Advertisement

Journal of Inherited Metabolic Disease

, Volume 29, Issue 5, pp 620–626 | Cite as

TAT gene mutation analysis in three Palestinian kindreds with oculocutaneous tyrosinaemia type II; characterization of a silent exonic transversion that causes complete missplicing by exon 11 skipping

  • G. Maydan
  • B. S. Andresen
  • P. P. Madsen
  • M. Zeigler
  • A. Raas-Rothschild
  • A. Zlotogorski
  • A. Gutman
  • S. H. Korman
Original Article

Summary

Deficiency of the hepatic cytosolic enzyme tyrosine aminotransferase (TAT) causes marked hypertyrosinaemia leading to painful palmoplantar hyperkeratoses, pseudodendritic keratitis and variable mental retardation (oculocutaneous tyrosinaemia type II or Richner–Hanhart syndrome). Parents may therefore seek prenatal diagnosis, but this is not possible by biochemical assays as tyrosine does not accumulate in amniotic fluid and TAT is not expressed in chorionic villi or amniocytes. Molecular analysis is therefore the only possible approach for prenatal diagnosis and carrier detection. To this end, we sought TAT gene mutations in 9 tyrosinaemia II patients from three consanguineous Palestinian kindreds. In two kindreds (7 patients), the only potential abnormality identified after sequencing all 12 exons and exon–intron boundaries was homozygosity for a silent, single-nucleotide transversion c.1224G > T (p.T408T) at the last base of exon 11. This was predicted to disrupt the 5′ donor splice site of exon 11 and result in missplicing. However, as TAT is expressed exclusively in liver, patient mRNA could not be obtained for splicing analysis. A minigene approach was therefore used to assess the effect of c.1224G > T on exon 11 splicing. Transfection experiments with wild-type and c.1224G > T mutant minigene constructs demonstrated that c.1224G > T results in complete exon 11 skipping, illustrating the utility of this approach for confirming a putative splicing defect when cDNA is unavailable. Homozygosity for a c.1249C > T (R417X) exon 12 nonsense mutation (previously reported in a French patient) was identified in both patients from the third kindred, enabling successful prenatal diagnosis of an unaffected fetus using chorionic villous tissue.

Keywords

Splice Site Prenatal Diagnosis Donor Splice Site Hereditary Spastic Paraplegia SSCP Analysis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

