Am J Hum Genet 1990 Aug;47(2):308-16

Different molecular basis for fumarylacetoacetate hydrolase deficiency in th
two clinical forms of hereditary tyrosinemia (type I)

Tanguay RM, Valet JP, Lescault A, Duband JL, Laberge C, Lettre F, Plante M
Centre Hospitalier de l'Universite Laval, Ste-Foy, Quebec, Canada

Abstract
Hereditary tyrosinemia is characterized by a deficiency of the enzyme
fumarylacetoacetate hydrolase (FAH; E.C.3.7.1.2), the last enzyme in the
catabolic pathway of tyrosine. FAH was purified from rat and human liver and was
used to immunize rabbits. Specific antibodies were used to probe protein
extracts of livers and other tissues of normal and tyrosinemic patients. No
immunoreactive FAH band was observed on immunoblots of liver, kidneys, and
lymphocytes from patients presenting with the acute form of hereditary
tyrosinemia. Patients with the chronic form had immunoreactive FAH at a level
approximately 20% of normal liver values, which was correlated with the measured
enzymatic activity. Immunoblot analysis of aborted fetal tissues revealed normal
FAH immunoreactivity in normal liver and kidneys. No FAH immunoreactivity was
found in liver and kidneys of tyrosinemic fetuses. The presence of FAH
immunoreactivity in normal fetal tissues suggests that deficient FAH activity in
tyrosinemia is not simply related to a developmentally regulated expression of
the enzyme. By this immunoblot assay, FAH was detected in most human tissues,
with maximal immunoreactivity in liver and kidneys and with only trace amounts
in chorionic villi and cultured amniocytes. These data confirm that the primary
defect in the acute form of hereditary tyrosinemia is an absence of FAH.
Moreover, these data suggest that both clinical forms of the disease have a
different molecular basis