Background
Methods
Human 22q11.2 region characterization
Gene conservation and function in model species
Results
Characterization of the human 22q11.2 deletion region
22q11.2 region gene conservation in model organisms
Human protein- coding genea
|
C. elegans
|
D. melanogaster
|
D. rerio
|
M. musculus
| ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Homologue (n = 17) | % | Modelb
| Homologue (n = 22) | % | Modelb
| Homologue (n = 37) | % | Modelb
| Homologue (n = 40) | % | Modelb
| |
DGCR6 | gdl | 37 | KO | dgcr6 | 65 | − | Dgcr6 | 92 | − | |||
PRODH
| CELE_B0513.5 | 46 | KD | slgA | 46 | KO, KD | LOC100537991 | 69 | − | Prodh | 82 | KO |
prodha | 63 | KO | ||||||||||
DGCR2 | dgcr2 | 64 | KO | Dgcr2 | 93 | KO | ||||||
DGCR14
| ess-2 | 30 | KO, KD | Es2 | 35 | KD | dgcr14 | 67 | − | Dgcr14 | 93 | KO |
TSSK2 | Tssk2 | 92 | KO | |||||||||
GSC2 | LOC101885810 | 52 | − | Gsc2 | 76 | KO | ||||||
SLC25A1
| K11H3.3 | 65 | KD | sea | 67 | KO, KD | slc25a1a | 78 | KD | Slc25a1 | 94 | KO |
slc25a1b | 84 | − | ||||||||||
HIRA
| K10D2.1 | 33 | KO, KD | Hira | 60 | KO, KD | hira | 78 | KD | Hira | 96 | KO |
MRPL40
| mrpl-40 | 30 | KD | mRpL40 | 40 | KO, KD | mrpl40 | 50 | − | Mrpl40 | 75 | KO |
C22orf39 | CG15908 | 32 | KO, KD | si:ch211..51 h9.6 | 49 | − | 2510002D24Rik | 72 | KO | |||
UFD1L
| ufd-1 | 41 | KD | Ufd1-like | 56 | KO, KD | ufd1l | 87 | KO | Ufd1l | 99 | KO |
CDC45
| evl-18 | 29 | KO, KD | CDC45L | 39 | KO, KD | cdc45 | 74 | KO | Cdc45 | 92 | KO |
CLDN5 | cldn5a | 57 | KO, KD | Cldn5 | 92 | KO | ||||||
cldn5b | 54 | − | ||||||||||
SEPT5 | sept5a | 84 | − | Sept5 | 99 | KO | ||||||
sept5b | 85 | − | ||||||||||
GP1BB | gp1bb | 46 | − | Gp1bb | 90 | KO | ||||||
TBX1
| mls-1 | 53 | KO, KD | org-1 | 58 | KO, KD | tbx1 | 72 | KO, KD | Tbx1 | 91 | KO |
GNB1L | CG13192 | 30 | KO, KD | gnb1l | 53 | − | Gnb1l | 82 | KO | |||
TXNRD2
| trxr-2 | 49 | KO, KD | Trxr-2 | 55 | KD | si:ch1073-179p4.3 | 71 | − | Txnrd2 | 86 | KO |
COMT | comta | 53 | − | Comt | 80 | KO | ||||||
comtb | 54 | − | ||||||||||
ARVCF | arvcfb | 64 | KO | Arvcf | 92 | KO | ||||||
TANGO2
| R186.1 | 29 | KD | Tango2 | 30 | KO, KD | tango2 | 64 | − | Tango2 | 88 | − |
DGCR8
| pash-1 | 25 | KO, KD | pasha | 37 | KO, KD | dgcr8 | 72 | KO | Dgcr8 | 95 | KO |
TRMT2A
| H24K24.4 | 27 | KD | CG3808 | 37 | KO, KD | trmt2a | 56 | KO | Trmt2a | 83 | KO |
RANBP1 | ranbp1 | 73 | KO | Ranbp1 | 93 | KO | ||||||
ZDHHC8 | zdhhc8b | 57 | KO | Zdhhc8 | 92 | KO | ||||||
LOC388849 | Gm7873 | 72 | − | |||||||||
RTN4R | rtn4r | 45 | KD | Rtn4r | 89 | KO | ||||||
SCARF2 | scarf2 | 52 | − | Scarf2 | 82 | KO | ||||||
KLHL22 | CG1812 | 30 | KO, KD | klhl22 | 60 | − | Klhl22 | 95 | − | |||
MED15
| mdt-15c
| 26 | KO, KD | MED15 | 32 | KO, KD | med15b
| 60 | KD | Med15 | 90 | − |
PI4KA
| CELE_Y75B8A.24 | 38 | KO, KD | PI4KIIIalpha | 45 | KO, KD | pi4kaa | 84 | KD | Pi4ka | 98 | KO |
SERPIND1 | serpind1 | 54 | − | Serpind1 | 82 | KO | ||||||
SNAP29
| snap-29 | 28 | KO, KD | Snap29 | 32 | KO, KD | snap29 | 51 | KD | Snap29 | 83 | KO |
CRKL | crkl | 82 | KD | Crkl | 97 | KO | ||||||
AIFM3
| F20D6.11 | 34 | KD | CG4199 | 38 | KO, KD | LOC100150876 | 66 | − | Aifm3 | 96 | − |
LZTR1 | CG3711 | 51 | KO, KD | lztr1 | 81 | − | Lztr1 | 95 | KO | |||
THAP7 | thap7 | 42 | KO | Thap7 | 93 | − | ||||||
P2RX6 | P2rx6 | 86 | KO | |||||||||
SLC7A4
| C50D2.2 | 43 | KD | CG13248 | 43 | KO, KD | slc7a4 | 64 | KO | Slc7a4 | 84 | − |
LRRC74B | si:ch211-173a9.8 | 41 | − | Lrrc74b | 68 | − |
Availability of knockout and knockdown models of 22q11.2 region homologues in model organisms
Lethality (Knockout models)a
| Knockout and knockdown phenotypes | |||||||
---|---|---|---|---|---|---|---|---|
Geneb
|
C. elegans
|
D. melanogaster
|
D. rerio
|
M. musculus
|
C. elegans
|
D. melanogaster
|
D. rerio
|
M. musculus
|
PRODH
