Missense mutation in SLIT2 associated with congenital myopia, anisometropia, connective tissue abnormalities, and obesity

Liu, Katherine Y.; Sengillo, Jesse D.; Vélez, Gabriel; Jauregui, Ruben; Sakai, Lynn Y.; Maumenee, Irene H.; Bassuk, Alexander G.; Mahajan, Vinit B.; Tsang, Stephen H.

doi:10.1186/s13023-018-0885-4

Cited by 9 publications

(5 citation statements)

References 46 publications

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“…Genes such as KCNE2 [ 115 ], DLL1 [ 116 ], ACVR1C [ 117 ], RGS3 [ 118 ], MLXIPL (MLX interacting protein like) [ 119 ], PAG1 [ 120 ], SLC2A10 [ 121 ] and GRB14 [ 122 ] play important role in type 2 diabetes mellitus progression. A recent investigation has indicated that genes such as GPIHBP1 [ 123 ], FGFRL1 [ 124 ], DAPK2 [ 125 ], MAP 3K5 [ 126 ], ANKK1 [ 127 ], GK (glycerol kinase) [ 128 ], SPHK1 [ 129 ], GNG3 [ 130 ], FSTL3 [ 131 ], SLIT2 [ 132 ], CCDC80 [ 133 ], RND3 [ 134 ], PTGER4 [ 135 ], RUNX1 [ 136 ], ADAM12 [ 137 ], OLR1 [ 138 ], THBS1 [ 139 ], CD28 [ 140 ], TRPV4 [ 141 ], ATRN (attractin) [ 142 ], MRC1 [ 143 ], SEMA3C [ 144 ], HTR2B [ 145 ], NOX4 [ 146 ], TACR1 [ 147 ], BAMBI [ 148 ], PDGFD (platelet derived growth factor D) [ 149 ], APLN (apelin) [ 150 ], MFAP5 [ 151 ] and LUM (lumican) [ 152 ] are associated with a development of obesity. A previous investigation found that genes such asDDR1 [ 153 ], TAB1 [ 154 ], NEK8 [ 155 ], SERPINE2 [ 156 ], FCGR2B [ 157 ], ANGPT2 [ 158 ], FN1 [ 159 ], SOCS5 [ 158 ], SMOC2 [ 160 ], CD2 [ 161 ] and SCN9A [ 162 ] expression were associated with a kidney diseases, but these genes might be responsible for advancement of obesity associated type 2 diabetes mellitus.…”

Section: Discussionmentioning

confidence: 99%

Investigation of candidate genes and mechanisms underlying obesity associated type 2 diabetes mellitus using bioinformatics analysis and screening of small drug molecules

Prashanth

Vastrad²,

Tengli

et al. 2021

BMC Endocr Disord

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Background Obesity associated type 2 diabetes mellitus is a metabolic disorder ; however, the etiology of obesity associated type 2 diabetes mellitus remains largely unknown. There is an urgent need to further broaden the understanding of the molecular mechanism associated in obesity associated type 2 diabetes mellitus. Methods To screen the differentially expressed genes (DEGs) that might play essential roles in obesity associated type 2 diabetes mellitus, the publicly available expression profiling by high throughput sequencing data (GSE143319) was downloaded and screened for DEGs. Then, Gene Ontology (GO) and REACTOME pathway enrichment analysis were performed. The protein - protein interaction network, miRNA - target genes regulatory network and TF-target gene regulatory network were constructed and analyzed for identification of hub and target genes. The hub genes were validated by receiver operating characteristic (ROC) curve analysis and RT- PCR analysis. Finally, a molecular docking study was performed on over expressed proteins to predict the target small drug molecules. Results A total of 820 DEGs were identified between healthy obese and metabolically unhealthy obese, among 409 up regulated and 411 down regulated genes. The GO enrichment analysis results showed that these DEGs were significantly enriched in ion transmembrane transport, intrinsic component of plasma membrane, transferase activity, transferring phosphorus-containing groups, cell adhesion, integral component of plasma membrane and signaling receptor binding, whereas, the REACTOME pathway enrichment analysis results showed that these DEGs were significantly enriched in integration of energy metabolism and extracellular matrix organization. The hub genes CEBPD, TP73, ESR2, TAB1, MAP 3K5, FN1, UBD, RUNX1, PIK3R2 and TNF, which might play an essential role in obesity associated type 2 diabetes mellitus was further screened. Conclusions The present study could deepen the understanding of the molecular mechanism of obesity associated type 2 diabetes mellitus, which could be useful in developing therapeutic targets for obesity associated type 2 diabetes mellitus.

