Correlation between biochemical findings, structural and enzymatic abnormalities in mutated HMBS identified in six Israeli families with acute intermittent porphyria

Ulbrichová, Dana; Schneider‐Yin, Xiaoye; Mamet, Rivka; Saudek, Vladimı́r; Martásek, Pavel; Minder, Elisabeth I.; Schoenfeld, Nili

doi:10.1016/j.bcmd.2008.11.001

Cited by 11 publications

(5 citation statements)

References 21 publications

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“…Finally, 15 studies were obtained for analysis. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]…”

Section: Search Resultsmentioning

confidence: 99%

“…Currently, some mutations have been tested for enzyme activity analysis in vitro, The enzyme activity of homozygotes of most mutations in vitro expressed <5%, which is consistent with the decrease of half the residual enzyme activity of heterozygotes in vivo. [9,10,20,21,23,24,32–38] However, some of the homozygotes in vitro expressed the enzyme activity close to normal, ex. c.532 G>A and c.176 C>T, the residual enzyme activity of the homozygote reached 81% in vitro, while the heterozygote residual enzyme activity was 40% in vivo, [10,34] the reasons for this phenomenon need to be further explored.…”

Section: Discussionmentioning

confidence: 99%

“…[9,10,20,21,23,24,32–38] However, some of the homozygotes in vitro expressed the enzyme activity close to normal, ex. c.532 G>A and c.176 C>T, the residual enzyme activity of the homozygote reached 81% in vitro, while the heterozygote residual enzyme activity was 40% in vivo, [10,34] the reasons for this phenomenon need to be further explored.…”

Section: Discussionmentioning

confidence: 99%

“…María-José et al [9] 55 25 PCR Fluorescence method Spanish Ulbrichova et al [10] 26 6 PCR Fluorescence method Israeli Yang et al [11] 24 21 PCR Fluorescence method Chinese To-Figueras et al [12] 16 10 PCR Fluorescence method Spanish Pischik et al [13] 20 9 PCR Fluorescence method Russian Solis et al [14] 3 1 PCR Fluorescence method Spanish Hessels et al [15] 3 1 PCR Fluorescence method Turkish Gregor et al [16] 20 16 DGGE Fluorescence method Polish Martinez et al [17] 14 13 DGGE Fluorescence method Italian Ramdall et al 2000 [18] 5 5 PCR Fluorescence method USA Martinez et al [19] 8 7 DGGE Fluorescence method Italian De Siervi et al [20] 22 4 PCR Fluorescence method Argentinean Maeda et al [22] 10 1 PCR Fluorescence method Japanese De Siervi et al [23] 12 5 PCR Fluorescence method Argentinean Solis et al [21] 9 8 PCR Fluorescence method Spanish DGGE = denaturing gradient gel electrophoresis, PCR = polymerase chain reaction.…”

Section: Author Year Sample Size No Of Mutation Detection Methods (Mu...mentioning

confidence: 99%

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HMBS gene mutations and hydroxymethylbilane synthase activity in acute intermittent porphyria: A systematic review

Li,

Lei,

Dong

et al. 2023

Medicine

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Background: Acute intermittent porphyria (AIP) is caused by a partial deficiency of hydroxymethylbilane synthase and affects heme biosynthesis. Mutations in the HMBS gene result in HMBS deficiency. AIP is a rare disease, and there been insufficient studies on it. This report describes the molecular epidemiology of HMBS gene defects and hydroxymethylbilane synthase activity levels in classical AIP. Methods: Databases of PubMed, CNKI, and Wang Fang Database were searched for eligible studies to investigate HMBS gene mutations in peripheral blood samples and HMBS activity in erythrocytes of patients with classical AIP. Relevant studies published up to July 15, 2023, from several databases were independently searched and selected by 2 reviewers. Accuracy data and relevant information were extracted from each eligible study by 2 independent researchers and analyzed using statistical software. Results: After pooling the accuracy data from 232 patients of the 15 eligible studies, 90.5% (210/232) of AIP patients had decreased erythrocyte hydroxymethylbilane synthase activity (<70%), and 96 different mutations were identified in 232 patients, including 33 missense (34.4%), 27 splice (28.1%), 19 deletion (19.8%), 8 nonsense (8.3%), 9 insertion (9.4%) mutations. Residual enzyme activities (%) for different groups of type were expressed using mean and 95% confidence interval (95% CI): missense (51.2, 48.5–53.9), splice (57.5, 52.0–59.1), deletion (54.9, 50.7–59.1), nonsense (52.2, 44.4–60.0), insertion (53.2, 47.4–59.0), group analysis P = .17. Subgroups of missense mutations, domain 1 (50.2, 46.0–54.4), domain 2 (52.8, 49.1–56.4), and domain 3 (49.2, 38.3–60.0), Subgroup analysis, P = .62. Conclusion: Different mutation types and mutation positions are not associated with the level of hydroxymethylbilane synthase activity. Erythrocyte hydroxymethylbilane synthase activity is often reduced to half of normal in patients with AIP, and the enzyme activity assay has a high diagnostic value in AIP. AIP is highly molecularly heterogeneous, with missense mutations being the most common, followed by splice mutations. R173W and G111R are high-frequency mutations and have been found in multiple families from different countries.