| − | No (KO) | Not assessed (KO, prodha); − (LOC100537991) | No (KO) | Reduced accumulation rate of newly synthesized proteins, extended life span, increased thermo-tolerance (KD) | Hyperprolinemia, locomotor defects including indecisive movement patterns and hypoactivity (KO); Not assessed (KD) | Not assessed (KO, prodha); − (LOC100537991) | Reduced male body weight and prepulse inhibition (genetic background dependent), impaired fear conditioning, regionally altered levels of proline (hyperprolinemia), glutamate, gamma-aminobutyric acid, and aspartate in the brain (KO) |
DGCR14
| Embryonic lethality (KO); No (het-KO) | − | − | Not assessed (KO) | Higher frequency of male progeny, meiotic prophase defect (KD); Deregulated mRNA processing (KO); Normal phenotype (het-KO) | Not assessed (KD) | − | Not assessed (KO) |
SLC25A1
| − | Embryonic lethality (KO) | − (slc25a1a, slc25a1b) | Majority die before 12 weeks post-natal (KO) | Normal when assessed for lethality, sterility, anatomical morphology, development, and growth (KD) | Chromosomal breaks and global loss of DNA acetylation (KO) | Mitochondrial depletion, flattened head, small heart, brain, inner ear, intestine, and mandibular arch skeleton with defect severity proportional to gene suppression, neuromuscular junction defects regardless of phenotype severity (KD, slc25a1a); Not assessed (slc25a1b) | Mice examined at two weeks are small and sickly, and show generalized hypoplasia, most severely in liver and bone marrow (KO) |
HIRA
| Embryonic lethality (KO) | Embryonic lethality (KO) | − | Embryonic lethality (KO); No (het-KO) | Not assessed (KO, KD) | Enhanced transcriptional suppression through variegation with transposable element probe, offspring of null mothers crossed with wild-type males do not develop while paternal null offspring show only partial lethality implying maternal effect (KO); Not assessed (KD) | Not assessed (KD) | Disrupted gastrulation, abnormal cardiac development (e.g., heart chambers), abnormal embryonic tissue morphology, abnormal placenta, craniofacial abnormalities, failure of brain to fuse and abnormal neural plate morphology (KO); Decreased leukocyte cell count (het-KO) |
MRPL40
| − | Embryonic lethality (KO) | − | Not assessed (KO) | Slow growth, larval arrest, reduced brood size, sterile progeny (KD) | Gross neuroanatomical defects due to under-proliferation of neuroblast cells during neurogenesis (KO); Not assessed (KD) | − | Not assessed (KO) |
UFD1L
| − | No (KO) | Embryonic lethality (KO) | Not assessed (KO); No (het-KO) | Slow growth, gonad development deficits, enlarged gut granules, locomotor defect with deviations in self-propelled movement, patchy coloration, reduced life span (KD) | Stress response reduced as determined by virus infection assay (KO); Not assessed (KD) | Decreased eye size, abnormal head shape due to hypoplasia and misarranged features, necrotic central nervous system, increased thickness of mandibular arch skeleton, hypoplastic gut and liver (KO) | Not assessed (KO); Viable with no obvious heart defects (het-KO) |
CDC45
| Embryonic lethality (KO) | Lethal in the larval stage (KO) | Not assessed (KO) | Embryonic lethality (KO); No (het-KO) | Everted vulva, reduced brood size, sterility associated with no sperm development (KO); Sister chromatid segregation defective in early embryo, reduced brood size (KD) | Gross neuroanatomy defective due to reduced cellular proliferation causing small neuroblast size in the developing brain (KO); Not assessed (KD) | Not assessed (KO) | Impaired proliferation of inner cell mass after embryo implantation (KO); Normal when assessed for size, behaviour, and sterility (het-KO) |
Lethality (Knockout models) | Knockout and knockdown phenotypes | |||||||
Genea
|
C. elegans
|
D. melanogaster
|
D. rerio
|
M. musculus
|
C. elegans
|
D. melanogaster
|
D. rerio
|
M. musculus
|
TBX1
