alf/hsdr-1 is a locus in the mouse defined by albino deletions to be essential for neonatal viability. Homozygous deletion of alf/hsdr-1 leads to a pleiotropic phenotype in liver and kidney, including impaired perinatal activation of hormone-dependent genes, and the induction of detoxifying enzymes and early-response genes. To elucidate the molecular basis of this complex phenotype, we have identified the gene mapping at alf/hsdr-1 by positional cloning, using overlapping albino locus deletions to define the location of alf/hsdr-1. The gene encodes fumarylacetoacetate hydrolase, F AH, an enzyme of tyrosine metabolism. Genetically determined FAH deficiency in man leads to a severe liver failure in infants. In mice, we find that the normal sites of expression of FAH correlate tightly with cell-types which display abnormalities in albino lethal mice. The identification of the Fah gene as a candidate for alf/hsdr-1 offers a novel explanation for the complex phenotype, one into which all aspects can be accommodated. The phenotype can now be understood as a sequence of responses to toxic electrophilic metabolites.

The albino-deletion complex on chromosome 7 in the mouse comprises at least 37 radiation-induced, recessive lethal deletions which define several loci essential for normal development before or after birth (Russell et al., 1982; Rinchik and Russell, 1990). One locus is necessary for survival beyond birth and has been proposed to play an important, regulatory role in the perinatal differentiation of hepatocytes (Gluecksohn-Waelsch, 1979). The locus is designated alf (/actor indicated by the albino lethal mutation, Ruppert et al., 1990) or hsdr-1 (hepatocyte-.specific developmental regulation 1, McKnight et al., 1989) and is referred to as alf/hsdr-1 here.

Mice homozygous for deletions that include alf/hsdr-1 die a few hours after birth. Lethality is associated with severe hypoglycaemia and pleiotropic effects on gene expression in the liver and kidney. The most extensively investigated defect is the failure of perinatal activation of several enzymes involved in gluconeogenesis, notably glu-cose-6-phosphatase (G6Pase), phosphoenolpyruvate car-boxykinase (PEPCK) and tyrosine aminotransferase (TAT), (Erickson et al., 1968; Gluecksohn-Waelsch, 1979; Schmid et al., 1985; Loose et al., 1986). Concomitant with the enzyme deficiencies are reductions in the abundance of a limited number of mRNAs in liver and kidney and decreased transcription of the respective genes (Loose et al., 1986; Morris et al., 1988; Ruppert et al., 1990). The severity of the deficit of TAT mRNA in late fetal and newborn albino lethal liver is illustrated by the northern analysis in Fig. 1. Analysis of a set of affected mRNAs identified by subtractive cDNA hybridization revealed that expression of most of the affected genes was normally inducible in liver by glucocorticoids and/or cAMP around birth (Ruppert et al., 1990). Since expression of G6Pase and TAT cannot be induced by exogenous hormones in liver of albino lethal mice (Thorndike et al., 1973; Schmid et al., 1985), it seemed likely that lack of hormone inducibility was the major component of the reduced expression. This conclusion led to models proposing that alf/hsdr-1 encoded a factor participating in hormonal activation of gene transcription (Gluecksohn-Waelsch, 1987). A specific deficit of factors in the signal transduction pathways for glucocorticoids and cAMP has not been found (Ruppert et al., 1990; DeFranco et al., 1991). Recently, however, transcripts for some transcription factors involved in liver-specific gene expression have been shown to be present at reduced levels. These include the CCAAT/enhancer binding protein C/EBP, and hepatic nuclear factors HNF-1 and HNF-4

Fig. 1.

Multiple effects on gene expression in mice carrying neonatally lethal albino deletions. Northern blot analysis of the expression of TAT, NMO and FOS mRNAs in fetal and newborn liver from albino lethal and wild-type mice. The fetal stages are indicated as days (d) post-coitum, and newborn as hours (hr) after birth. Each lane contains 10 μ g total RNA.

Fig. 1.

Multiple effects on gene expression in mice carrying neonatally lethal albino deletions. Northern blot analysis of the expression of TAT, NMO and FOS mRNAs in fetal and newborn liver from albino lethal and wild-type mice. The fetal stages are indicated as days (d) post-coitum, and newborn as hours (hr) after birth. Each lane contains 10 μ g total RNA.