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Section: Discussionmentioning

confidence: 99%

Investigation of candidate genes and mechanisms underlying obesity associated type 2 diabetes mellitus using bioinformatics analysis and screening of small drug molecules

Prashanth

Vastrad²,

Tengli

et al. 2021

BMC Endocr Disord

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“…Despite being mostly known for its role in axon guidance and neuron cell migration in both vertebrates and invertebrates (Kidd et al , 1999; Jen et al , 2004), a role for Slit‐Robo signalling in morphogenesis is not novel. A patient with a translocation mutation affecting ROBO2 has been described to have clinodactyly and syndactyly in addition to kidney and urinary tract defects (Lu et al , 2007), while a dominant de novo missense mutation in SLIT2 was found in a patient with myopia and dermal connective tissue defects (Liu et al , 2018). Perturbation of Slit‐Robo signalling leads to cardiac malformation in human, mouse, zebrafish and Drosophila (MacMullin & Jacobs, 2006; Fish et al , 2011; Mommersteeg et al , 2015; Kruszka et al , 2017).…”

Section: Discussionmentioning

confidence: 99%

Slit‐Robo signalling establishes a Sphingosine‐1‐phosphate gradient to polarise fin mesenchyme

et al. 2022

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Immigration of mesenchymal cells into the growing fin and limb buds drives distal outgrowth, with subsequent tensile forces between these cells essential for fin and limb morphogenesis. Morphogens derived from the apical domain of the fin, orientate limb mesenchyme cell polarity, migration, division and adhesion. The zebrafish mutant stomp displays defects in fin morphogenesis including blister formation and associated loss of orientation and adhesion of immigrating fin mesenchyme cells. Positional cloning of stomp identifies a mutation in the gene encoding the axon guidance ligand, Slit3. We provide evidence that Slit ligands derived from immigrating mesenchyme act via Robo receptors at the apical ectodermal ridge (AER) to promote release of sphingosine‐1‐phosphate (S1P). S1P subsequently diffuses back to the mesenchyme to promote their polarisation, orientation, positioning and adhesion to the interstitial matrix of the fin fold. We thus demonstrate the coordination of the Slit‐Robo and S1P signalling pathways in fin fold morphogenesis. Our work introduces a mechanism regulating the orientation, positioning and adhesion of its constituent cells.

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“…Despite being mostly known for its role in axon guidance and neuron cell migration in both vertebrates and invertebrates (Jen et al, 2004; Kidd et al, 1999), a role for Slit-Robo signalling in morphogenesis is not novel. A patient with a translocation mutation affecting ROBO2 has been described to have clinodactyly and syndactyly in addition to kidney and urinary tract defects (Lu et al, 2007), while a dominant de novo missense mutation in SLIT2 was found in a patient with myopia and dermal connective tissue defects (Liu et al, 2018). Perturbation of Slit-Robo signalling leads to cardiac malformation in human, mouse, zebrafish and Drosophila (Fish et al, 2011; Kruszka et al, 2017; MacMullin and Jacobs, 2006; Mommersteeg et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Slit-Robo Signalling Establishes a Sphingosine-1-Phosphate Gradient to Polarise Fin Mesenchyme and Establish Fin Morphology

Mahabaleshwar

P.V.

Loo

et al. 2021

Preprint

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Immigration of mesenchymal cells into the growing fin and limb buds drives distal outgrowth, with subsequent tensile forces between these cells essential for fin and limb morphogenesis. Morphogens derived from the apical domain of the fin, orientate limb mesenchyme cell polarity, migration, division and adhesion. The zebrafish mutant stomp displays defects in fin morphogenesis including blister formation and associated loss of orientation and adhesion of immigrating fin mesenchyme cells. Positional cloning of stomp identified a mutation in the gene encoding the axon guidance ligand, Slit3. We provide evidence that Slit ligands derived from immigrating mesenchyme act via Robo receptors at the Apical Ectodermal Ridge (AER) to promote release of sphingosine-1-phosphate (S1P). S1P subsequently diffuses back to the mesenchyme to promote their polarisation, orientation, positioning and adhesion to the interstitial matrix of the fin fold. We thus demonstrate coordination of the Slit-Robo and S1P signalling pathways in fin fold morphogenesis. Our work introduces a mechanism regulating the orientation, positioning and adhesion of its constituent cells.

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Missense mutation in SLIT2 associated with congenital myopia, anisometropia, connective tissue abnormalities, and obesity

Cited by 9 publications

References 46 publications

Investigation of candidate genes and mechanisms underlying obesity associated type 2 diabetes mellitus using bioinformatics analysis and screening of small drug molecules

Investigation of candidate genes and mechanisms underlying obesity associated type 2 diabetes mellitus using bioinformatics analysis and screening of small drug molecules

Slit‐Robo signalling establishes a Sphingosine‐1‐phosphate gradient to polarise fin mesenchyme

Slit-Robo Signalling Establishes a Sphingosine-1-Phosphate Gradient to Polarise Fin Mesenchyme and Establish Fin Morphology

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