Several studies in Drosophila have investigated phenotypes associated with fly orthologs of specific genes within the 22q11.2 deletion region. These include Dmel\sea (orthologous to human SLC25A1; see FBhh0000951), Dmel\Lztr1 (orthologous to human LZTR1) and Dmel\mRpL40 (orthologous to human MRPL40).
None of these human genes (SLC25A1, LZTR1, MRPL40) has been introduced into flies.
LZTR1 encodes an adaptor protein of an E3 ubiquitin-protein ligase complex that is involved in regulation of RAS-MAPK signaling. LZTR1 is implicated in dominant and recessive forms of Noonan syndrome (see MIM:600574). In flies, pan-neuronal knockdown of Dmel\Lztr1 results in reduced night-time sleep, a phenotype characteristic of many psychiatric disorders.
Both SLC25A1 and MRPL40 act in the mitochondria, SLC25A1 as a a carrier protein within the inner mitochondrial membrane and MRPL40 as a component of the mitochondrial ribosome. In flies, hemideficiency of Dmel\sea results in defects in synapse morphology, neurotransmission, plasticity, and sleep patterns. RNAi-mediated pan-neuronal knockdown of either sea or mRpL40 results in increased the complexity of the synapses as determined by increased number of synaptic boutons and total branch length per synapse. This phenotype is also observed for pan-neuronal knockdown of Dmel\mRpL15 (the human MRPL15 gene is not within the chromosome 22q11.2 deletion). Simultaneous knockdown of sea and either mRpL40 or mRpL15 results in a similar, but not more extreme, phenotype. It is postulated that Drosophila mitochondrial citrate transporter (sea) and mitochondrial ribosome subunits reside on a common genetic pathway necessary for synapse development and function. These results support the hypothesis that impaired mitochondrial protein synthesis contributes to the neurodevelopmental phenotypes observed in 22q11.2 microdeletion syndrome.
[updated Sep. 2021 by FlyBase; FBrf0222196]
[DIGEORGE SYNDROME; DGS](https://omim.org/entry/188400)
[T-BOX TRANSCRIPTION FACTOR 1; TBX1](https://omim.org/entry/602054)
DiGeorge syndrome (DGS) comprises hypocalcemia arising from parathyroid hypoplasia, thymic hypoplasia, and outflow tract defects of the heart. Disturbance of cervical neural crest migration into the derivatives of the pharyngeal arches and pouches can account for the phenotype.
[from MIM:188400; 2021.06.22]
The features of 22q11.2 deletion syndrome vary widely, even among affected members of the same family. People with 22q11.2 deletion syndrome commonly have heart abnormalities that are often present from birth, recurrent infections caused by problems with the immune system, and distinctive facial features. [MedlinePlus: 22q11.2 deletion syndrome; 2021.06.22]
In some patients psychiatric illness is observed, including autism spectrum disorder (20% of children), schizophrenia (25% of adults), attention deficit disorder, anxiety, perseveration, and difficulty with social interactions. [Gene Reviews: 22q11.2 Deletion Syndrome; 2021.06.2]
22q11.2DS is an autosomal dominant contiguous gene deletion syndrome. [Gene Reviews: 22q11.2 Deletion Syndrome; 2021.06.2]
Most cases of DiGeorge syndrome result from a deletion of chromosome 22q11.2 (the DiGeorge syndrome chromosome region, or DGCR). [from MIM:188400; 2021.06.22]
MRPL40 is a nuclear gene that encodes a component of mitochondrial ribosome large subunit. [Gene Cards, MRPL40; 2021.09.07]
LZTR1 encodes a substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex; the LZTR1 protein appears to contribute to the ubiquitination of protein(s) functioning as positive modulator(s) of the RAS-MAPK signaling pathway. [Gene Cards, LZTR1; 2021.09.07]
SLC25A1 encodes a member of a nuclear-encoded mitochondrial carrier subfamily of solute carrier proteins; it translocates small metabolites across the mitochondrial membrane. It is known to transport citrate and was originally designated 'mitochondrial citrate transporter' or 'citrate transport protein' (CTP). [Gene Cards; SLC25A1; 2019.01.08]
One to one: 1 human gene to 1 Drosophila gene.
One to one: 1 human gene to 1 Drosophila gene.
One to one: 1 human gene to 1 Drosophila gene.
High-scoring ortholog of human LZTR1 (1 Drosophila to 1 human). Dmel\sea shares 51% identity and 67% similarity with the human gene.
High-scoring ortholog of human SLC25A1 (1 Drosophila to 1 human). Dmel\sea shares 64% identity and 77% similarity with the human gene.
High-scoring ortholog of human MRPL40 (1 Drosophila to 1 human). Dmel\mRpL40 shares 40% identity and 64% similarity with the human gene.