In addition to the reduced expression of specific genes in liver and kidney, some genes have been found to be overexpressed. These appear to fall into two categories. The first set encodes enzymes involved in oxidative and non-oxidative detoxification reactions: UDP-glucoronyltransferase (Ugt-1), glutathione S-transferase B (Gt-1) and NAD(P)H:menadione oxido-reductase (NMO), (Thaler et al., 1976; Gatmaitan et al., 1977; Petersen et al., 1989). NMO mRNA is highly induced by fetal day 16.5 in albino lethal liver, whereas the transcript is not detected in wildtype liver (Fig. 1). These enzymes belong to the aryl hydro-carbon [Ah] battery (Nebert et al., 1990), and it has been proposed that a locus encoding a negative regulator of the Ah battery, designated Nmo-ln, is removed by lethal albino deletions (Nebert et al., 1990). The second category appears to comprise genes with the common property of induction in response to DNA damage. This includes three gadd genes (growth arrest and DNA damage inducible, Fornace et al., 1989), and c-fos (Ruppert et al., 1992). Whereas FOS mRNA is readily detected only 0-1 h after birth in wild-type liver, it is present at high levels from fetal day 18.5 and maintained up to 13 h after birth in albino lethal liver (Fig. 1). A sustained induction of FOS mRNA accompanies DNA damage by alkylating agents (Hollander and For-nace, 1989). Of the gadd transcripts induced in albino lethal liver, one, gaddl53, has recently been identified to encode a member of the C/EBP family, CHOP-10, a putative inhibitor of C/EBP-like transcription factors (Ron and Habener, 1992).

As well as effects on gene expression, ultrastructural abnormalities visible by electron microscopy have been described in liver and kidney (Trigg and Gluecksohn-Waelsch, 1973). They develop late in gestation and affect the membranes of the rough endoplasmic reticulum, Golgi apparatus and nuclear membrane. These abnormalities may account for a reduced synthesis of serum proteins by the albino lethal liver (Garland et al., 1976). (McKnight et al., 1989; Ruppert et al., 1990; Gonzalez et al., 1990; Tonjes et al., 1992).

The diverse nature of the phenotype made it difficult to predict a simple function for the alf/hsdr-1 gene product upon which a biochemical approach to its identification could be based. Instead, we attempted to isolate the gene mapping at alf/hsdr-1 by positional cloning, taking advantage of the fact that the locus is defined by a large number of chromosomal deletions around the albino locus, c. Complementation analysis of c-locus deletions indicates that alf/hsdr-1 is the first essential locus proximal to c (Russell et al., 1982). A panel of overlapping deletions that do or do not involve alf/hsdr-1 was used to order molecular markers. In parallel, pulsed-field gel electrophoresis was employed to link the markers physically and create a long-range restriction map of the albino-deletion complex. This revealed that lethal albino deletions encompassing alf/hsdr-1 were large; cI4CoS, for example, a deletion which has been the subject of much analysis at the phenotypical level, proved to be approx. 3800 kb (Fig. 2A; Kelsey et al., unpublished data). However, by comparing with deletions such as c,,DSD that complement c14CoS for neonatal lethality and do not, therefore, extend to alf/hsdr-1, it was possible to exclude most of the c,4CoS deletion and define an approx. 310 kb minimal interval for the candidate gene (Fig. 2A; Schedl et al., unpublished data). To obtain new probes within the interval, chromosome jumping was undertaken from two flanking markers, RN226.1 proximally (Klebig et al., 1992) and palb 18 distally (Niswander et al., 1991). Eight jumps in libraries based on rare-cutting enzymes Xmal, Sall and Zi.s.sHII were made, and more than 100 kb of the approx. 310 kb interval cloned in phage contigs (Fig. 2B; Schedl et al., unpublished data). Transcription units mapping within the contigs were identified by zoo blot and northern analysis. The contig designated RN which overlaps the proximal end of the cI4CoS deletion was found to contain the gene for fumarylacetoacetate hydrolase (FAH; Fig. 2B; Klebig et al., 1992; Ruppert et al., 1992). FAH catalyses the final step in the degradation of tyrosine, the hydrolysis of fumarylacetoacetate, FAA. FAH deficiency is known to be the underlying defect in an inborn error of metabolism in man, hereditary tyrosinaemia type I (HT; Kvittingen, 1986; Goldsmith and Laberge, 1989). HT presents as a severe liver failure which is fatal in the first months of life if liver transplantation cannot be performed. Liver damage is thought to come about from the accumulation of the highly electrophilic tyrosine metabolite FAA, which is considered to be toxic (Laberge et al., 1986). The existence of this human disease suggests that absence of FAH might account for or contribute to the liver phenotype of albino lethal mice.

Fig. 2.

Identification of a candidate gene for alf/hsdr-1 by positional cloning. In (A), the location of alf/hsdr-1 is shown on the chromosome proximal to c, and defined as lying between the ends of albino deletions cI4CoS and c”DSD, which are represented by the stippled bars. The distribution of Zi.v.vHII sites (Bss) over the region spanned by the c4CoS deletion is shown on the lower line. (B) shows a high resolution physical analysis of the minimal region for alf/hsdr-1. The series of chromosome jumps made from flanking markers RN226.1 and palbl8 is shown by the arcs. The solid lines indicate contigs cloned across the region, and the location of a selection of rare-cutter sites is shown. The stippled bars represent the c,4CoS and c7/D5Ddeletions. The minimal region for the location of alf/hsdr-1 is shown; the broken arrow indicates the possibility that the gene for alf/hsdr-1 could extend beyond the c,4CoS deletion. The thick arrow demotes the location of the Fah gene.

