Frequent mutation reversion inversely correlates with clinical severity in a genetic liver disease, hereditary tyrosinemia

Demers, Sylvie I.; Russo, Pierre; Lettre, Francine; Tanguay, Robert M.

doi:10.1016/s0046-8177(03)00406-4

Cited by 56 publications

(25 citation statements)

References 28 publications

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“…Mosaicism due to somatic gene reversion has been observed in the immune system as well as in various other disease entities. [1][2][3][4][5][6]17,[35][36][37] Here we report a novel X-(S)CID family with a unique mutation in the extracellular part of CD132.…”

Section: Introductionmentioning

confidence: 86%

A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells

Kuijpers

Leeuwen²,

Barendregt

et al. 2013

Haematologica

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Mutations in the common gamma chain (γ c , CD132, encoded by the IL2RG gene) can lead to B + T − NK − X-linked severe combined immunodeficiency, as a consequence of unresponsiveness to γc-cytokines such as interleukins-2, -7 and -15. Hypomorphic mutations in CD132 may cause combined immunodeficiencies with a variety of clinical presentations. We analyzed peripheral blood mononuclear cells of a 6-year-old boy with normal lymphocyte counts, who suffered from recurrent pneumonia and disseminated mollusca contagiosa. Since proliferative responses of T cells and NK cells to γc -cytokines were severely impaired, we performed IL2RG gene analysis, showing a heterozygous mutation in the presence of a single X-chromosome. Interestingly, an IL2RG reversion to normal predominated in both naïve and antigen-primed CD8 + T cells and increased over time. Only the revertant CD8 + T cells showed normal expression of CD132 and the various CD8 + T cell populations had a different T-cell receptor repertoire. Finally, a fraction of γδ + T cells and differentiated CD4 + CD27 − effector-memory T cells carried the reversion, whereas NK or B cells were repeatedly negative. In conclusion, in a patient with a novel IL2RG mutation, gene-reverted CD8 + T cells accumulated over time. Our data indicate that selective outgrowth of particular T-cell subsets may occur following reversion at the level of committed T progenitor cells. A reversion of an IL2RG mutation in combined immunodeficiency

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Section: Introductionmentioning

confidence: 86%

A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells

Kuijpers

Leeuwen²,

Barendregt

et al. 2013

Haematologica

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“…Both fumaryl-acetoacetate and maleyl-acetoacetate are thought to be involved in liver toxicity, which is found in tyrosinemia type I patients and includes progressive liver failure and development of hepatocellular carcinoma (HCC) early in life. 19 Using the mouse model of Fah deficiency, Grompe and colleagues 3 demonstrated that normal hepatocytes transplanted in the these animals were able to replace Ͼ80% of host liver. However, if transplanted Fah-deficient mice were exposed to the drug 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, which limits the accumulation of toxic metabolites fumaryl-acetoacetate and maleyl-acetoacetate in host cells, no selective growth advantage for donor-derived hepatocytes was observed.…”

Section: (Ii) the Fumaryl-acetoacetate Hydrolase (Fah)-null Mouse Andmentioning

confidence: 99%

“…Patients with The fumaryl-acetoacetate hydrolase (Fah) null mouse 3,19 The mouse model of progressive familial intrahepatic cholestasis 9,22 The retrorsine-based rat model for hepatocyte transplantation and liver repopulation [4][5][6]23 858 Marongiu et al AJP April 2008, Vol. 172, No.…”

Section: (Ii) the Fumaryl-acetoacetate Hydrolase (Fah)-null Mouse Andmentioning

confidence: 99%

Liver Repopulation and Carcinogenesis: Two Sides of the Same Coin?

Marongiu

Doratiotto

Montisci

et al. 2008

The American Journal of Pathology

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Liver repopulation by transplanted normal hepatocytes has been described in a number of experimental settings. Extensive repopulation can also occur from the selective proliferation of endogenous normal hepatocytes, both in experimental animals and in the human liver. This review highlights the intriguing association between clinical and experimental conditions related to liver repopulation and an increased risk for development of hepatocellular carcinoma. It is suggested that any microenvironment that is able to sustain the clonal growth of normal transplanted (or endogenous) hepatocytes is also geared to select for the emergence of rare resistant cells with an altered phenotype. Whereas the first pathway leads to liver repopulation with normal histology, the latter results in the growth of focal proliferative lesions and carries an increased risk of neoplastic disease. The implications of this association are discussed, both in terms of pathogenetic significance and possible therapeutic exploitation.

