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

Abstract

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.

Tyrosinemia type II: Mutation update, 11 novel mutations and description of 5 independent subjects with a novel founder mutation

“…Indeed, we report a case (patient 141), diagnosed at age 54, with both skin and neurological symptoms but no ocular phenotype. Seasonal variation in ocular and cutaneous symptoms, as in our patient 136, have already been noted by Hanhart and related to changes in temperature, but could also be related to diet, making it more difficult to reach solid diagnostic conclusions from specific symptoms observed at a given time point during the course of disease. Furthermore, even tyrosine plasma levels appear inconclusive in the prediction of specific phenotypes, as asymptomatic individuals presenting with high tyrosinemia do exist.…”

“…Regarding plasma tyrosine levels, patient 85 showed the highest value with 2836 µmol/L, while patient 97, asymptomatic at age 21, exhibited the lowest serum levels at 515 µmol/L (Table ).…”

“…Skin symptoms are mostly represented by painful hyperkeratotic plaques of soles and palms, which usually develop after the first year of life, although they may appear earlier. Intellectual disability is a relatively common feature but may be mild or absent …”

Tyrosine aminotransferase: biochemical and structural properties and molecular dynamics simulations

“…In tyrosinemia type II, tyrosine accumulates in blood, eventually causing lesions in the patients (al-Hemidan and al-Hazzaa, 1995). In humans, more than 15 mutations have been identified in the patients of tyrosinemia type II in Italy, France, USA and the UK (Natt et al, 1992; Endo, 1998; Charfeddine et al, 2006; Maydan et al, 2006; Minami-Hori et al, 2006; Meissner et al, 2008; Pasternack et al, 2009). Tyrosinemia type II is often associated with consanguinity.…”

Relaxed Evolution in the Tyrosine Aminotransferase Gene Tat in Old World Fruit Bats (Chiroptera: Pteropodidae)

“…Deficiency of TAT, which is caused by genetic mutations in the Tat gene, in humans leads to tyrosinemia type II syndrome characterized by elevated blood tyrosine levels, mental retardation, etc [8]. To date, more than 15 distinct mutations [8], [9], [10], [11], [12], [13], [14], [15] have been identified in humans that cause tyrosinemia type II.…”