A splicing mutation in the hydroxymethylbilane synthase gene in a Japanese family with acute intermittent porphyria

Maeda, Naota; Horie, Yutaka; Sasaki, Yoko; Ueta, Etsuko; Adachi, Kaori; Nanba, Eiji; Kawasaki, Hironaka; Kudo, Yoshiro; Kondo, Masao

doi:10.1016/s0009-9120(99)00043-0

Cited by 4 publications

(6 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This patient was diagnosed in Northeast Japan, and this area has been called "Holland Village". Moreover, a splicing mutation recently reported by Maeda et al (1999) is similar to that from the Netherlands (Llewellyn et al 1996): a C-to-G transversion at position Ϫ3 of the acceptor site of intron 11 leading to exon 12 skipping. Such a similarity of gene abnormality may suggest that these European and Japanese AIP families could have a common ancestor.…”

Section: Discussionmentioning

confidence: 61%

“…In Japan, five kinds of mutations in the HMBS gene have been described in six unrelated Japanese families so far (Daimon et al 1993;Daimon et al 1994;Morita et al 1995;Tomie et al 1998;Maeda et al 1999) (Fig. 4), with four of the families having the same mutations as those reported in Europe.…”

Section: Discussionmentioning

confidence: 90%

“…In Japan, however, molecular analyses have been documented in only six families (Daimon et al 1993;Daimon et al 1994;Morita et al 1995;Tomie et al 1998;Maeda et al 1999) to date.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Two deletion mutations in the hydroxymethylbilane synthase gene in two unrelated Japanese patients with acute intermittent porphyria

et al. 2000

View full text Add to dashboard Cite

Acute intermittent porphyria (AIP) is an autosomal dominant inherited disease caused by a decreased activity of hydroxymethylbilane synthase (HMBS). Regarding the abnormalities of the HMBS gene, many different mutations have been reported worldwide; however, few families from Japan have been studied. In this work, we investigated the presence of mutations in two unrelated Japanese patients with AIP. Mutational analysis was performed using the polymerase chain reaction-single strand conformation polymorphism (SSCP) method, followed by DNA sequencing. Reliable restriction enzyme cleavage assays were also established for the pedigree analyses. Unique SSCP patterns were noted in exons 12 and 15 of the HMBS gene. Sequencing revealed different mutations in each patient: a two-base deletion of CT at nucleotide 730-731 (730delCT), and also a two-base deletion of CA at position 982-983 (982delCA). Both of the deletion mutations lead to truncated proteins with an abnormal C-terminus, which would be expected to decrease the stability and/or activity of HMBS. Using the cleavage assays, we were able to definitively identify gene carriers in the family. This study adds a novel mutation to those that have been previously reported, and emphasizes that molecular analysis would be very useful not only for the identification of asymptomatic gene carriers in the family but also for the detection of ancestral founders in porphyria families.

show abstract

Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 90%

See 1 more Smart Citation

Two deletion mutations in the hydroxymethylbilane synthase gene in two unrelated Japanese patients with acute intermittent porphyria

et al. 2000

View full text Add to dashboard Cite

show abstract

“…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%

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

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.

show abstract

“…A novel splicing pathogenic variant (c.648_651+1delCCAGG) was identified in the family using Sanger sequencing. This mutation occurs in the junction region of exon 10 and intron 10, thus depriving the junction region of the GU-AG splice site[ 17 ] and preventing the intron cleavase enzyme from recognizing the splicing site; therefore, the whole of intron 10 is retained in the mature mRNA when the pre-mRNA is spliced. However, because the retained intron sequence contains a stop codon, it causes early termination of translation, potentially producing a shortened protein.…”

Section: Discussionmentioning

confidence: 99%

Novel hydroxymethylbilane synthase gene mutation identified and confirmed in a woman with acute intermittent porphyria: A case report

Zhou¹,

Wang²,

Jiang³

et al. 2022

World J Clin Cases

View full text Add to dashboard Cite

BACKGROUND Acute intermittent porphyria (AIP) is a rare autosomal dominant porphyrin metabolic disease caused by a mutation in the hydroxymethylbilane synthase ( HMBS ) gene. This study aimed to explore the clinical manifestations of a patient with AIP, to identify a novel HMBS gene mutation in the proband and some of her family members, and to confirm the pathogenicity of the variant. CASE SUMMARY A 22-year-old Chinese woman developed severe abdominal pain, lumbago, sinus tachycardia, epileptic seizure, hypertension, and weakness in lower limbs in March, 2018. Biochemical examinations indicated hypohepatia and hyponatremia. Her last menstrual period was 45 d prior to admission, and she was unaware of the pregnancy, which was confirmed by a pregnancy test after admission. Sunlight exposure of her urine sample for 1 h turned it from yellow to wine red. Urinary porphyrin test result was positive. Based on these clinical manifestations, AIP was diagnosed. After increasing her daily glucose intake (250–300 g/d), abdominal pain was partially relieved. Three days after hospitalization, spontaneous vaginal bleeding occurred, which was confirmed as spontaneous abortion; thereafter, her clinical symptoms completely resolved. Genetic testing revealed a novel heterozygous splicing variant of the HMBS gene in exon 10 (c.648_651+1delCCAGG) in the proband and four other family members. The pathogenicity of the variant was verified through bioinformatic methods and a minigene assay. CONCLUSION We identified a novel HMBS gene mutation in a Chinese patient with AIP and confirmed its pathogenicity.

show abstract

A splicing mutation in the hydroxymethylbilane synthase gene in a Japanese family with acute intermittent porphyria

Cited by 4 publications

References 23 publications

Two deletion mutations in the hydroxymethylbilane synthase gene in two unrelated Japanese patients with acute intermittent porphyria

Two deletion mutations in the hydroxymethylbilane synthase gene in two unrelated Japanese patients with acute intermittent porphyria

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

Novel hydroxymethylbilane synthase gene mutation identified and confirmed in a woman with acute intermittent porphyria: A case report

Contact Info

Product

Resources

About