Etude sur la tyrosinemie hereditaire au Saguenay-Lac-St-Jean: Frequence et expression de la mutation IVS12+5g to A

Abstract

Une deficience de la fumarylacetoacetate hydrolase (FAH), le dernier enzyme du sentier de degradation de la tyrosine, cause la tyrosinemie de type I (THI, McKusick #276700), maladie metabolique qui touche principalement le foie. Deux formes cliniques existent et jusqu'a 26 mutations causales ont ete rapportees. Certaines mutations sont plus frequentes et/ou se retrouvent dans des populations particulieres. C'est le cas des mutations $\rm IVS12 + 5g \to a,$ IVS6-1g $\to$ t et W262X. Differents tests ont ete mis au point pour detecter ces mutations. Une etude plus approfondie demontre une frequence de 95,4% de la mutation IVS12 + 5g $\to$ a sur les alleles deficients au Saguenay-Lac-St-Jean (SLSJ). Des individus presentant des phenotypes cliniques differents ont ete etudies pour verifier si les variations proviennent du geenotype. La mutation IVS12 + 5g $\to$ a est responsable des deux formes cliniques de la THI au SLSJ. Il est suggere que les differences cliniques observees dependent de reversions de la mutation causale dans le foie. Ces reversions sont observees dans des nodules de regeneration qui expriment alors une proteine active.

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A deficiency of fumarylacetoacetate hydrolase (FAH), the last enzyme in the tyrosine degradation pathway, causes tyrosinemia type I (THI, McKusick #276700), a metabolic disease that mainly affects the liver. Two clinical forms exist and up to 26 causal mutations have been reported. Some mutations are more common and/or found in particular populations. This is the case for the $\rm IVS12 + 5g \to a,$ IVS6-1g $\to$ t and W262X mutations. Different tests have been developed to detect these mutations. A more in-depth study demonstrates a frequency of 95.4% of the IVS12 + 5g $\to$ a mutation on deficient alleles in Saguenay-Lac-St-Jean (SLSJ). Individuals with different clinical phenotypes were studied to verify whether the variations arise from the genotype. The IVS12 + 5g $\to$ a mutation is responsible for the two clinical forms of IHT in SLSJ. It is suggested that the observed clinical differences depend on reversals of the causative mutation in the liver. These reversions are observed in regeneration nodules which then express an active protein.