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Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT

Abstract

Familial hypercholanemia (FHC) is characterized by elevated serum bile acid concentrations, itching, and fat malabsorption1,2. We show here that FHC in Amish individuals is associated with mutations in tight junction protein 2 (encoded by TJP2, also known as ZO-2) and bile acid Coenzyme A: amino acid N-acyltransferase (encoded by BAAT). The mutation of TJP2, which occurs in the first PDZ domain, reduces domain stability and ligand binding in vitro. We noted a morphological change in hepatic tight junctions. The mutation of BAAT, a bile acid–conjugating enzyme3, abrogates enzyme activity; serum of individuals homozygous with respect to this mutation contains only unconjugated bile acids. Mutations in both TJP2 and BAAT may disrupt bile acid transport and circulation. Inheritance seems to be oligogenic, with genotype at BAAT modifying penetrance in individuals homozygous with respect to the mutation in TJP2.

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Figure 1: Families with FHC.
Figure 2: Linkage disequilibrium and haplotypes in 9q12–q13.
Figure 3: Comparison of wild-type and V48A mutant TJP2-PDZ1 peptides.
Figure 4: Percent amino-acid conjugation of serum bile acids.

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References

  1. Morton, D.H. et al. Abnormal hepatic sinusoidal bile acid transport in an Amish kindred is not linked to FIC1 and is improved by ursodiol. Gastroenterology 119, 188–195 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Shneider, B.L. et al. Hepatic basolateral sodium-dependent-bile acid transporter expression in two unusual cases of hypercholanemia and in extrahepatic biliary atresia. Hepatology 25, 1176–1183 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Falany, C.N., Johnson, M.R., Barnes, S. & Diasio, R.B. Glycine and taurine conjugation of bile acids by a single enzyme. Molecular cloning and expression of human liver bile acid CoA:amino acid N-acyltransferase. J. Biol. Chem. 269, 19375–19379 (1994).

    CAS  PubMed  Google Scholar 

  4. Letunic, I. et al. Recent improvements to the SMART domain-based sequence annotation resource. Nucleic Acids Res. 30, 242–244 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Harris, B.Z. & Lim, W.A. Mechanism and role of PDZ domains in signaling complex assembly. J. Cell Sci. 114, 3219–3231 (2001).

    CAS  PubMed  Google Scholar 

  6. Itoh, M. et al. Direct binding of three tight junction-associated MAGUKs, ZO-1, TJP2, and ZO-3, with the COOH termini of claudins. J. Cell Biol. 147, 1351–1363 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mitic, L.L., Van Itallie, C.M. & Anderson, J.M. Molecular physiology and pathophysiology of tight junctions I. Tight junction structure and function: lessons from mutant animals and proteins. Am. J. Physiol. Gastrointest. Liver Physiol. 279, G250–G254 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Jesaitis, L.A. & Goodenough, D.A. Molecular characterization and tissue distribution of ZO-2, a tight junction protein homologous to ZO-1 and the Drosophila discs-large tumor suppressor protein. J. Cell Biol. 124, 949–961 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Tsukita, S., Furuse, M. & Itoh, M. Multifunctional strands in tight junctions. Nat. Rev. Mol. Cell Biol. 2, 285–293 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. McCarthy, K.M. et al. Inducible expression of claudin-1-myc but not occludin-VSV-G results in aberrant tight junction strand formation in MDCK cells. J. Cell Sci. 113 Pt 19, 3387–3398 (2000).

    CAS  PubMed  Google Scholar 

  11. Heiskala, M., Peterson, P.A. & Yang, Y. The roles of claudin superfamily proteins in paracellular transport. Traffic 2, 93–98 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Dawson, P.A. Bile Secretion and the Enterohepatic Circulation of Bile Acids. in Gastrointestinal and Liver Disease (eds. Feldman, M., Friedman, L.S. & Sleisenger, M.H.) 1051–1062 (Saunders, Philadelphia, 2002).

    Google Scholar 

  13. Rahner, C., Stieger, B. & Landmann, L. Structure–function correlation of tight junctional impairment after intrahepatic and extrahepatic cholestasis in rat liver. Gastroenterology 110, 1564–1578 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Koga, A. & Todo, S. Morphological and functional changes in the tight junctions of the bile canaliculi induced by bile duct ligation. Cell Tissue Res. 195, 267–276 (1978).

    Article  CAS  PubMed  Google Scholar 

  15. Setchell, K.D. & O'Connell, N.C. Disorders of Bile Acid Synthesis and Metabolism: A Metabolic Basis for Liver Disease. in Liver Disease in Children (eds. Suchy, F.J., Sokol, R.J. & Balistreri, W.F.) 701–734 (Lippincott Williams & Wilkins, Philadelphia, 2001).

    Google Scholar 

  16. Noe, J., Stieger, B. & Meier, P.J. Functional expression of the canalicular bile salt export pump of human liver. Gastroenterology 123, 1659–1666 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Ronchi, G. & Desmet, V.J. Histochemical study of gamma glutamyl transpeptidase (GGT) in experimental intrahepatic and extrahepatic cholestasis. Beitr. Pathol. 150, 316–321 (1973).

    Article  CAS  PubMed  Google Scholar 

  18. Mahapatra, A.K. & Suri, A. Anterior encephaloceles: a study of 92 cases. Pediatr. Neurosurg. 36, 113–118 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Chen, C.M. et al. Polychaetoid is required to restrict segregation of sensory organ precursors from proneural clusters in Drosophila. Mech. Dev. 57, 215–227 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Colas, J.F. & Schoenwolf, G.C. Towards a cellular and molecular understanding of neurulation. Dev. Dyn. 221, 117–145 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Bull, L.N. et al. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat. Genet. 18, 219–224 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Hostetler, J.A. Amish Society (The Johns Hopkins University Press, Baltimore, 1993).

  23. Terwilliger, J.D. A powerful likelihood method for the analysis of linkage disequilibrium between trait loci and one or more polymorphic marker loci. Am J. Hum. Genet. 56, 777–787 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Hillier, B.J., Christopherson, K.S., Prehoda, K.E., Bredt, D.S. & Lim, W.A. Unexpected modes of PDZ domain scaffolding revealed by structure of nNOS-syntrophin complex. Science 284, 812–815 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Harris, B.Z., Hillier, B.J. & Lim, W.A. Energetic determinants of internal motif recognition by PDZ domains. Biochemistry 40, 5921–5930 (2001).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank the individuals with FHC and their family members for their participation; I. Herskowitz for support and contributions; S. Service for software and advice; C. Hendrickson, J. Doherty, J. Woo, H. Yoon, E. Song, J. Vargas, R. Senkus, M. Maksimak, E. Cunningham, D. Agard, A. Frankel, V. Calabro, K. Novak and R. K. Guy for advice, assistance and the use of equipment; and N. Risch, N. Freimer, C. Slates, W. Hsueh, A. Slavotinek, R. Kelley and F. Collins for discussions. This work was supported by grants from the US National Institutes of Health, the Howard Hughes Medical Institute, the University of California San Francisco Program in Human Genetics and the Tetrad Graduate Program.

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Correspondence to Laura N. Bull.

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Carlton, V., Harris, B., Puffenberger, E. et al. Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT. Nat Genet 34, 91–96 (2003). https://doi.org/10.1038/ng1147

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