This report describes hyperprolinemia, type II (HYRPRO2); HYRPRO2 exhibits autosomal recessive inheritance. The human gene implicated in this disease is ALDH4A1, a nuclear gene that encodes a mitochondrial enzyme which catalyzes the second step of the proline degradation pathway; this is a necessary step in the pathway interconnecting the urea and tricarboxylic acid cycles. There is a single orthologous gene in Drosophila, P5CDh1, for which multiple genetic reagents have been generated including RNAi-targeting constructs, alleles caused by insertional mutagenesis, overexpression constructs, and a CRISPR/Cas9-based TKO construct.
The human ALDH4A1 gene has not been introduced into flies.
Animals homozygous for a severe loss-of-function mutation of P5CDh1 exhibit proline levels twice that of normal and typically die during the larval or pupal stage. Mitochondria exhibit morphological abnormalities, suggesting that the ALDH4A1 protein is required for normal mitochondrial homeostasis.
[updated Apr. 2023 by FlyBase; FBrf0222196]
[HYPERPROLINEMIA, TYPE II; HYRPRO2](https://omim.org/entry/239510)
[ALDEHYDE DEHYDROGENASE, FAMILY 4, SUBFAMILY A, MEMBER 1; ALDH4A1](https://omim.org/entry/606811)
Hyperprolinemia type II results in proline levels in the blood between 10 and 15 times higher than normal, and high levels of a related compound called pyrroline-5-carboxylate. This form of the disorder is more likely than type I to involve seizures or intellectual disability that vary in severity. [MedlinePlus, Hyperprolinemia; 2023.04.21]
Hyperprolinemia type II (HYRPRO2) is caused by homozygous or compound heterozygous mutation in the pyrroline-5-carboxylate dehydrogenase gene (P5CDH, now ALDH4A1). [from MIM:239510; 2023.04.20]
ALDH4A1 encodes a protein that belongs to the aldehyde dehydrogenase family of proteins. This enzyme is a mitochondrial matrix NAD-dependent dehydrogenase which catalyzes the second step of the proline degradation pathway, converting pyrroline-5-carboxylate to glutamate. This is a necessary step in the pathway interconnecting the urea and tricarboxylic acid cycles. [GeneCards, ALDH4A1; 2023.05.02]
One to one: 1 human gene to 1 Drosophila gene.
High-scoring ortholog of human ALDH4A1 (1 Drosophila to 1 human).
