This report describes a model of chromosome 3q29 deletion syndrome, wherein a region containing 21 genes is deleted from chromosome 3.
Knocking down several of the 15 fly orthologs of genes in the deletion (both ubiquitously and targeting specific tissues) causes multiple phenotypes, including climbing difficulties, eye and wing defects, and lethality. When pairwise crosses are made, generating 94 two-gene knockdown combinations, pairs including Cbp20 exacerbated defects caused by either gene in the pair, suggesting that synthetic enhancement of defects caused by combinations of genes in the human deletion is responsible for its phenotype. In particular, programmed cell death defects are seen in paired gene knockdowns including Cbp20, which can be rescued by expression of the apoptosis inhibitor Diap1.
The human ortholog of Cbp20 is NCBP2, which like its fly ortholog Cbp20 is part of the RNA cap binding complex. There are no known disease associations with NCBP2 alone. NCBP2 is the single high-scoring ortholog of Cbp20 and vice versa. NCBP2 has not yet been introduced to Drosophila.
The only fly ortholog of genes in this deletion which also has individual associated Human Disease Model reports is dlg1, which is associated with multiple cancer models.
[updated April 2020 by FlyBase; FBrf0222196]
[CHROMOSOME 3q29 DELETION SYNDROME](https://omim.org/entry/609425)
[CHROMOSOME 3q29 DELETION SYNDROME](https://omim.org/entry/609425)
The 1.6 Mbp recurrent deletion was initially identified in individuals with a range of neurodevelopmental features, including intellectual disability, microcephaly, craniofacial features, and speech delay. The deletion confers a >40-fold increase in risk for schizophrenia as well as a >20-fold increase in risk for autism. More recently, two studies have reported decreases in body and brain sizes as well ,as a range of behavioral and social defects in mouse models of the entire deletion, mimicking the human developmental phenotypes associated with the deletion. (From Singh et al. 2020 and references therein, FBrf0245012.)
Willatt et al. 2005 (pubmed:15918153.) identified a 3q29 deletion phenotype that included mild to moderate mental retardation, with only slightly dysmorphic facial features that were similar in most patients: long and narrow face, short philtrum, and high nasal bridge. Autism, gait ataxia, chest wall deformity, and long and tapering fingers were noted in at least 2 of the 6 patients. Additional features, including microcephaly, cleft lip and palate, horseshoe kidney and hypospadias, ligamentous laxity, recurrent middle ear infections, and abnormal pigmentation, were observed, each in a single patient. [from MIM:609425, 2020.04.27]
The 3q29 microdeletion is about 1.5 Mb in length. It encompasses 22 genes, including PAK2 and DLG1, which are autosomal homologues of two known X-linked mental retardation genes, PAK3 and DLG3. The presence of two nearly identical low-copy repeat sequences in BAC clones on each side of the deletion breakpoint suggests that nonallelic homologous recombination is the likely mechanism of disease causation in this syndrome. (From Willatt et al. 2005, pubmed:15918153.)
Kaminsky et al 2011 (pubmed:21844811) performed a large CNV case-control study comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. The 3q29 deletion was identified in 9 cases and no controls for a p value of 0.0147 and a frequency of 1 in 1,750 cases. [from MIM:609425, 2020.04.27]
NCBP2 encodes a subunit of the nuclear cap-binding complex (CBC), which binds to the 5' end of mRNA and microRNA in the nucleus. Given the role of the CBC in post-transcriptional regulatory mechanisms such as nonsense-mediated decay, alternative splicing and mRNA transport, it is possible that disruption of this complex could result in changes to a broad set of genes and biological processes. In fact, our analysis of differentially-expressed genes in Cbp20 knockdown flies showed disruption of synaptic transmission, cellular respiration, and several metabolic pathways. (From Singh et al. 2020 and references therein, FBrf0245012.)
One to one: 1 human gene to 1 Drosophila gene.
Single, high-ranking ortholog of human NCBP2.
