Unexpected Effects of a Heterozygous Dnmt1 Null Mutation on Age-Dependent DNA Hypomethylation and Autoimmunity

Yung, Raymond; Ray, Donna; Eisenbraun, Julie K.; Deng, Chun; Attwood, J.; Eisenbraun, Michael D.; Johnson, Kent J.; Miller, Richard A.; Hanash, Samir M.; Richardson, Bruce C.

doi:10.1093/gerona/56.6.b268

Cited by 39 publications

(24 citation statements)

References 34 publications

(39 reference statements)

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“…If AdoHcy is elevated in AdoHcy hydrolase-deficient patients during early gestation, as it was found to be in the cord blood of patient 2, the complex reprogramming of DNA methylation that occurs during embryonic development (Reik et al 2001) might be affected. A situation with certain similarities to that found in the present patients has been described by Yung and colleagues (Yung et al 2001). These authors found, surprisingly, that with age both lymphocyte and brain DNA became more methylated in mice heterozygous for a null mutation in DNA methyltransferase 1 (Dnmt1) than did the DNA of control mice.…”

Section: Metabolic Abnormalities and Changes During Therapysupporting

confidence: 87%

S‐Adenosylhomocysteine hydrolase deficiency: A second patient, the younger brother of the index patient, and outcomes during therapy

Barić

Ćuk

Fumić

et al. 2005

J of Inher Metab Disea

116

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SummaryS-Adenosylhomocysteine (AdoHcy) hydrolase deficiency has been proven in a human only once, in a recently described Croatian boy. Here we report the clinical course and biochemical abnormalities of the younger brother of this proband. This younger brother has the same two mutations in the gene encoding AdoHcy hydrolase, and has been monitored since birth. We report, as well, outcomes during therapy for both patients. The information obtained suggests that the disease starts in utero and is characterized primarily by neuromuscular symptomatology (hypotonia, sluggishness, psychomotor delay, absent tendon reflexes, delayed myelination). The laboratory abnormalities are markedly increased creatine kinase and elevated aminotransferases, as well as specific amino acid aberrations that pinpoint the aetiology. The latter include, most importantly, markedly elevated plasma AdoHcy. Plasma S-adenosylmethionine (AdoMet) is also elevated, as is methionine (although the hypermethioninaemia may be absent or nonsignificant in the first weeks of life). The disease seems to be at least to some extent treatable, as shown by improved myelination and psychomotor development during dietary methionine restriction and supplementation with creatine and phosphatidylcholine.*Correspondence: Department of Pediatrics, University Hospital Center, Kišpatićeva 12, Rebro, 10000 Zagreb, Croatia. E-mail: ibaric@kbc-zagreb.hr. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptS-Adenosylhomocysteine (AdoHcy) hydrolase (adenosylhomocysteinase, EC 3.3.1.1) is the enzyme that catalyses hydrolysis of AdoHcy to adenosine and homocysteine (De La Haba and Cantoni 1959). Its deficiency (McKusick 180960) had been proven in a human only once, in a Croatian boy we reported recently (Barić et al 2004). The index patient presented with myopathy, characterized by hypotonia and delayed psychomotor development from birth, abnormally slow brain myelination (noted in MRI studies of the brain at 12.7 months) and mild hepatitis-like findings. The main biochemical abnormalities were marked increases of creatine kinase and aminotransferases, prolonged prothrombin time, low albumin, and specific amino acid aberrations indicative of the aetiology: hypermethioninaemia with almost normal total plasma homocysteine and very elevated plasma AdoHcy (up to 150 × normal) and SAdenosylmethionine (AdoMet) (up to 30 times normal). Activity of AdoHcy hydrolase was severely diminished: about 3% of control in liver and 9−15% of the mean controls in fibroblasts and red blood cells. The specific metabolic defect had been identified and the patient started on therapy by age 12.8 months. Here we report a second patient (patient 2), a brother of the proband. Patient 2 has been monitored since birth and was started on therapy at age 3.4 months, by which time the diagnosis of AdoHcy hydrolase deficiency had been clearly established. We report, also, outcomes during therapy in both patients. METHODS Metabolite assaysAmino acids were measured by i...

