Hmbs, encoding hydroxymethylbilane synthase, is a crucial gene in the heme biosynthesis pathway. Heme is an essential component of many proteins, such as hemoglobin, and is involved in various biological processes like oxygen transport and electron transfer. Mutations in Hmbs can lead to acute intermittent porphyria (AIP), highlighting its significance in maintaining normal physiological functions [1,2,3,4].

In AIP patients, 90.5% have decreased erythrocyte hydroxymethylbilane synthase activity (<70%). A total of 96 different mutations were identified in 232 patients, with missense (34.4%) being the most common, followed by splice (28.1%) mutations. Different mutation types and positions are not associated with the level of hydroxymethylbilane synthase activity. Also, the enzyme activity assay has high diagnostic value in AIP [1]. In Chinese AIP patients, 97 variants were detected in 160 unrelated families, with missense mutations being the most common and c.517C>T being the most frequent variant. Clinical phenotypes are related to the type of variants, such as more severe symptoms for those causing premature stop codons, frameshifts or affecting the enzyme activity center [2].

In conclusion, Hmbs is vital for heme biosynthesis. Its dysfunction due to mutations is closely associated with AIP. Studies on AIP patients with Hmbs mutations help reveal the role of Hmbs in preventing this porphyria, providing insights into the diagnosis, understanding of genotype-phenotype associations, and potential treatment strategies for AIP [1,2].

References:

1. Li, Shuang, Lei, Jia-Jia, Dong, Bai-Xue, Ren, Yi, Yang, Jing. . HMBS gene mutations and hydroxymethylbilane synthase activity in acute intermittent porphyria: A systematic review. In Medicine, 102, e35144. doi:10.1097/MD.0000000000035144. https://pubmed.ncbi.nlm.nih.gov/37773850/

2. Ren, Yi, Li, Shuang, Lei, Jia-Jia, Dong, Bai-Xue, Yang, Jing. 2023. Clinical feature and genetic analysis of HMBS gene in Chinese patients with acute intermittent porphyria: a systematic review. In Frontiers in genetics, 14, 1291719. doi:10.3389/fgene.2023.1291719. https://pubmed.ncbi.nlm.nih.gov/38148975/

3. Bustad, Helene J, Kallio, Juha P, Vorland, Marta, Aarsand, Aasne K, Martinez, Aurora. 2021. Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators. In International journal of molecular sciences, 22, . doi:10.3390/ijms22020675. https://pubmed.ncbi.nlm.nih.gov/33445488/

4. Wang, Bruce, Bonkovsky, Herbert L, Lim, Joseph K, Balwani, Manisha. 2023. AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review. In Gastroenterology, 164, 484-491. doi:10.1053/j.gastro.2022.11.034. https://pubmed.ncbi.nlm.nih.gov/36642627/