| No (KO) | Partial embryonic lethality (KO) | Embryonic lethality (KO) | Embryonic lethality (KO); No (het-KO) | Abnormal uterine cell fate due to transcriptional abnormalities (KO); Normal when assessed for sterility, anatomical morphology, and development (KD) | Severely malformed or absent adult muscle precursors and supportive alary heart muscles (KO); Not assessed (KD) | Severely abnormal cardiac development (e.g., absent aortic arch), severe pouch defects and abnormal facial skeletal development, abnormal inner ear morphology (KO); Severely abnormal cardiac development (e.g., absent aortic arches) and thymus (KD) | Severely abnormal cardiac development (e.g., aortic arch), abnormal inner, middle, and outer ear morphology, abnormal lymphangiogenesis, abnormal cranial base morphology (KO); Mild cardiac abnormalities (e.g., fourth aortic arch arteries) and decreased prepulse inhibition (het-KO) |
TXNRD2
| – | – | – | Embryonic lethality (KO) | Hypersensitive to protein aggregation induced paralysis (KD) but otherwise normal when assessed for morphology and development (KO, KD) | Not assessed (KD) | – | Severe anemia and growth retardation due to perturbed cardiac development and augmented apoptosis of hematopoietic cells (KO) |
TANGO2
| – | Not assessed (KO) | Not assessed (KO) | – | Not assessed (KD) | Not assessed (KO, KD) | – | – |
DGCR8
| No (KO) | Lethal before end of pupal stage (KO) | Not assessed (KO) | Embryonic lethality (KO); No (het-KO) | Accumulation of miRNA target protein, decreased lifespan (KO); Reduced miRNA processing, accumulation of target mRNA, vulva defects, enhanced locomotor deficits of unc mutant (uncoordinated) phenotypes (KD) | Abnormal olfactory projection and mushroom body neuron morphology and neurophysiology (KO); Not assessed (KD) | Not assessed (KO) | Reduced dendritic spine number, reduced dendritic complexity, decreased prepulse inhibition and abnormal spatial working memory (het-KO) |
TRMT2A
| No (KD) | No (KO) | Not assessed (KO) | Not assessed (KO) | Not maternally sterile but otherwise not assessed (KD) | Not sterile (KO); Not assessed (KD) | Not assessed (KO) | Not assessed (KO) |
MED15
| Reduced lifespan (KO) | Pupal lethality (KO) | – | – | Sterile, small, increased apoptosis, decreased protein expression, changes in mRNA expression, intestinal morphology, reduced lifespan, uncoordinated locomotion (KD); Hypersensitivity to toxin exposure (KO, KD) | Abnormal wing development (KO, het-KO); Abnormal wing development and shortened legs, formation of ectopic sensory organs and induced cellular apoptosis (KD) | Disruption of dorsal/ventral patterning and mesoderm development (KD) | – |
PI4KA
| Embryonic lethality (KO) | Lethal before end of larval stage (KO) | – | Embryonic lethality (KO) | Slow growth and sterility (KD) | Abnormal eye morphology, neuromuscular junction overgrowth (KO); Not assessed (KD) | Decreased eye, head, and mesenchymal cell proliferation, increased apoptosis and necrosis of brain cells (KD) | Premature death due to degeneration of mucosal cells in the stomach and intestines (KO) |
SNAP29
| Embryonic lethality (KO) | Pupal lethality (KO) | – | Pre-weaning lethality (KO) | Defects in secretion from intestinal epithelial cells (KO); Sterility associated with endomitotic oocytes and pre-mitotic maturation of the oocyte, abnormal localization of phospholipid membrane components (KD) | Not assessed (KO); Synaptic defects characterized by abnormal basal neurotransmission. Lethality observed in the pupal stage (KD) | Disrupted pigmentation, epidermal irregular spatial pattern, disorganized keratinocyte cell surface (KD) | Not assessed (KO) |
AIFM3
| – | No (KO) | – | – | Normal when assessed for lifespan and sterility, anatomical morphology, development, and growth (KD) | Not sterile (KO); Not assessed (KD) | – | – |
SLC7A4
| – | Not assessed (KO) | Not assessed (KO) | – | Normal when assessed for sterility and anatomical morphology (KD) | Not assessed (KO, KD) | Not assessed (KO) | – |