DIP2 is a unique regulator of diacylglycerol lipid homeostasis in eukaryotes

Mondal, Sudipta; Kinatukara, Priyadarshan; Singh, Simran Jeet; Shambhavi, Sakshi; Patil, Gajanan S.; Dubey, Noopur; Singh, Shailesh Kumar; Pal, Biswajit; Shekar, P Chandra; Kamat, Siddhesh S.; Sankaranarayanan, Rajan

doi:10.7554/elife.77665

Cited by 6 publications

(5 citation statements)

References 119 publications

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“…DIP2C encodes a highly expressed protein in the brain and a member of the highly conserved DIP2 (Disco-interacting protein 2) family implicated in neuronal morphology and development and lipids’ metabolism (Ma et al 2019 ; Mondal et al 2022 ; Mukhopadhyay et al 2002 ; Nitta et al 2017 ; Noblett et al 2019 ; Oo et al 2020 ). A previous study reported 19 patients with submicroscopic deletion of chromosome 10p15.3 that included DIP2C and/or ZMYND11 in all the cases.…”

Section: Discussionmentioning

confidence: 99%

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

Yahia,

Li,

Lejerkrans

et al. 2024

Hum. Genet.

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Developmental language disorder (DLD) overlaps clinically, genetically, and pathologically with other neurodevelopmental disorders (NDD), corroborating the concept of the NDD continuum. There is a lack of studies to understand the whole genetic spectrum in individuals with DLD. Previously, we recruited 61 probands with severe DLD from 59 families and examined 59 of them and their families using microarray genotyping with a 6.8% diagnostic yield. Herein, we investigated 53 of those probands using whole exome sequencing (WES). Additionally, we used polygenic risk scores (PRS) to understand the within family enrichment of neurodevelopmental difficulties and examine the associations between the results of language-related tests in the probands and language-related PRS. We identified clinically significant variants in four probands, resulting in a 7.5% (4/53) molecular diagnostic yield. Those variants were in PAK2, MED13, PLCB4, and TNRC6B. We also prioritized additional variants for future studies for their role in DLD, including high-impact variants in PARD3 and DIP2C. PRS did not explain the aggregation of neurodevelopmental difficulties in these families. We did not detect significant associations between the language-related tests and language-related PRS. Our results support using WES as the first-tier genetic test for DLD as it can identify monogenic DLD forms. Large-scale sequencing studies for DLD are needed to identify new genes and investigate the polygenic contribution to the condition.

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Section: Discussionmentioning

confidence: 99%

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

Yahia,

Li,

Lejerkrans

et al. 2024

Hum. Genet.

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show abstract

“…The neuronal defects observed in dip-2(0) sax-2(0) double mutants are generally a combination of more severe or more penetrant versions of the single mutant phenotypes, suggesting that DIP-2 and SAX-2 play partly redundant roles in maintenance of neuronal morphology. The orthologs of DIP-2 function in lipid metabolism 25 , whereas SAX-2/Fry family members are thought to have multiple functions including as scaffolds for SAX-1/NDR kinases 20 . We find that overexpression of DIP-2 did not compensate for loss of SAX-2.…”

Section: Discussionmentioning

confidence: 99%

“…Drosophila 23 and in vertebrates 24 . DIP2 family members are thought to regulate the activation of fatty acids and/or accumulation of diacylglycerol via their adenylate-forming domains (AFDs), also known as fatty acyl-AMP ligase-like (FAAL-like, FLD) domains 25 .…”

Section: Dip2 Proteins Function In Neuronal Morphology Maintenance An...mentioning

confidence: 99%

“…DIP2 proteins function in neuronal morphology maintenance and axon branching in Drosophila 23 and in vertebrates 24 . DIP2 family members are thought to regulate the activation of fatty acids and/or accumulation of diacylglycerol via their adenylate-forming domains (AFDs), also known as fatty acyl-AMP ligase-like (FAAL-like, FLD) domains 25 . Mammalian DIP2B has been implicated in neuronal tubulin acetylation in axon outgrowth 26 .…”

