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PLoS Genet 2021 Apr 05;174:e1009112. doi: 10.1371/journal.pgen.1009112.
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Functional assessment of the "two-hit" model for neurodevelopmental defects in Drosophila and X. laevis.

Pizzo L , Lasser M , Yusuff T , Jensen M , Ingraham P , Huber E , Singh MD , Monahan C , Iyer J , Desai I , Karthikeyan S , Gould DJ , Yennawar S , Weiner AT , Pounraja VK , Krishnan A , Rolls MM , Lowery LA , Girirajan S .

We previously identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental outcomes, where severely affected probands carried an excess of rare pathogenic variants compared to mildly affected carrier parents. We hypothesized that the 16p12.1 deletion sensitizes the genome for disease, while "second-hits" in the genetic background modulate the phenotypic trajectory. To test this model, we examined how neurodevelopmental defects conferred by knockdown of individual 16p12.1 homologs are modulated by simultaneous knockdown of homologs of "second-hit" genes in Drosophila melanogaster and Xenopus laevis. We observed that knockdown of 16p12.1 homologs affect multiple phenotypic domains, leading to delayed developmental timing, seizure susceptibility, brain alterations, abnormal dendrite and axonal morphology, and cellular proliferation defects. Compared to genes within the 16p11.2 deletion, which has higher de novo occurrence, 16p12.1 homologs were less likely to interact with each other in Drosophila models or a human brain-specific interaction network, suggesting that interactions with "second-hit" genes may confer higher impact towards neurodevelopmental phenotypes. Assessment of 212 pairwise interactions in Drosophila between 16p12.1 homologs and 76 homologs of patient-specific "second-hit" genes (such as ARID1B and CACNA1A), genes within neurodevelopmental pathways (such as PTEN and UBE3A), and transcriptomic targets (such as DSCAM and TRRAP) identified genetic interactions in 63% of the tested pairs. In 11 out of 15 families, patient-specific "second-hits" enhanced or suppressed the phenotypic effects of one or many 16p12.1 homologs in 32/96 pairwise combinations tested. In fact, homologs of SETD5 synergistically interacted with homologs of MOSMO in both Drosophila and X. laevis, leading to modified cellular and brain phenotypes, as well as axon outgrowth defects that were not observed with knockdown of either individual homolog. Our results suggest that several 16p12.1 genes sensitize the genome towards neurodevelopmental defects, and complex interactions with "second-hit" genes determine the ultimate phenotypic manifestation.

PubMed ID: 33819264
PMC ID: PMC8049494
Article link: PLoS Genet
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: arid1b cacna1a cbl cdr2 dscam eef2k gjb2 lgals4.2 mosmo ncbp2 polr3e polr3e ppp4c pten setd5 trrap ube3a uqcrc2 vwa3a
GO keywords: forebrain development [+]
Morpholinos: cdr2 MO1 mosmo MO1 mosmo MO2 polr3e MO1 setd5 MO1 uqcrc2 MO1 uqcrc2 MO2

Disease Ontology terms: intellectual disability
Phenotypes: Xla Wt + cdr2 MO (Fig. 2 G H) [+]

Article Images: [+] show captions
References [+] :
Altschul, Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. 1997, Pubmed