Evidence for SH2 domain-containing 5'-inositol phosphatase-2 (SHIP2) contributing to a lymphatic dysfunction.
The lymphatic vasculature plays a critical role in a number of disease conditions of increasing prevalence, such as autoimmune disorders, obesity, blood vascular diseases, and cancer metastases. Yet, unlike the blood vasculature, the tools available to interrogate the molecular basis of lymphatic dysfunction/disease have been lacking. More recently, investigators have reported that dysregulation of the PI3K pathway is involved in syndromic human diseases that involve abnormal lymphatic vasculatures, but there have been few compelling results that show the direct association of this molecular pathway with lymphatic dysfunction in humans. Using near-infrared fluorescence lymphatic imaging (NIRFLI) to phenotype and next generation sequencing (NGS) for unbiased genetic discovery in a family with non-syndromic lymphatic disease, we discovered a rare, novel mutation in INPPL1 that encodes the protein SHIP2, which is a negative regulator of the PI3K pathway, to be associated with lymphatic dysfunction in the family. In vitro interrogation shows that SHIP2 is directly associated with impairment of normal lymphatic endothelial cell (LEC) behavior and that SHIP2 associates with receptors that are associated in lymphedema, implicating its direct involvement in the lymphatic vasculature.
Center for Molecular Imaging, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas, United States of America; The University of Texas Graduate School of Biomedical Sciences at Houston, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Germaine D
GD
Agollah
Division of Genomics and Bioinformatics, Center for Molecular Imaging, The Brown Foundation Institute of Molecular Medicine, Houston, Texas, United States of America.
Manuel L
ML
Gonzalez-Garay
Center for Molecular Imaging, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas, United States of America.
John C
JC
Rasmussen
Center for Molecular Imaging, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas, United States of America.
I-Chih
IC
Tan
Center for Molecular Imaging, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas, United States of America.
Melissa B
MB
Aldrich
Center for Molecular Imaging, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas, United States of America.
Chinmay
C
Darne
Memorial Hermann Hospital Center for Lymphedema Management, Houston, Texas, United States of America.
Caroline E
CE
Fife
Memorial Hermann Hospital Center for Lymphedema Management, Houston, Texas, United States of America.
Renie
R
Guilliod
Memorial Hermann Hospital Center for Lymphedema Management, Houston, Texas, United States of America.
Erik A
EA
Maus
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
Philip D
PD
King
Center for Molecular Imaging, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas, United States of America.
Eva M
EM
Sevick-Muraca
D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008209:Lymphedema / Q000235:genetics* / Q000473:pathology*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics*; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D061848:Optical Imaging / Q000379:methods; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry* / Q000235:genetics*; D017354:Point Mutation; D017422:Sequence Analysis, DNA; D018909:src Homology Domains; D000099151:MAP Kinase Kinase Kinase 7
D017228:Hepatocyte Growth Factor; D020930:MAP Kinase Kinase Kinases; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases; D000099151:MAP Kinase Kinase Kinase 7; C066855:HGF protein, human; C098706:INPPL1 protein, human