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Section: Metabolic Abnormalities and Changes During Therapysupporting

confidence: 87%

S‐Adenosylhomocysteine hydrolase deficiency: A second patient, the younger brother of the index patient, and outcomes during therapy

Barić

Ćuk

Fumić

et al. 2005

J of Inher Metab Disea

116

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“…Interestingly, mouse knockout models for Dnmt1 and Dnmt3b have also shown defects in global DNA methylation (Yung et al 2001;Dodge et al 2005). Heterozygous Dnmt1 null mutation mice developed autoimmunity, although surprisingly, they displayed increased DNA methylation levels (Yung et al 2001). In humans, decreased levels of DNMT1 mRNA had previously been shown for T-cells isolated from SLE patients .…”

Section: Discussionmentioning

confidence: 96%

“…In parallel, a robust decrease in the global content of DNA methylation as well as a reduction of DNMT1 and DNMT3B mRNA levels were observed. Interestingly, mouse knockout models for Dnmt1 and Dnmt3b have also shown defects in global DNA methylation (Yung et al 2001;Dodge et al 2005). Heterozygous Dnmt1 null mutation mice developed autoimmunity, although surprisingly, they displayed increased DNA methylation levels (Yung et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus

Javierre¹,

Fernández²,

Richter³

et al. 2009

Genome Res.

593

434

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Monozygotic (MZ) twins are partially concordant for most complex diseases, including autoimmune disorders. Whereas phenotypic concordance can be used to study heritability, discordance suggests the role of non-genetic factors. In autoimmune diseases, environmentally driven epigenetic changes are thought to contribute to their etiology. Here we report the first high-throughput and candidate sequence analyses of DNA methylation to investigate discordance for autoimmune disease in twins. We used a cohort of MZ twins discordant for three diseases whose clinical signs often overlap: systemic lupus erythematosus (SLE), rheumatoid arthritis, and dermatomyositis. Only MZ twins discordant for SLE featured widespread changes in the DNA methylation status of a significant number of genes. Gene ontology analysis revealed enrichment in categories associated with immune function. Individual analysis confirmed the existence of DNA methylation and expression changes in genes relevant to SLE pathogenesis. These changes occurred in parallel with a global decrease in the 5-methylcytosine content that was concomitantly accompanied with changes in DNA methylation and expression levels of ribosomal RNA genes, although no changes in repetitive sequences were found. Our findings not only identify potentially relevant DNA methylation markers for the clinical characterization of SLE patients but also support the notion that epigenetic changes may be critical in the clinical manifestations of autoimmune disease.[Supplemental material is available online at http://www.genome.org. The sequence data from this study have been submitted to the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo) under accession no. GSE19033.]Human monozygotic (MZ) twins exhibit variable degrees of concordance for complex diseases, such as cancer, cardiovascular diseases, or autoimmune disorders. Whereas concordance rates close to 100% in identical twins apply to coinheritance of mutant genes that are dominant and highly penetrant, most diseases or traits show a concordance in identical twins in the broad range of 5%-75% (Nance 1978). Most of the twin-based studies have focused on the concordance between siblings that has led to the identification of traitspecific genes (Hrubec and Robinette 1984), while less attention has been paid to the degree of discordance, which suggests the participation of factors other than pure genetic changes. Recently, interest has shifted toward exploring the molecular mechanisms involved in determining phenotypic differences. The increasing recognition of the influence of epigenetics in phenotypic outcomes continues to open up new lines of research involving twin studies. DNA methylation and histone modifications, the major sources of epigenetic information, regulate gene expression levels and provide an alternative mechanism for modulating gene function to those arising from genetic changes (Esteller 2008). Interestingly, epigenetic changes are

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“…We recently investigated the effect of DNA methylation in the development of autoimmunity in aging, by examining the effect of Dnmt1 deficiency on the development of autoimmunity in aging mice (71,72). While homozygous Dnmt1 knockout is embryonically lethal, young heterozygous animals have globally hypomethylated DNA and are phenotypically normal (73).…”

Section: Cross-talk Between Epigenetics Aging and Late-life Diseasesmentioning

confidence: 99%

Epigenetics, aging, and autoimmunity

Yung

Julius

2008

Autoimmunity

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The decline in immunocompetence with age is accompanied by the increase in the incidence of autoimmune diseases. Aging of the immune system, or immunosenescence, is characterized by a decline of both T and B cell function, and paradoxically the presence of low grade chronic inflammation. There is growing evidence that epigenetics, the study of inherited changes in gene expression that are not encoded by the DNA sequence itself, changes with aging. Interestingly, emerging evidence suggests a key role for epigenetics in human pathologies, including inflammatory and neoplastic disorders. Here we will review the potential mechanisms that contribute to the increase in autoimmune responses in aging. In particular, we will discuss how epigenetic alterations, especially DNA methylation and histone acetylation, are accumulated during aging and how these events contribute to autoimmunity risk.

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Unexpected Effects of a Heterozygous Dnmt1 Null Mutation on Age-Dependent DNA Hypomethylation and Autoimmunity

Cited by 39 publications

References 34 publications

S‐Adenosylhomocysteine hydrolase deficiency: A second patient, the younger brother of the index patient, and outcomes during therapy

S‐Adenosylhomocysteine hydrolase deficiency: A second patient, the younger brother of the index patient, and outcomes during therapy

Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus

Epigenetics, aging, and autoimmunity

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