Section: Introductionmentioning

confidence: 99%

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Dopey-dependent regulation of extracellular vesicles maintains neuronal morphology

Park,

Noblett,

Pitts

et al. 2024

Preprint

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Mature neurons maintain their distinctive morphology for extended periods in adult life. Compared to developmental neurite outgrowth, axon guidance, and target selection, relatively little is known of mechanisms that maintain mature neuron morphology. Loss of function in C. elegans DIP-2, a member of the conserved lipid metabolic regulator Dip2 family, results in progressive overgrowth of neurites in adults. We find that dip-2 mutants display specific genetic interactions with sax-2, the C. elegans ortholog of Drosophila Furry and mammalian FRY. Combined loss of DIP-2 and SAX-2 results in severe disruption of neuronal morphology maintenance accompanied by increased release of neuronal extracellular vesicles (EVs). By screening for suppressors of dip-2 sax-2 double mutant defects we identified gain-of-function (gf) mutations in the conserved Dopey family protein PAD-1 and its associated phospholipid flippase TAT-5/ATP9A. In dip-2 sax-2 double mutants carrying either pad-1(gf) or tat-5(gf) mutation, EV release is reduced and neuronal morphology across multiple neuron types is restored to largely normal. PAD-1(gf) acts cell autonomously in neurons. The domain containing pad-1(gf) is essential for PAD-1 function, and PAD-1(gf) protein displays increased association with the plasma membrane and inhibits EV release. Our findings uncover a novel functional network of DIP-2, SAX-2, PAD-1, and TAT-5 that maintains morphology of neurons and other types of cells, shedding light on the mechanistic basis of neurological disorders involving human orthologs of these genes.

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“…Ma et al, 2019;Mondal et al, 2022;Mukhopadhyay et al, 2002;Nitta et al, 2017;Noblett et al, 2019;Oo et al, 2020). A previous study reported 19 patients with submicroscopic deletion of chromosome 10p15.3 that included DIP2C and/or ZMYND11 in all the cases.…”

mentioning

confidence: 94%

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

Yahia,

Li,

Lejerkrans

et al. 2023

Preprint

View full text Add to dashboard Cite

Background Developmental language disorder (DLD) overlaps clinically, genetically, and pathologically with other neurodevelopmental disorders (NDD), corroborating the concept of the NDD continuum. There is a lack of studies to understand the whole genetic spectrum in individuals with DLD. Methods Previously, we recruited 61 probands with severe DLD from 59 families and examined 59 of them and their families using microarray genotyping with a 6.8% diagnostic yield. Herein, we investigated 53 of those probands using whole exome sequencing (WES). Additionally, we used polygenic risk scores (PRS) to understand the within family enrichment of neurodevelopmental difficulties and examine the associations between the results of language-related tests in the probands and language-related PRS. Results We identified clinically significant variants in five probands, resulting in a 9.4% (5/53) molecular diagnostic yield. Those variants were in CHD3, PAK2, MED13, PLCB4, and TNRC6B. We also prioritized additional variants for future studies for their role in DLD, including high-impact variants in PARD3 and DIP2C. PRS did not explain the aggregation of neurodevelopmental difficulties in these families. However, we detected positive associations between neurodevelopmental difficulties and PRS for educational attainment and cognitive performance within the families (p = 0.006 and 0.02, respectively). We did not detect significant associations between PRS for language quantitative measures and their corresponding PRS. Conclusion Our results support using WES as the first-tier genetic test for DLD as it can identify monogenic DLD forms. Large-scale sequencing studies for DLD are needed to identify new genes and investigate the polygenic contribution to the conditions.

show abstract

DIP2 is a unique regulator of diacylglycerol lipid homeostasis in eukaryotes

Cited by 6 publications

References 119 publications

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

Dopey-dependent regulation of extracellular vesicles maintains neuronal morphology

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

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