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“…45 However, at least one part of this paradigm does not fit with what has been found in humans with hereditary tyrosinemia-that is, that dysplasia and carcinoma have only been found to arise from the damaged cell compartment. 46 It is possible that this difference relates to the net balance of carcinogenic and anticarcinogenic factors in each compartment in the 2 different diseases. For instance, activation of NF B and of autophagy is present in the damaged cell compartment in the ␣1AT deficiency models but not in the tyrosinemia model.…”

Section: Hypothetical Model For Hepatocellular Carcinoma In ␣1at Defimentioning

confidence: 99%

Alpha-1-Antitrypsin Deficiency: A New Paradigm for Hepatocellular Carcinoma in Genetic Liver Disease *

2005

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Liver disease in alpha-1-antitrypsin (␣1AT) deficiency is caused by a gain-of-toxic function mechanism engendered by the accumulation of a mutant glycoprotein in the endoplasmic reticulum (ER). The extraordinary degree of variation in phenotypical expression of this liver disease is believed to be determined by genetic modifiers and/or environmental factors that influence the intracellular disposal of the mutant glycoprotein or the signal transduction pathways that are activated. Recent investigations suggest that a specific repertoire of signaling pathways are involved, including the autophagic response, mitochondrial-and ER-caspase activation, and nuclear factor kappaB (NF B) activation. Whether activation of these signaling pathways, presumably to protect the cell, inadvertently contributes to liver injury or perhaps protects the cell from one injury and, in so doing, predisposes it to another type of injury, such as hepatocarcinogenesis, is not yet known. Recent studies also suggest that hepatocytes with marked accumulation of ␣1ATZ, globule-containing hepatocytes, engender a cancer-prone state by surviving with intrinsic damage and by chronically stimulating in 'trans' adjacent relatively undamaged hepatocytes that have a selective T he classic form of alpha-1-antitrypsin (␣1AT) deficiency, associated with homozygosity for the ␣1ATZ allele, is the most common genetic cause of liver disease in children. It also causes chronic liver injury and hepatocellular carcinoma in adults. 1 Moreover, the predilection for hepatocellular carcinoma in homozygotes for the Z allele is significantly greater than that attributable to cirrhosis alone. 1 The histopathological hallmark of the disease is intracellular globules in hepatocytes that stain positively with periodic acid-Schiff (PAS) after treatment with diastase, the so-called PAS-positive/ diastase-resistant globules. Early studies showed that these globules represent the mutant glycoprotein, ␣1ATZ, retained in the rough endoplasmic reticulum (ER) of liver cells (reviewed in Perlmutter 2 ). Although considerable discussion of these globules is found in the literature as well as investigation of their origin, relatively limited discussion, or investigation, has taken place, regarding the curious fact that many hepatocytes in these patients do not have globules (Fig. 1). Studies of the Z#2 mouse model, generated by using a human ␣1ATZ genomic fragment as transgene, 3 have shown that these globuledevoid cells occupy an increasing proportion of the liver as the animal ages and ultimately become the site of adenomas and carcinomas. 4 In more recent studies using the PiZ mouse model, another transgenic mouse created with a human ␣1ATZ genomic fragment, 5 we have shown that there is increased proliferation of these globule-devoid hepatocytes at a rate that is directly proportional to the number of globule-containing hepatocytes. 6

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Frequent mutation reversion inversely correlates with clinical severity in a genetic liver disease, hereditary tyrosinemia

Cited by 56 publications

References 28 publications

A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells

A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells

Liver Repopulation and Carcinogenesis: Two Sides of the Same Coin?

Alpha-1-Antitrypsin Deficiency: A New Paradigm for Hepatocellular Carcinoma in Genetic Liver Disease *

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