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“…Finally, 15 studies were obtained for analysis. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]…”

Section: Search Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Author Year Sample Size No Of Mutation Detection Methods (Mu...mentioning

confidence: 99%

See 2 more Smart Citations

HMBS gene mutations and hydroxymethylbilane synthase activity in acute intermittent porphyria: A systematic review

Li,

Lei,

Dong

et al. 2023

Medicine

View full text Add to dashboard Cite

show abstract

“…Although functional expression in vitro and thermal stability study can predict the pathogenicity of variants better than in silico analysis, there are still certain limitations. Previous studies have revealed that the residual activity of HMBS enzyme expressed in vitro is not consistent with the activity in red blood cells in vivo (29), and the enzyme activity in red blood cells failed to reflect the level in liver accurately (30). Thus, functional studies should be utilized cautiously and its reproducibility should be focused on (31).…”

Section: The International Porphyrin Collaboration Has Beenmentioning

confidence: 98%

Acute intermittent porphyria: prevalence of pathogenic HMBS variants in China, and epidemiological survey in Hebei Province, China

Tian

et al. 2022

Ann Transl Med

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Background: Acute intermittent porphyria (AIP) is a rare inherited disorder with extremely low prevalence. Early detection of patients with potential pathogenic hydroxymethylbilane synthase (HMBS) variants is crucial for clinical prognosis. This study was designed to investigate the prevalence of pathogenic HMBS variants in Chinese population. Methods:The China Metabolic Analysis Project (ChinaMAP) database was employed to predict the prevalence of pathogenic HMBS variants in the Chinese population according to the variant interpretation guidelines of The American College of Medical Genetics and Genomics (ACMG). And the prevalence of pathogenic HMBS variants in Mixed American (AMR), African/African American (AFR), and Non-Finnish European (NFE) populations were estimated based on the Genome Aggregation Database (gnomAD) genome V3.0 database according to the guidelines of ACMG. An epidemiological investigation of AIP was conducted in Hebei Province, China through collecting the annual newly-diagnosed AIP cases of inpatients in 32 comprehensive grade III A hospitals from January 2011 to December 2020 in Hebei, China.Results: A total of 5 pathogenic/likely pathogenic (P/LP) HMBS variants were identified and the prevalence of pathogenic HMBS variants was predicted to be 1/1,765. Furthermore, based on the gnomAD genome V3.0 database, the estimated prevalence of pathogenic HMBS variants was 1/1,367, 1/1,403, and 1/621 in AMR, AFR, and NFE populations, respectively. The distribution of these variants varied among different racial populations. Moreover, AIP patients were predominantly hospitalized in comprehensive grade III A tertiary hospitals in Hebei province over a 10-year period. A total of 39 patients were newly-diagnosed with AIP, and a majority of them were female (n=36). The annual incidence between 2011 and 2017 {0.03 [95% confidence interval (CI): 0.01 to 0.11] to 0.05 (95% CI: 0.07 to 0.14) per million population} was generally lower than [0.07 (95% CI: 0.03 to 0.17) to 0.08 (95% CI: 0.03 to 0.18) per million] in 2018 and thereafter.Conclusions: China has made great strides in the management of AIP. More nationwide epidemiological surveys and study of the prevalence rate of AIP patients in China are urgently required.

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Assessing predictions on fitness effects of missense variants in HMBS in CAGI6

Zhang,

Kinch,

Katsonis

et al. 2024

Hum. Genet.

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Correlation between biochemical findings, structural and enzymatic abnormalities in mutated HMBS identified in six Israeli families with acute intermittent porphyria

Cited by 11 publications

References 21 publications

HMBS gene mutations and hydroxymethylbilane synthase activity in acute intermittent porphyria: A systematic review

HMBS gene mutations and hydroxymethylbilane synthase activity in acute intermittent porphyria: A systematic review

Acute intermittent porphyria: prevalence of pathogenic HMBS variants in China, and epidemiological survey in Hebei Province, China

Assessing predictions on fitness effects of missense variants in HMBS in CAGI6

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