Fig. 2.

Identification of a candidate gene for alf/hsdr-1 by positional cloning. In (A), the location of alf/hsdr-1 is shown on the chromosome proximal to c, and defined as lying between the ends of albino deletions cI4CoS and c”DSD, which are represented by the stippled bars. The distribution of Zi.v.vHII sites (Bss) over the region spanned by the c4CoS deletion is shown on the lower line. (B) shows a high resolution physical analysis of the minimal region for alf/hsdr-1. The series of chromosome jumps made from flanking markers RN226.1 and palbl8 is shown by the arcs. The solid lines indicate contigs cloned across the region, and the location of a selection of rare-cutter sites is shown. The stippled bars represent the c,4CoS and c7/D5Ddeletions. The minimal region for the location of alf/hsdr-1 is shown; the broken arrow indicates the possibility that the gene for alf/hsdr-1 could extend beyond the c,4CoS deletion. The thick arrow demotes the location of the Fah gene.

The positive and negative effects on gene expression that characterize the alf/hsdr-1 phenotype occur in liver and kidney. In situ hybridization analysis with probes for TAT and PEPCK identified the affected cell-types as parenchymal cells in the liver and proximal convoluted tubule cells in the kidney (Ruppert et al., 1990). The same two cell-types manifest the ultrastructural abnormalities (Trigg and Gluecksohn-Waelsch, 1973). To obtain an indication that absence of the Fah gene could contribute to this pleiotropic phenotype, the sites of expression of FAH mRNA were examined. Northern blot analysis of wild-type mouse tissues detected high levels of FAH mRNA specifically in liver and kidney. Furthermore, expression was found to commence by fetal day 16.5 in both organs (Ruppert et al., 1992). In situ hybridization was carried out to refine the correlation between sites of expression and the phenotype. Fig. 3A shows the detection of FAH transcripts in wildtype kidney (fetal day 18): hybridization is localized to the proximal convoluted tubules and is absent from structures such as glomeruli and collecting ducts. PEPCK mRNA, whose expression is strongly reduced in lethal albino liver and kidney (Ruppert et al., 1990), is also detected specifically in proximal convoluted tubules in wild-type kidney (Fig. 3B). The elevated expression of NMO mRNA in the lethal albino kidney occurs in the same cell-type (Fig. 3C). In liver, expression of FAH and PEPCK mRNAs in wildtype, and NMO mRNA in lethal albino mice, is restricted to hepatocytes (data not shown). The precise coincidence between the sites of FAH expression and the alf/hsdr-1 phenotype is strong correlative evidence that absence of FAH underlies the phenotype. Functional evidence has come from our ability to reproduce changes in gene expression similar to those seen in the albino lethal liver in primary hepatocyte cultures treated with tyrosine metabolites (Ruppert et al., 1992). In conclusive experiments in transgenic mice, we have been able to show that an FAH cDNA transgene restores viability to lethal albino c,4CoS mice (G. K., S. R. and F. Beermann, unpublished observations).

Fig. 3.

The expression pattern of FAH correlates with the alf/hsdr-1 phenotype. In situ hybridization of sections of fetal day-18 kidney with probes for FAH (A), PEPCK (B) and NMO-1 (C). (A) and (B) are sections of wild-type kidney, (C) is a section of albino lethal kidney. Dark field illumination is shown.

Fig. 3.

The expression pattern of FAH correlates with the alf/hsdr-1 phenotype. In situ hybridization of sections of fetal day-18 kidney with probes for FAH (A), PEPCK (B) and NMO-1 (C). (A) and (B) are sections of wild-type kidney, (C) is a section of albino lethal kidney. Dark field illumination is shown.