PCR

polymerase chain reaction

SSCP

single-strand conformation polymorphism

TAT

tyrosine aminotransferase

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. al Essa MA, Rashed MS, Ozand PT (1999) Tyrosinaemia type II: an easily diagnosed metabolic disorder with a rewarding therapeutic response. East Mediterr Health J 5: 1204–1207.PubMedGoogle Scholar
  2. al Hemidan AI, al Hazzaa SA (1995) Richner–Hanhart syndrome (tyrosinemia type II). Case report and literature review. Ophthalmic Genet 16: 21–26.Google Scholar
  3. Buist NRM, Kennaway NG, Fellman JH (1985) Tyrosinemia type II: hepatic cytosol tyrosine aminotransferase deficiency (the Richner–Hanhart syndrome). In: Bickel H, Wachtel U, eds. Inherited Diseases of Amino Acid Metabolism. Stuttgart: Thieme, 203–235.Google Scholar
  4. Charfeddine C, Monastiri K, Mokni M, et al (2006) Clinical and mutational investigations of tyrosinemia type II in Northern Tunisia: Identification and structural characterization of two novel TAT mutations. Mol Genet Metab 88: 184–191.PubMedCrossRefGoogle Scholar
  5. el Badramany MH, Fawzy AR, Farag TI (1995) Familial Richner–Hanhart syndrome in Kuwait: twelve-year clinical reassessment by a multidisciplinary approach. Am J Med Genet 60: 353–355.PubMedCrossRefGoogle Scholar
  6. Hargrove JL, Mackin RB (1984) Organ specificity of glucocorticoid-sensitive tyrosine aminotransferase. Separation from aspartate aminotransferase isoenzymes. J Biol Chem 259: 386–393.PubMedGoogle Scholar
  7. Huhn R, Stoermer H, Klingele B, et al (1998) Novel and recurrent tyrosine aminotransferase gene mutations in tyrosinemia type II. Hum Genet 102: 305–313.PubMedCrossRefGoogle Scholar
  8. Laake K, Jansen L, Hahnemann JM, et al (2000) Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia. Hum Mutat 16: 232–246.PubMedCrossRefGoogle Scholar
  9. Lemonnier F, Charpentier C, Odievre M, Larregue M, Lemonnier A (1979) Tyrosine aminotransferase isoenzyme deficiency. J Pediatr 94: 931–932.PubMedCrossRefGoogle Scholar
  10. Lerner MR, Boyle JA, Mount SM, Wolin SL, Steitz JA (1980) Are snRNPs involved in splicing? Nature 283: 220–224.PubMedCrossRefGoogle Scholar
  11. Macsai MS, Schwartz TL, Hinkle D, Hummel MB, Mulhern MG, Rootman D (2001) Tyrosinemia type II: nine cases of ocular signs and symptoms. Am J Ophthalmol 132: 522–527.PubMedCrossRefGoogle Scholar
  12. Madsen PP, Kibaek M, Roca X, et al (2006) Short/branched-chain acyl-CoA dehydrogenase deficiency due to an IVS3+3A > G mutation that causes exon skipping. Hum Genet 118: 680–690.PubMedCrossRefGoogle Scholar
  13. Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16: 1215.PubMedGoogle Scholar
  14. Minami-Hori M, Ishida-Yamamoto A, Katoh N, Takahashi H, Iizuka H (2006) Richner–Hanhart syndrome: report of a case with a novel mutation of tyrosine aminotransferase. J Dermatol Sci 41: 82–84.Google Scholar
  15. Mitchell GA, Grompe M, Lambert M, Tanguay RM (2001) Hypertyrosinemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill, 1777–1805.Google Scholar
  16. Natt E, Westphal EM, Toth-Fejel SE, et al (1987) Inherited and de novo deletion of the tyrosine aminotransferase gene locus at 16q22.1-q22.3 in a patient with tyrosinemia type II. Hum Genet 77: 352–358.PubMedCrossRefGoogle Scholar
  17. Natt E, Kida K, Odievre M, Di Rocco M, Scherer G (1992) Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II. Proc Natl Acad Sci USA 89: 9297–9301.PubMedCrossRefGoogle Scholar
  18. Ohno K, Brengman JM, Felice KJ, Cornblath DR, Engel AG (1999) Congenital end-plate acetylcholinesterase deficiency caused by a nonsense mutation and an A→G splice-donor-site mutation at position +3 of the collagenlike-tail-subunit gene (COLQ): how does G at position +3 result in aberrant splicing? Am J Hum Genet 65: 635–644.PubMedCrossRefGoogle Scholar
  19. Rehak A, Selim MM, Yadav G (1981) Richner–Hanhart syndrome (tyrosinaemia-II) (report of four cases without ocular involvement). Br J Dermatol 104: 469–475.Google Scholar
  20. Rettenmeier R, Natt E, Zentgraf H, Scherer G (1990) Isolation and characterization of the human tyrosine aminotransferase gene. Nucleic Acids Res 18: 3853–3861.PubMedGoogle Scholar
  21. Rogers J, Wall R (1980) A mechanism for RNA splicing. Proc Natl Acad Sci USA 77: 1877–1879.PubMedCrossRefGoogle Scholar
  22. Schrijver I, Koerper MA, Jones CD, Zehnder JL (2002) Homozygous factor V splice site mutation associated with severe factor V deficiency. Blood 99: 3063–3065.PubMedCrossRefGoogle Scholar
  23. Shapiro MB, Senapathy P (1987) RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res 15: 7155–7174.PubMedGoogle Scholar
  24. Stenson PD, Ball EV, Mort M, et al (2003) Human Gene Mutation Database (HGMD): 2003 update. Hum Mutat 21: 577–581.PubMedCrossRefGoogle Scholar
  25. Svenson IK, Ashley-Koch AE, Gaskell PC, et al (2001) Identification and expression analysis of spastin gene mutations in hereditary spastic paraplegia. Am J Hum Genet 68: 1077–1085.PubMedCrossRefGoogle Scholar
  26. Tallab TM (1996) Richner–Hanhart syndrome: importance of early diagnosis and early intervention. J Am Acad Dermatol 35: 857–859.PubMedCrossRefGoogle Scholar
  27. Valikhani M, Akhyani M, Jafari A, Barzegari M, Toosi S (2006) Oculocutaneous tyrosinaemia or tyrosinaemia type 2: a case report. J Eur Acad Dermatol Venereol 20: 591–594.Google Scholar
  28. Yadav GC, Reavey PC (1988) Aminoacidopathies: a review of 3 years experience of investigations in a Kuwait hospital. J Inherit Metab Dis 11: 277–284.PubMedCrossRefGoogle Scholar
  29. Zhuang Y, Weiner AM (1986) A compensatory base change in U1 snRNA suppresses a 5′ splice site mutation. Cell 46: 827–835.PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer 2006

Authors and Affiliations

  • G. Maydan
    • 1
  • B. S. Andresen
    • 4
  • P. P. Madsen
    • 4
  • M. Zeigler
    • 2
  • A. Raas-Rothschild
    • 2
  • A. Zlotogorski
    • 3
  • A. Gutman
    • 1
  • S. H. Korman
    • 1
  1. 1.Department of Clinical BiochemistryHadassah – Hebrew University Medical CenterJerusalemIsrael
  2. 2.Department of GeneticsHadassah – Hebrew University Medical CenterJerusalemIsrael
  3. 3.Department DermatologyHadassah – Hebrew University Medical CenterJerusalemIsrael
  4. 4.Research Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Sciences and Institute of Human GeneticsAarhus UniversityAarhusDenmark

Personalised recommendations