Aldh18a1, also known as P5CS (pyrroline-5-carboxylate synthetase), is a gene encoding a bifunctional enzyme involved in the de novo biosynthesis of proline and ornithine. This enzyme participates in arginine and proline metabolism pathways [3]. Dysfunction of Aldh18a1 can lead to a variety of human disorders, highlighting its biological importance. Genetic models, such as gene-knockout mouse models, could potentially provide more insights into its functions.

Mutations in Aldh18a1 have been associated with multiple conditions. In a 10-year-old boy, a de novo pathogenic variant in Aldh18a1 led to a rare form of metabolic cutis laxa, complicated by atlantoaxial instability and spinal cord compression after a minor fall, suggesting the need for cervical spine screening in patients with such mutations [1]. In MYCN-amplified neuroblastoma, Aldh18a1 forms a positive feedback loop with MYCN, regulating each other's expression. Inhibiting Aldh18a1 can induce a less proliferative phenotype and tumor regression in xenograft models [2]. Homozygous variants in Aldh18a1 result in alterations in amino acid and antioxidant metabolism, including reduced levels of glutamate, proline, glutathione, and putrescine, along with changes in transcript abundance of metabolic and extracellular matrix-related genes in patient fibroblasts [3].

In conclusion, Aldh18a1 is crucial for proline and ornithine biosynthesis and is involved in amino acid and antioxidant metabolism. Research using models, though not specifically KO/CKO mouse models in the provided references, has shown its significance in diseases like cutis laxa and neuroblastoma. Understanding Aldh18a1's functions can offer potential therapeutic strategies for these associated disorders.

References:

1. Lucas, Alexandra T, Lin, Angela E, Cohen, Andrew, Sahai, Inderneel, Carroll, Ryan W. 2023. Atlantoaxial instability associated with ALDH18A1 mutation. In American journal of medical genetics. Part A, 191, 2898-2902. doi:10.1002/ajmg.a.63388. https://pubmed.ncbi.nlm.nih.gov/37655511/

2. Guo, Yu-Feng, Duan, Jiang-Jie, Wang, Jun, Bian, Xiu-Wu, Yu, Shi-Cang. . Inhibition of the ALDH18A1-MYCN positive feedback loop attenuates MYCN-amplified neuroblastoma growth. In Science translational medicine, 12, . doi:10.1126/scitranslmed.aax8694. https://pubmed.ncbi.nlm.nih.gov/32075946/

3. Colonna, Maxwell B, Moss, Tonya, Mokashi, Sneha, Lyons, Michael J, Steet, Richard. . Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism. In Human molecular genetics, 32, 732-744. doi:10.1093/hmg/ddac226. https://pubmed.ncbi.nlm.nih.gov/36067040/