<i>S</i>‐Adenosylhomocysteine hydrolase deficiency in a 26‐year‐old man

Buist, Neil R. M.; Glenn, B.; Wagner, Conrad; Stabler, Sally P.; Allen, Robert H.; Pogribny, Igor P.; Schulze, Andreas; Zeisel, Steven H.; Barić, Ivo; Mudd, S. Harvey

doi:10.1007/s10545-006-0240-0

Cited by 66 publications

(83 citation statements)

References 23 publications

(52 reference statements)

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“…These findings argue that a heritable reduction in Ahcy activity may be a predisposing genetic risk factor for hepatic steatosis. Consistent with such a role for AHCY in humans, steatosis and liver injury were reported in hypermethioninemic patients recently shown to carry homozygous AHCY mutations (Baric et al, 2005;Baric et al, 2004;Buist et al, 2006).…”

Section: Introductionsupporting

confidence: 60%

“…The firstidentified patient also demonstrated biochemical hepatitis and mitochondrial abnormalities on liver biopsy at the age of 12 months (Baric et al, 2004), whereas the second patient had no demonstrable liver abnormalities, presumably because of an earlier diagnosis at age 3 months (Baric et al, 2005). A third, 26-year-old patient had comparable motor and neurological symptoms, in addition to hepatic steatosis and mitochondrial abnormalities evident on liver electron micrographs (Buist et al, 2006). It is intriguing that within this group of three AHCY-deficient patients, there appears to be a progression of mild to moderate liver disease with age, similar to our findings with the dtp heterozygotes.…”

Section: Relationship Of the Zebrafish And Human Ahcy Deficiency Phenmentioning

confidence: 94%

“…Clinical manifestations of human AHCY deficiency have been reported in only three patients (Baric et al, 2005;Baric et al, 2004;Buist et al, 2006). Motor and neurological defects were the prominent presenting symptoms in two siblings that are compound heterozygotes for two hypomorphic AHCY alleles.…”

Section: Relationship Of the Zebrafish And Human Ahcy Deficiency Phenmentioning

confidence: 99%

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TNFα-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafishs-adenosylhomocysteine hydrolase

et al. 2009

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Hepatic steatosis and liver degeneration are prominent features of the zebrafish ducttrip (dtp) mutant phenotype. Positional cloning identified a causative mutation in the gene encoding S-adenosylhomocysteine hydrolase (Ahcy). Reduced Ahcy activity in dtp mutants led to elevated levels of S-adenosylhomocysteine (SAH) and, to a lesser degree, of its metabolic precursor Sadenosylmethionine (SAM). Elevated SAH in dtp larvae was associated with mitochondrial defects and increased expression of tnfa and pparg, an ortholog of the mammalian lipogenic gene. Antisense knockdown of tnfa rescued hepatic steatosis and liver degeneration in dtp larvae, whereas the overexpression of tnfa and the hepatic phenotype were unchanged in dtp larvae reared under germ-free conditions. These data identify an essential role for tnfa in the mutant phenotype and suggest a direct link between SAH-induced methylation defects and TNF expression in human liver disorders associated with elevated TNFα. Although heterozygous dtp larvae had no discernible phenotype, hepatic steatosis was present in heterozygous adult dtp fish and in wildtype adult fish treated with an Ahcy inhibitor. These data argue that AHCY polymorphisms and AHCY inhibitors, which have shown promise in treating autoimmunity and other disorders, may be a risk factor for steatosis, particularly in patients with diabetes, obesity and liver disorders such as hepatitis C infection. Supporting this idea, hepatic injury and steatosis have been noted in patients with recently discovered AHCY mutations.

