Pccb, encoding the β -subunit of propionyl-CoA carboxylase, is a nuclear-encoded mitochondrial gene. Propionyl-CoA carboxylase is crucial for converting propionyl-CoA to methylmalonyl-CoA in the tricarboxylic acid cycle, playing a significant role in the metabolism of branched-chain amino acids, odd-numbered chain length fatty acids, cholesterol, and other metabolites [3,4].

Mutations in Pccb can lead to propionic acidemia (PA), an autosomal recessive metabolic disorder. A case report described a PA patient with an adult-onset phenotype and novel compound heterozygous mutations in Pccb, presenting with neuropsychiatric symptoms [2]. In Japanese neonatal screening, a common Pccb variant (c.1304T>C) was found, leading to a higher-than-expected disease frequency, with some patients showing cardiac complications [5]. In a study of Chinese patients, five novel Pccb variants were identified, expanding the mutation spectrum [6]. A Saudi Arabian study detected nine different Pccb variants in PA patients [7]. Also, Pccb has been linked to schizophrenia. Knockdown of Pccb in human forebrain organoids led to dysregulation of genes related to GABA-ergic synapse, decreased GABA levels, and SCZ-related phenotypes such as hyper-neuroactivities and reduced neural network synchronization [1,8].

In conclusion, Pccb is essential for normal metabolism, and its mutations are associated with propionic acidemia, which can present with various clinical manifestations including neuropsychiatric symptoms and cardiac complications. The link of Pccb to schizophrenia through its regulation of GABAergic pathways also highlights its importance in neuropsychiatric disease research. Research on Pccb using human-based models like forebrain organoids has provided valuable insights into its role in disease-related biological processes [1,2,5,7-9].

References:

1. Zhang, Wendiao, Zhang, Ming, Xu, Zhenhong, Chen, Chao, Meng, Qingtuan. 2023. Human forebrain organoid-based multi-omics analyses of PCCB as a schizophrenia associated gene linked to GABAergic pathways. In Nature communications, 14, 5176. doi:10.1038/s41467-023-40861-2. https://pubmed.ncbi.nlm.nih.gov/37620341/

2. Li, Yingxuan, Wang, Miaomiao, Huang, Zhaoyang, Ye, Jing, Wang, Yuping. 2022. Novel compound heterozygous variants in the PCCB gene causing adult-onset propionic acidemia presenting with neuropsychiatric symptoms: a case report and literature review. In BMC medical genomics, 15, 59. doi:10.1186/s12920-022-01202-2. https://pubmed.ncbi.nlm.nih.gov/35296328/

3. Marchuk, Hannah, Wang, You, Ladd, Zachary Alec, Chen, Xiaoxin, Zhang, Guo-Fang. 2023. Pathophysiological mechanisms of complications associated with propionic acidemia. In Pharmacology & therapeutics, 249, 108501. doi:10.1016/j.pharmthera.2023.108501. https://pubmed.ncbi.nlm.nih.gov/37482098/

4. Ugarte, M, Pérez-Cerdá, C, Rodríguez-Pombo, P, Ohura, T, Gravel, R A. . Overview of mutations in the PCCA and PCCB genes causing propionic acidemia. In Human mutation, 14, 275-82. doi:. https://pubmed.ncbi.nlm.nih.gov/10502773/

5. Tajima, Go, Kagawa, Reiko, Sakura, Fumiaki, Sasai, Hideo, Okada, Satoshi. 2021. Current Perspectives on Neonatal Screening for Propionic Acidemia in Japan: An Unexpectedly High Incidence of Patients with Mild Disease Caused by a Common PCCB Variant. In International journal of neonatal screening, 7, . doi:10.3390/ijns7030035. https://pubmed.ncbi.nlm.nih.gov/34203287/

6. Yang, Xiaoxuan, Li, Dongyan, Tu, Chaofeng, Du, Juan, Zhang, Qianjun. 2021. Novel variants of the PCCB gene in Chinese patients with propionic acidemia. In Clinica chimica acta; international journal of clinical chemistry, 519, 18-25. doi:10.1016/j.cca.2021.03.019. https://pubmed.ncbi.nlm.nih.gov/33798502/

7. Al-Hamed, Mohamed H, Imtiaz, Faiqa, Al-Hassnan, Zuhair, Moghrabi, Nabil, AlSayed, Moeenaldeen. 2019. Spectrum of mutations underlying Propionic acidemia and further insight into a genotype-phenotype correlation for the common mutation in Saudi Arabia. In Molecular genetics and metabolism reports, 18, 22-29. doi:10.1016/j.ymgmr.2018.12.004. https://pubmed.ncbi.nlm.nih.gov/30705822/

8. Zhang, Wendiao, Zhang, Ming, Xu, Zhenhong, Chen, Chao, Meng, Qingtuan. 2023. Human forebrain organoids-based multi-omics analyses reveal PCCB's regulation on GABAergic system contributing to schizophrenia. In Research square, , . doi:10.21203/rs.3.rs-2674668/v1. https://pubmed.ncbi.nlm.nih.gov/37034773/