Dubin-Johnson Syndrome

A number sign (#) is used with this entry because of evidence that Dubin-Johnson syndrome (DJS) is caused by homozygous or compound heterozygous mutation in the CMOAT gene (ABCC2; 601107) on chromosome 10q24.

Description

Dubin-Johnson syndrome is an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, an increase in the urinary excretion of coproporphyrin isomer I, deposition of melanin-like pigment in hepatocytes, and prolonged retention of sulfobromophthalein, but otherwise normal liver function (summary by Wada et al., 1998).

Clinical Features

Dubin and Johnson (1954) described 12 patients with a distinct entity characterized clinically by 'constitutional hyperbilirubinemia' and histologically by the presence in the liver cells of striking amounts of an amorphous brown pigment. The disorder manifested as a form of chronic or intermittent jaundice in young people. The most common symptoms were abdominal pain and fatigue; jaundice, dark urine, and slight enlargement of the liver were the only signs present. The jaundice fluctuated in intensity and was aggravated by intercurrent diseases. The prognosis is excellent.

In early reports, the Dubin-Johnson syndrome was described twice in mother and son (Beker and Read, 1958; Wolf et al., 1960), but at least 7 instances of multiple affected sibs with normal parents were described (Du and Rogers, 1967). Calderon and Goldgraber (1961) described a Peruvian patient whose parents were first cousins. Du and Rogers (1967) described 3 affected sisters whose clinically normal parents were first cousins once removed. Three offspring of 1 affected sister had normal livers (by inspection at laparotomy in 2 and by autopsy in the third).

Shani et al. (1970) stated that the characteristics of DJS are hyperbilirubinemia, deposition of melanin-like pigment in otherwise normal liver cells, in some cases hepatomegaly and abdominal pain, prolonged retention of sulfobromophthalein (which may show a higher concentration at 60 to 90 minutes than at 45 minutes), and otherwise normal liver function. Shani et al. (1970) studied 101 patients with the Dubin-Johnson syndrome ascertained in Israel between 1955 and 1969. Age at onset of jaundice varied from 10 weeks to 56 years. Penetrance is reduced in females. Sixty-four of the cases were Iranian Jews. Parents of affected sibships were consanguineous in 45% of cases as compared with a frequency of 26% among Iranian Jews generally. Segregation analysis yielded results consistent with autosomal recessive inheritance with reduced penetrance. The authors suggested that minor abnormalities may occur in heterozygotes. This suggestion is supported by the findings of Butt et al. (1966), who performed an extensive family study with liver biopsies and other examinations in many relatives.

In the Israel group of cases of DJS, Seligsohn et al. (1970) reported a striking association with deficiency of factor VII (613878). The association was limited to Iranian Jews. Adam (1972) stated that this association has been seen not only in Iranian Jews but also in Iraqi and Moroccan Jews, in Ashkenazim and perhaps in other Europeans. Kondo (1980) found no instance of factor VII deficiency in Japanese cases of DJS.

Arias (1971) gave a useful review of all hereditary hyperbilirubinemias.

Wolkoff et al. (1973) found that urinary coproporphyrin I is a good indicator of the homozygote and heterozygote states in the Dubin-Johnson syndrome. Normals excreted 24.8% of urinary coproporphyrin as coproporphyrin I, whereas homozygotes and heterozygotes excreted 88.9 and 31.6%, respectively. The standard errors of these means were 1.3%, 1.3%, and 1.2%, respectively.

In an isolated area of Japan, Kondo et al. (1974) found 40 cases of definite and 8 cases of probable DJS, distributed in 25 sibships of 22 families. Parental consanguinity was found in 52%.

Nakata et al. (1979) reported a Japanese patient diagnosed in the neonatal period. Both parents and both grandfathers showed ratios of coproporphyrin isomer I to total urinary coproporphyrin in excess of 40%, characteristic of heterozygotes. The proband's ratio was 97%.

Swartz et al. (1987) used electron spin resonance to analyze the hepatic pigment from a hepatoma in a patient with Dubin-Johnson syndrome. They demonstrated that the pigment associated with Dubin-Johnson syndrome has no free radical in the absence of light, thus distinguishing the pigment from typical melanin or its closely related polymers.

