ABCMdb

PMID: 12624161

Gendrot C, Bacq Y, Brechot MC, Lansac J, Andres C
A second heterozygous MDR3 nonsense mutation associated with intrahepatic cholestasis of pregnancy.
J Med Genet. 2003 Mar;40(3):e32., [PubMed]

Sentences

No. Mutations Sentence Comment

128 ABCB4 p.Arg957* However, clinical and epidemiological studies suggest mainly hormonal and genetic factors.1-3 7 Genetic factors have been suggested by the existence of familial cases and by the high incidence of ICP in some ethnic groups, such as the Araucanos Indians of Chile.8 The multidrug resistance 3 (MDR3, ABCB4, 171060) gene, localised on 7q21.1, was first reported to be involved in ICP by de Vree et al.9 In a large consanguineous family, subjects affected by a subtype of progressive familial intrahepatic cholestasis called PFIC3 were homozygous for a nonsense mutation in exon 23 (R957X) and women affected by ICP were heterozygous; in another family, the same authors reported a homozygous deletion of exon 6 (426-432del) in a PFIC3 patient with consanguineous, healthy parents.9 A mutation in exon 14 of MDR3 (1744delT) was identified in another large pedigree in which all PFIC patients were homozygous for the mutation and women with ICP were heterozygous.10 11 Dixon et al12 investigated eight women affected by ICP with increased serum GGT activity and no familial history of PFIC.12 A missense mutation of exon 14 (A546D) was found in one patient. Login to comment 131 ABCB4 p.Ser320Phe Two of them, from independent and non-consanguineous families, had a homozygous missense mutation in exon 9 (S320F) and the third woman had a heterozygous 1 bp insertion in exon 12 (1327insA), with an early stop codon. Login to comment 156 ABCB4 p.Arg144* In the first patient, the sequence analysis showed a heterozygous substitution (CGA- TGA) in codon 144, which creates a stop codon (R144X) (fig 1). Login to comment 162 ABCB4 p.Arg144* The R144X mutation destroys a SalI restriction site and we used a PCR restriction test to search for this mutation in the control group. Login to comment 163 ABCB4 p.Arg144* No R144X mutation was detected in any of the 100 DNA samples. Login to comment 166 ABCB4 p.Arg144* This R144X mutation is the most proximal truncating mutation reported in this disease, unique to pregnancy (fig 1). Login to comment 169 ABCB4 p.Ser320Phe By contrast, we did not find the six mutations of MDR3 already described in exons 6, 9, 12, 14, and 23 in patients suffering from ICP, PFIC, or cholestasis during pregnancy associated with chronic liver disease.9-13 The role of MDR3 is essential for the secretion of phosphatidylcholine into bile, as has been shown for its close murine homologue Mdr2.15 The Mdr2 knockout mouse is completely unable to secrete phosphatidylcholine into bile and develops mild liver disease, since the augmentation of free biliary bile acids alters the canalicular membrane of the hepatocyte.14 15 In patients with PFIC3, human bile salts are very hydrophobic and the absence of human phosphatidylcholine translocater coded by MDR3 results in serious liver disease.16 The apparent heterozygous status of our patient is in agreement with previous studies in consanguineous families.9 11 In these studies, women affected by ICP were heterozygous for the familial mutation, whereas patients affected by PFIC3 were homozygous.9 10 Moreover, a homozygous state for the missense mutation S320F was observed in two women suffering from chronic liver disease with clinical and biological features outside pregnancy.13 The discovery of these mutations in MDR3 opens the way for a better understanding of the pathogenesis of ICP. Login to comment