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Section: Introductionsupporting

confidence: 60%

Section: Relationship Of the Zebrafish And Human Ahcy Deficiency Phenmentioning

confidence: 94%

Section: Relationship Of the Zebrafish And Human Ahcy Deficiency Phenmentioning

confidence: 99%

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TNFα-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafishs-adenosylhomocysteine hydrolase

et al. 2009

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“…(18,19) Human AHCY deficiency, such as in hypermethionemia, results in severe biochemical abnormalities, including plasma elevations of 150-fold in SAH, 30-fold in SAM and 12-fold in methionine. (20,21) So far, three mutations in the AHCY gene have been found to reduce the activity of the AHCY enzyme, resulting in the signs and symptoms of hypermethionemia. (22,23) AHCY orthologues have been identified in many species, including bacteria, nematodes, yeast, plants, insects and vertebrates.…”

mentioning

confidence: 99%

The IRBIT domain adds new functions to the AHCY family

2008

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SummaryDuring the past few years, the IRBIT domain has emerged as an important add-on of S-adenosyl-L-homocystein hydrolase (AHCY), thereby creating the new family of AHCY-like proteins. In this review, we discuss the currently available data on this new family of proteins. We describe the IRBIT domain as a unique part of these proteins and give an overview of its regulation via (de)phosphorylation and proteolysis. The second part of this review is focused on the potential functions of the AHCY-like proteins. We propose that the IRBIT domain serves as an anchor for targeting AHCY-like proteins towards cytoplasmic targets. This leads to regulation of (i) The AHCY family AHCY S-adenosyl-L-homocystein (SAH) hydrolase (AHCY) is a ubiquitous, tetrameric enzyme that catalyzes the reversible hydrolysis of SAH to adenosine and L-homocysteine. SAH is formed as a by-product of S-adenosyl-L-methionine (SAM) through transmethylation reactions. The hydrolysis of SAH is required to maintain low cellular concentrations of SAH, which is a product inhibitor of S-adenosyl-L-methionine (SAM)-dependent transmethylation reactions.(1-4) Inhibition of AHCY results in the intracellular accumulation of SAH, causing a significant increase in the intracellular SAH/SAM ratio and the subsequent inhibition of SAM-dependent methylations.( 5 -8) SAM is the major methyl donor for delivery of methyl groups to DNA, RNA, proteins and cellular metabolites in eukaryotes and SAH hydrolysis is the only source of homocysteine in mammals.(9) AHCY has become an attractive target for design of broad-spectrum antiviral agents because of the inhibitory effects of elevated intracellular SAH concentrations on viral mRNA cap-methylating enzymes. (10,11) In addition to these antiviral effects, AHCY inhibitors have also been attributed antiparasitic, (12,13) anti-arthritic (14) and immunosuppressive (15) effects.The importance of AHCY for mammalian survival is suggested by the fact that a chromosomal deletion that includes the gene encoding AHCY causes embryonic lethality in mice.(16) Elevated homocysteine levels have been reported as a risk factor for dementia and Alzheimer's disease, (17) and as a possible risk marker for vascular disease. (18,19) Human AHCY deficiency, such as in hypermethionemia, results in severe biochemical abnormalities, including plasma elevations of 150-fold in SAH, 30-fold in SAM and 12-fold in methionine. (20,21) So far, three mutations in the AHCY gene have been found to reduce the activity of the AHCY enzyme, resulting in the signs and symptoms of hypermethionemia. (22,23) AHCY orthologues have been identified in many species, including bacteria, nematodes, yeast, plants, insects and vertebrates. In contrast, the AHCY-like (AHCYL) family members AHCYL1 (also termed IRBIT, the inositol 1,4, 5-trisphosphate (IP 3 ) receptor (IP 3 R) binding protein released by IP 3 ) and AHCYL2 (KIAA0828 in human) are only predicted in segmented multicellular organisms, like vertebrates (eg Takifugu rubripes (fugu fish), Danio rerio (zebrafish), Xen...

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“…Deletion of SAHH in mice is embryonically lethal (14). Human SAHH deficiency is a rare genetic disorder and is characterized by up to 140-fold elevated plasma AdoHcy levels with a significant decrease in the SAM/AdoHcy ratio, typically leading to severe pathological consequences and death in childhood (6,(15)(16)(17).…”

mentioning

confidence: 99%