Molecular analysis of acute intermittent porphyria: mutation screening in 20 patients in Germany reveals 11 novel mutations

Brasch, Léon von; Zang, Chuanbing; Haverkamp, Thomas; Schlechte, Horst; Heckers, H.; Petrides, Petro E.

doi:10.1016/j.bcmd.2003.12.003

Cited by 13 publications

(11 citation statements)

References 25 publications

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“…However, only six of these had <3% of WT expressed activity or reduced thermostability. Review of the original reports for the other six variants identified 13 reportedly symptomatic AIP patients who had variants encoding p.T59I [Schneider‐Yin et al., ], p.E86V [Floderus et al., ], p.R225Q [Floderus et al., ; von Brasch et al., ], or p.R321H [Schuurmans et al., ; von Brasch et al., ; Anyaegbu et al., ; Cerbino et al., ]. However, the pathogenicity of most of these patients was not verified by elevated urinary ALA or PBG levels with the exception of (1) three patients with p.R321H who also had a second and pathogenic HMBS mutation [von Brasch et al., ; Cerbino et al., ]; and (2) one patient with p.R321H who had significantly increased urinary ALA or PBG concentrations, suggesting the presence of an unidentified second and pathogenic mutation [Anyaegbu et al., ] (Supp.…”

Section: Discussionmentioning

confidence: 99%

Acute Intermittent Porphyria: Predicted Pathogenicity ofHMBSVariants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease

et al. 2016

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Acute Intermittent Porphyria results from hydroxymethylbilane synthase (HMBS) mutations that markedly decrease HMBS enzymatic activity. This dominant disease is diagnosed when heterozygotes have life-threatening acute attacks, while most heterozygotes remain asymptomatic and undiagnosed. Although >400 HMBS mutations have been reported, the prevalence of pathogenic HMBS mutations in genomic/exomic databases, and the actual disease penetrance are unknown. Thus, we interrogated genomic/exomic databases, identified non-synonymous variants (NSVs) and consensus splice-site variants (CSSVs) in various demographic/racial groups, and determined the NSV’s pathogenicity by prediction algorithms and in vitro expression assays. Caucasians had the most: 58 NSVs and two CSSVs among ~92,000 alleles, a 0.00575 combined allele frequency. In silico algorithms predicted 14/58 NSVs as “likely-pathogenic”. In vitro expression identified 10/58 NSVs as likely-pathogenic (seven predicted in silico), which together with two CSSVs had a combined allele frequency of 0.00056. Notably, six presumably pathogenic mutations/NSVs in the Human Gene Mutation Database were benign. Compared to the recent prevalence estimate of symptomatic European heterozygotes (~0.000005), the prevalence of likely-pathogenic HMBS mutations among Caucasians was >100 times more frequent. Thus, the estimated penetrance of acute attacks was ~1% of heterozygotes with likely-pathogenic mutations, highlighting the importance of predisposing/protective genes and environmental modifiers that precipitate/prevent the attacks.

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Section: Discussionmentioning

confidence: 99%

Acute Intermittent Porphyria: Predicted Pathogenicity ofHMBSVariants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease

et al. 2016

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“…Hesperidin (hesperetin-7-rutinoside) is the major flavonoid of oranges, found largely as glycosides, which are hydrolyzed to their active forms by intestinal bacteria [ 6 ]. Sweet orange juice contains narirutin (30–84 mg/L) and hesperidin (235–407 mg/L) [ 7 – 9 ]. SREBPs are members of the basic helix-loop- helix-leucine zipper (bHLH-Zip) family of transcription factors thatdirectly activate the transcription of more than 30 genes dedicated to the biosynthesis and uptake of cholesterol, fatty acid, triglycerides and phospholipids.…”

Section: Introductionmentioning

confidence: 99%

Role of hesperetin in LDL-receptor expression in hepatoma HepG2 cells

Bawazeer

Choudhry

Zamzami

et al. 2016

BMC Complement Altern Med

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BackgroundHigh plasma concentration of low-density lipoprotein cholesterol (LDL-c) plays a significant role in the incidence of atherosclerosis and coronary heart diseases. The aim of this study was to investigate the mechanism by which the citrus flavonoid, hesperetin, regulates the LDL receptor (LDLr) gene in the human liver using the human hepatoma cell line, HepG2.MethodsLuciferase reporter gene assays were performed (in the absence of lipoprotein) to measure the activity of the LDLr promoter and the promoters of the sterol regulatory element binding protein (SREBP) transcription factors that control the LDLr promoter.ResultsOnly SREBP-1 promoter activity was significantly increased 4 h after exposure to 200 μM hesperetin. However, after 24 h incubation with 200 μM hesperetin, the activities of all the promoter-constructs, SREBP-1a, -1c, -2 and LDLr, were significantly increased. The effects of 200 μM hesperetin on elevating LDLr mRNA levels were possibly due to regulation of LDLr gene transcription by SREBP-la and SREBP-2.ConclusionsWe conclude that 200 μM hesperetin was likely to have stimulated LDLr gene expression in human hepatoma HepG2 cells via increased phosphorylation of PI3K andERK1/2, which increased SREBP-1a and SREBP-2 mRNA levels and enhanced the maturation of the encoded proteins. This may lead to lower plasma LDL cholesterol; therefore, diets supplemented with hesperidin might provide cardio-protective effects and reduce mortality and morbidity from coronary heart diseases.

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“…Peripheral neuropathy might be a late-onset feature or result from the HMBS variant (absent in gnomAd). A different variant in the same splice site (c.499-1G>A) causes acute intermittent porphyria (autosomal dominant disorder with recurrent attacks of gastrointestinal, vegetative, neurological dysfunction, including peripheral neuropathy) [7]. However, vomiting and hyperpyrexia are also common in HLD10 [3].…”

Section: E U R O P E a N J O U R N A L O F N E U R O L O G Y L E T T mentioning

confidence: 99%

Prolonged survival in a patient with a novel pyrroline‐5‐carboxylase reductase 2 genetic variant

Spagnoli

Pavlidis

Salerno

et al. 2019

Euro J of Neurology

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Molecular analysis of acute intermittent porphyria: mutation screening in 20 patients in Germany reveals 11 novel mutations

Cited by 13 publications

References 25 publications

Acute Intermittent Porphyria: Predicted Pathogenicity ofHMBSVariants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease

Acute Intermittent Porphyria: Predicted Pathogenicity ofHMBSVariants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease

Role of hesperetin in LDL-receptor expression in hepatoma HepG2 cells

Prolonged survival in a patient with a novel pyrroline‐5‐carboxylase reductase 2 genetic variant

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