Splicing mutations, mainly IVS6-1(G>T), account for 70% of fumarylacetoacetate hydrolase (FAH) gene alterations, including 7 novel mutations, in a survey of 29 tyrosinemia type I patients

2002 ◽  
Vol 20 (3) ◽  
pp. 180-188 ◽  
Author(s):  
J.A. Arranz ◽  
F. Piñol ◽  
L. Kozak ◽  
C. Pérez-Cerdá ◽  
B. Cormand ◽  
...  
Keyword(s):  
Type I ◽  
Novel Mutations ◽  
Splicing Mutations ◽  
Tyrosinemia Type I ◽  
Fumarylacetoacetate Hydrolase ◽  
Gene Alterations

scholarly journals Identification of Novel Mutations in FAH Gene and Prenatal Diagnosis of Tyrosinemia in Indian Family

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
Jayesh J. Sheth ◽  
Chitra M. Ankleshwaria ◽  
Rajeshwari Pawar ◽  
Frenny J. Sheth
Keyword(s):  
Prenatal Diagnosis ◽  
Secondary Structure ◽  
Point Mutation ◽  
Splice Site ◽  
Experimental Program ◽  
Type I ◽  
Novel Mutations ◽  
Potential Donor ◽  
Tyrosinemia Type I ◽  
Fumarylacetoacetate Hydrolase

Carrier of tyrosinemia type I was diagnosed by sequencingFAH(fumarylacetoacetate hydrolase) gene. It leads to the identification of heterozygous status for both c.648C>G (p.Ile216Met) and c.1159G>A (p.Gly387Arg) mutations in exons 8 and 13, respectively, in the parents. The experimental program PolyPhen, SIFT, and MT predicts former missense point mutation as “benign” that creates a potential donor splice site and later one as “probably damaging” which disrupts secondary structure of protein.

A Single Mutation of the Fumarylacetoacetate Hydrolase Gene in French Canadians with Hereditary Tyrosinemia Type I

1994 ◽  
Vol 331 (6) ◽  
pp. 353-357 ◽  
Author(s):  
Markus Grompe ◽  
Maryse St.-Louis ◽  
Sylvie I. Demers ◽  
Muhsen Al-Dhalimy ◽  
Barbara Leclerc ◽  
...  
Keyword(s):  
Type I ◽  
Single Mutation ◽  
French Canadians ◽  
Tyrosinemia Type I ◽  
Fumarylacetoacetate Hydrolase ◽  
Hereditary Tyrosinemia

scholarly journals Hereditary tyrosinemia type I–associated mutations in fumarylacetoacetate hydrolase reduce the enzyme stability and increase its aggregation rate

2019 ◽  
Vol 294 (35) ◽  
pp. 13051-13060 ◽  
Author(s):  
Iratxe Macias ◽  
Ana Laín ◽  
Ganeko Bernardo-Seisdedos ◽  
David Gil ◽  
Esperanza Gonzalez ◽  
...  
Keyword(s):  
Enzyme Stability ◽  
Type I ◽  
Aggregation Rate ◽  
Tyrosinemia Type I ◽  
Fumarylacetoacetate Hydrolase ◽  
Hereditary Tyrosinemia

Two novel mutations involved in hereditary tyrosinemia type I

1995 ◽  
Vol 4 (2) ◽  
pp. 319-320 ◽  
Author(s):  
Maryse St-Louis ◽  
Jacques Poudrier ◽  
Daniel Phaneuf ◽  
Barbara Lecierc ◽  
Rachel Laframboise ◽  
...  
Keyword(s):  
Type I ◽  
Novel Mutations ◽  
Tyrosinemia Type I ◽  
Hereditary Tyrosinemia

scholarly journals Therapeutic Targeting of Fumaryl Acetoacetate Hydrolase in Hereditary Tyrosinemia Type I

2021 ◽  
Vol 22 (4) ◽  
pp. 1789
Author(s):  
Jon Gil-Martínez ◽  
Iratxe Macias ◽  
Luca Unione ◽  
Ganeko Bernardo-Seisdedos ◽  
Fernando Lopitz-Otsoa ◽  
...  
Keyword(s):  
Autosomal Recessive Disorder ◽  
Type I ◽  
Secondary Effects ◽  
Pharmacological Chaperones ◽  
Liver And Kidney ◽  
Tyrosinemia Type I ◽  
Fumarylacetoacetate Hydrolase ◽  
Hereditary Tyrosinemia ◽  
First Time

Fumarylacetoacetate hydrolase (FAH) is the fifth enzyme in the tyrosine catabolism pathway. A deficiency in human FAH leads to hereditary tyrosinemia type I (HT1), an autosomal recessive disorder that results in the accumulation of toxic metabolites such as succinylacetone, maleylacetoacetate, and fumarylacetoacetate in the liver and kidney, among other tissues. The disease is severe and, when untreated, it can lead to death. A low tyrosine diet combined with the herbicidal nitisinone constitutes the only available therapy, but this treatment is not devoid of secondary effects and long-term complications. In this study, we targeted FAH for the first-time to discover new chemical modulators that act as pharmacological chaperones, directly associating with this enzyme. After screening several thousand compounds and subsequent chemical redesign, we found a set of reversible inhibitors that associate with FAH close to the active site and stabilize the (active) dimeric species, as demonstrated by NMR spectroscopy. Importantly, the inhibitors are also able to partially restore the normal phenotype in a newly developed cellular model of HT1.

scholarly journals The Importance of Succinylacetone: Tyrosinemia Type I Presenting with Hyperinsulinism and Multiorgan Failure Following Normal Newborn Screening

2020 ◽  
Vol 6 (2) ◽  
pp. 39
Author(s):  
Jessica R. C. Priestley ◽  
Hana Alharbi ◽  
Katharine Press Callahan ◽  
Herodes Guzman ◽  
Irma Payan-Walters ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Multiorgan Failure ◽  
Failure To Thrive ◽  
Acute Onset ◽  
Critically Ill Children ◽  
Hyperinsulinemic Hypoglycemia ◽  
Specific Marker ◽  
Type I ◽  
Tyrosinemia Type I ◽  
Fumarylacetoacetate Hydrolase

Tyrosinemia type I (TT1) is an inborn error of tyrosine metabolism with features including liver dysfunction, cirrhosis, and hepatocellular carcinoma; renal dysfunction that may lead to failure to thrive and bone disease; and porphyric crises. Once fatal in most infantile-onset cases, pre-symptomatic diagnosis through newborn screening (NBS) protocols, dietary management, and pharmacotherapy with nitisinone have improved outcomes. Succinylacetone provides a sensitive and specific marker for the detection of TT1 but is not universally utilized in screening protocols for the disease. Here, we report an infant transferred to our facility for evaluation and management of hyperinsulinism who subsequently developed acute-onset liver, respiratory, and renal failure around one month of life. She was found to have TT1 caused by novel pathogenic variant in fumarylacetoacetate hydrolase (c.1014 delC, p.Cys 338 Ter). Her NBS, which utilized tyrosine as a primary marker, had been reported as normal, with a tyrosine level of 151 µmol/L (reference: <280 µmol/L). Retrospective analysis of dried blood spot samples via tandem mass spectrometry showed detectable succinylacetone ranging 4.65–10.34 µmol/L. To our knowledge, this is the first patient with TT1 whose initial presenting symptom was hyperinsulinemic hypoglycemia. The case highlights the importance of maintaining a high suspicion for metabolic disease in critically ill children, despite normal NBS. We also use the case to advocate for NBS for TT1 using succinylacetone quantitation.

Sign in / Sign up

Export Citation Format

Share Document