3 in a patient with progressive familial intrahepatic cholestasis type 3.
abstract: Experimental evidence has been provided that a histidine-loop within the nucleotide binding domain of ABC transporter is essential for efficient function of this class of transporter proteins. Here we report the first patient with a mutation of the putative histidine-loop of a human ABC transporter, the multi drug resistance protein 3 (MDR3). The patient presented at the age of 4 years with a history of severe pruritus, elevated serum gamma-glutamyltransferase and bile acid levels since several years suggesting the diagnosis of progressive familial intrahepatic cholestasis type 3 (PFIC-3) due to defects in MDR3. Liver biopsy demonstrated an apparently normal MDR3 expression, however, genetic analysis revealed a novel homozygous mutation in the ABCB4 gene (c.3691C>T) in the patient. This mutation was associated with a change of histidine to tyrosine at amino acid position 1231 of MDR3 (p.H1231Y). As shown by sequence alignment, this amino acid corresponds to the highly conserved histidine of the "H-loop", which is critical for ATP-hydrolysis, suggesting an essential role of histidine 1231 of human MDR3.
authors: Medical Center Mrcheveli Tbilisi, Georgia.
authors: Tamar
authors: T
authors: Dzagania
authors: Guido
authors: G
authors: Engelmann
authors: Dieter
authors: D
authors: Häussinger
authors: Lutz
authors: L
authors: Schmitt
authors: Christa
authors: C
authors: Flechtenmacher
authors: Irakli
authors: I
authors: Rtskhiladze
authors: Ralf
authors: R
authors: Kubitz
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism* / Q000172:deficiency; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism / Q000473:pathology; D001665:Binding Sites / Q000235:genetics; D002675:Child, Preschool; D002780:Cholestasis, Intrahepatic / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D003241:Consanguinity; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D006639:Histidine / Q000737:chemistry; D006720:Homozygote; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D006639:Histidine; C095122:multidrug resistance protein 3