caa a22 4500 467933774 CHVBK 20180406152951.0 cr unu---uuuuu 170328e20061001xx s 000 0 eng 10.1007/s10545-006-0407-8 doi (NATIONALLICENCE)springer-10.1007/s10545-006-0407-8 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 [Elektronische Daten] [G. Maydan, B. Andresen, P. Madsen, M. Zeigler, A. Raas-Rothschild, A. Zlotogorski, A. Gutman, S. Korman] 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. SSIEM and Springer, 2006 Maydan G. Department of Clinical Biochemistry, Hadassah - Hebrew University Medical Center, Jerusalem, Israel aut Andresen B. Research Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Sciences and Institute of Human Genetics, Aarhus University, Aarhus, Denmark aut Madsen P. Research Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Sciences and Institute of Human Genetics, Aarhus University, Aarhus, Denmark aut Zeigler M. Department of Genetics, Hadassah - Hebrew University Medical Center, Jerusalem, Israel aut Raas-Rothschild A. Department of Genetics, Hadassah - Hebrew University Medical Center, Jerusalem, Israel aut Zlotogorski A. Department Dermatology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel aut Gutman A. Department of Clinical Biochemistry, Hadassah - Hebrew University Medical Center, Jerusalem, Israel aut Korman S. Department of Clinical Biochemistry, Hadassah - Hebrew University Medical Center, Jerusalem, Israel aut Journal of Inherited Metabolic Disease Kluwer Academic Publishers 29/5(2006-10-01), 620-626 0141-8955 29:5<620 2006 29 10545 https://doi.org/10.1007/s10545-006-0407-8 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10545-006-0407-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Maydan G. Department of Clinical Biochemistry, Hadassah - Hebrew University Medical Center, Jerusalem, Israel aut NATIONALLICENCE 700 1- Andresen B. Research Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Sciences and Institute of Human Genetics, Aarhus University, Aarhus, Denmark aut NATIONALLICENCE 700 1- Madsen P. Research Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Sciences and Institute of Human Genetics, Aarhus University, Aarhus, Denmark aut NATIONALLICENCE 700 1- Zeigler M. Department of Genetics, Hadassah - Hebrew University Medical Center, Jerusalem, Israel aut NATIONALLICENCE 700 1- Raas-Rothschild A. Department of Genetics, Hadassah - Hebrew University Medical Center, Jerusalem, Israel aut NATIONALLICENCE 700 1- Zlotogorski A. Department Dermatology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel aut NATIONALLICENCE 700 1- Gutman A. Department of Clinical Biochemistry, Hadassah - Hebrew University Medical Center, Jerusalem, Israel aut NATIONALLICENCE 700 1- Korman S. Department of Clinical Biochemistry, Hadassah - Hebrew University Medical Center, Jerusalem, Israel aut NATIONALLICENCE 773 0- Journal of Inherited Metabolic Disease Kluwer Academic Publishers 29/5(2006-10-01), 620-626 0141-8955 29:5<620 2006 29 10545 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer