This report describes CODAS syndrome (cerebral, ocular, dental, auricular, and skeletal abnormalities syndrome); CODAS syndrome exhibits autosomal recessive inheritance. The human gene implicated in this disease is LONP1, a protease found in the mitochondrial matrix with a role in degradation of misfolded or damaged polypeptides; it may also have other functions within the mitochondria. There is a single orthologous gene in Drosophila, Dmel\Lon, for which RNAi-targeting constructs, alleles caused by insertional mutagenesis, and amorphic alleles created by targeted recombination have been generated.
A tagged UAS construct of human Hsap\LONP1 has been introduced into flies, but has not been characterized in the context of this disease model.
Animals homozygous for an amorphic allele of Dmel\Lon typically die during the second instar larval stage. Animals with a relatively weak knockdown of Lon, effected by RNAi, survive to adulthood and are fertile, but exhibit locomotor defects and shortened adult lifespan. These animals exhibit progressive respiratory chain defects resulting in a a progressive age-dependent decline in oxidative phosphorylation capacity. Sequestration of mitochondrially encoded transcripts in highly dense ribonucleoparticles and accumulation of unfolded mitochondrial proteins is observed in the Lon animals, similar to mitochondrial phenotypes observed for CODAS syndrome. A small number of physical and genetic interactions have been described for Dmel\Lon; see below and in the Lon gene report.
[updated Apr. 2019 by FlyBase; FBrf0222196]
[CODAS SYNDROME](https://omim.org/entry/600373)
[LON PEPTIDASE 1, MITOCHONDRIAL; LONP1](https://omim.org/entry/605490)
CODAS syndrome is a rare disorder characterized by a distinctive constellation of features that includes developmental delay, craniofacial anomalies, cataracts, ptosis, median nasal groove, delayed tooth eruption, hearing loss, short stature, delayed epiphyseal ossification, metaphyseal hip dysplasia, and vertebral coronal clefts (summary by Strauss et al., 2015; pubmed:25574826). [from MIM:600373; 2019.04.11]
CODAS syndrome is caused by homozygous or compound heterozygous mutation in the LONP1 gene. [from MIM:600373; 2019.04.11]
Transmission electron microscopy of a patient's lymphoblast cell lines (LCLs) showed enlarged mitochondria with swollen intra- or intercristal compartments, uniform vesicular structures, and electron-dense intramitochondrial inclusions, suggestive of abnormal inner-membrane topology. [from MIM:600373; 2019.04.11]
LONP1 encodes a mitochondrial matrix protein that belongs to the Lon family of ATP-dependent proteases. This protein mediates the selective degradation of misfolded, unassembled or oxidatively damaged polypeptides in the mitochondrial matrix. It may also have a chaperone function in the assembly of inner membrane protein complexes, and participate in the regulation of mitochondrial gene expression and maintenance of the integrity of the mitochondrial genome. [Gene Cards, LONP1; 2019.04.11]
Many to one: 2 human to 1 Drosophila; the second human gene is LONP2.
High-scoring ortholog of human LONP1; low-scoring ortholog of LONP2 (1 Drosophila to 2 human). Dmel\Lon shares 62% identity and 76% similarity with human LONP1.