Using double-label immunofluorescence and confocal laser scanning microscopy with antibodies directed against MRP and dipeptidyl peptidase IV (102720), Kartenbeck et al. (1996) demonstrated selective absence of the canalicular isoform of MRP (CMOAT, ABCC2) in the hepatocytes of a patient with Dubin-Johnson syndrome. Another isoform of MRP was detected, however, in the lateral hepatocyte membrane of the patient. Moreover, MRP was present on immunoblots of erythrocyte membranes from Dubin-Johnson syndrome and normal humans. These findings were analogous to previous observations on the localization of the rat homolog of MRP and its canalicular isoform in normal and transport-deficient Wistar rat liver (Mayer et al., 1995).

Inheritance

The Dubin-Johnson syndrome is an autosomal recessive disorder (Shani et al., 1970; Wada et al., 1998).

Population Genetics

The usefulness of inbred groups for the study of rare recessives is nicely illustrated by this disorder, which occurs with a minimal frequency of 1 per 1,300 among Iranian Jews (Shani et al., 1970).

Mapping

Zimniak (1993) suggested that the defect in Dubin-Johnson syndrome may reside in the CMOAT gene, which maps to chromosome 10q24. Van Kuijck et al. (1997) also suggested that CMOAT was a very strong candidate for the site of the mutation in DJS.

Molecular Genetics

Consistent with findings of defects in the homologous cmoat gene in 2 rat models of hyperbilirubinemia (Paulusma et al., 1996; Ito et al., 1997), Wada et al. (1998) reported 2 deletions and a missense mutation in the active transport family signature region of the CMOAT gene (ABCC2; 601107.0001-601107.0003) in patients with DJS.

In a 63-year-old Japanese man with DJS, born of first-cousin parents, Kajihara et al. (1998) identified homozygosity for a splice site mutation in the ABCC2 gene (601107.0006).

Toh et al. (1999) identified 3 mutations, 2 of which were novel, in the MRP2/CMOAT gene in DJS patients (601107.0001 and 601107.0003-601107.0004).

Mor-Cohen et al. (2001) analyzed the ABCC2 gene in 35 Israeli DJS patients from 24 unrelated families, most of whom were ascertained previously by Shani et al. (1970) and had been followed for more than 3 decades, including 22 patients from 13 Iranian Jewish families, 5 from 4 Moroccan Jewish families, 2 from mixed Moroccan and Iranian families, 3 of Ashkenazi Jewish origin, and 3 of Turkish, Kurdish, and Afghan Jewish origin, respectively. All 22 Iranian Jewish patients were homozygous for an I1173F mutation (601107.0007) in ABCC2, and all 5 Moroccan Jewish patients were homozygous for an R1150H mutation (601107.0008). Both mutations were unique to those specific populations.

In 2 brothers with neonatal-onset DJS, Pacifico et al. (2010) identified compound heterozygosity for an R768W mutation (601107.0001) and a nonsense mutation (R1066X; 601107.0009) in the ABCC2 gene. Both mutations had previously been found in adult patients, although compound heterozygosity for the 2 mutations was novel.

Animal Model

The identification of the transport-deficient mutant rat strain, TR(-), which shows chronic conjugated hyperbilirubinemia as in human Dubin-Johnson syndrome, contributed to the functional characterization of CMOAT. Paulusma et al. (1996) noted that detoxification of many endogenous and xenobiotic lipophilic compounds in the liver is accomplished by transferase-mediated conjugation with glutathione, glucuronide, or sulfate moieties, resulting in negatively charged, amphiphilic compounds that are efficiently secreted into bile or urine. Hepatobiliary excretion of these conjugates is mediated by an ATP-dependent transport system, called CMOAT (canalicular multispecific organic anion transporter), located in the apical, or canalicular, membrane of the hepatocyte. Paulusma et al. (1996) identified a cDNA for rat CMOAT and also presented evidence that, while multidrug-resistance-associated protein-1 (MRP; 158343) shows a basolateral location in hepatocytes, CMOAT shows an exclusively canalicular localization. Their observation implied that CMOAT and not MRP is involved in biliary organic anion transport. They presented sequence data indicating that the 2 have different sequences, making it unlikely that they are derived from a single gene by differential splicing and suggesting instead that MRP and CMOAT are encoded by 2 different genes. Paulusma et al. (1996) found that a 1-bp deletion in the CMOAT gene, which resulted in reduced mRNA levels and a truncated nonviable protein, was responsible for the impaired transport of organic compounds from liver to bile in the TR(-) rat.