The discovery that the Fah gene is disrupted and that tyrosine metabolism, in consequence, is blocked in albino lethal mice, offers a means for rationalizing the multiple components of the neonatal lethal phenotype (Fig. 4A). Contrary to the prediction that alf/hsdr-1 encodes a regulatory factor, the characteristic changes in gene expression must be viewed as phenomena secondary to the absence of FAH. It is possible to speculate how these secondary effects come about, and these hypotheses can be tested. FAA, the tyrosine metabolite likely to accumulate, is highly electrophilic and a potential alkylating agent (Laberge et al., 1986). Induction of NMO, Gt-1 and Ugt-1 (Thaler et al., 1976; Gatmaitan et al., 1977; Petersen et al., 1989), can be considered to be attempts to detoxify the liver and kidney. NMO and Gt-1 expression is inducible by a variety of electrophilic agents (Talalay et al., 1988) and, consistent with a role in detoxification, over-expression of NMO mRNA is an early component of the phenotype and occurs in the same cell-types that should normally express FAH. Therefore, we would reject the hypothesis that a negative regulatory locus for NMO expression, Nmo-ln, maps within the albino deletions (Nebert et al., 1990). The ultrastructural abnormalities (Trigg and Gluecksohn-Waelsch, 1973) are likely to be a manifestation of the presence of highly reactive compounds. Induction of the gadd and c-fos genes might be a response to DNA or other intracellular damage precipitated by FAA (Fornace et al., 1989; Holbrook and Fornace, 1991; Ruppert et al., 1992). These genes are induced before birth, which could be considered to be early responses to the electrophilic metabolite(s).

Fig. 4.

Toxic tyrosine metabolites and specific effects on gene expression. Our current working model for the routes by which electrophilic tyrosine metabolites accumulating as a result of FAH deficiency could induce the diverse phenomena that characterize the alf/hsdr-1 phenotype is shown schematically in (A). (B) illustrates the mechanisms by which the perinatal, hormone induction of the TAT gene could be blocked in the albino lethal liver, as discussed in the text.

Fig. 4.

Toxic tyrosine metabolites and specific effects on gene expression. Our current working model for the routes by which electrophilic tyrosine metabolites accumulating as a result of FAH deficiency could induce the diverse phenomena that characterize the alf/hsdr-1 phenotype is shown schematically in (A). (B) illustrates the mechanisms by which the perinatal, hormone induction of the TAT gene could be blocked in the albino lethal liver, as discussed in the text.

The failure to activate hormone-dependent genes is the component of the phenotype that becomes pronounced around birth. Taking the TAT gene as prototype for this set of genes, several mechanisms can be envisaged by which activation is impaired, considering that the signal transduction pathways for glucocorticoids and cAMP are apparently intact (Ruppert et al., 1990; DeFranco et al., 1991). They are outlined in Fig. 4B. Activation of TAT gene expression around birth is dependent upon permissive effects of glucocorticoids and cAMP, and the elements mediating this regulation have been defined for the rat gene (Nitsch et al., 1991). Three far-upstream enhancers each contribute a unique aspect of tissue-specificity and/or hormonal regulation (Nitsch et al., 1990). The enhancer at -2.5kb is responsible for regulation by glucocorticoids (Jantzen et al., 1987), and binding sites for the glucocorticoid receptor and transcription factors C/EBP and HNF-3 have been identified (Becker et al., 1986; Jantzen et al., 1987; Grange et al., 1991; D. Nitsch, personal communication). The gaddl53 gene, highly induced in albino lethal liver, encodes the C/EBP-like protein CHOP-10 (Ron and Habener, 1992). CHOP-10 is a putative dominant inhibitor of C/EBP proteins; it contains a leucine zipper domain capable of dimerizing with C/EBP and preventing recognition of C/EBP sites. CHOP-10 over-expression, therefore, could contribute to down-regulation of the glucocorticoid enhancer of the TAT gene. C/EBP may also play a role in PEPCK gene expression (Park et al., 1990). The sustained expression of FOS in lethal albino liver may also affect glucocorticoid induction. Many studies have indicated that FOS can antagonize glucocorticoid induction (Jonat et al., 1990; Lucibello et al., 1990; Yang-Yen et al., 1990; Shemshedini et al., 1991), although the mechanism remains to be established. Finally, of the transcription factors whose expression is down-regulated in albino lethal liver (Tonjes et al., 1992), HNF-4 is an important factor for TAT expression. The cAMP-inducible enhancer at -3.6 kb contains an HNF-4 site as one of the crucial elements (Boshart et al., 1990; D. Nitsch, personal communication). It remains to be determined how expression of the HNF-4 gene is reduced in the albino lethal liver, but it is conceivable that over-expression of CHOP-10, FOS or other early response genes might be involved.

In conclusion, with the identification that the Fah gene is disrupted, the components of the neonatal lethal albino phenotype become explicable as a sequence of events stemming from the accumulation of a reactive metabolite(s). These include induction of detoxification mechanisms and early-response genes, the latter possibly in response to DNA damage, and altered activity of key transcription factors. Future experiments will be designed to deepen the understanding of these events.

We should like to thank Doris Nitsch for sharing with us her views on the regulation of the rat TAT gene. We are grateful to G. Withers for photographic work and C. Schneider for excellent secretarial assistance. This work was supported by the Deutsche Forschungsgemeinschaft through SFB 229 and the Leibniz Programm, and the Fonds der Chemischen Industrie.

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