title: Lymphatic abnormalities are associated with RASA1 gene mutations in mouse and man.
abstract: Mutations in gene RASA1 have been historically associated with capillary malformation-arteriovenous malformation, but sporadic reports of lymphatic involvement have yet to be investigated in detail. To investigate the impact of RASA1 mutations in the lymphatic system, we performed investigational near-infrared fluorescence lymphatic imaging and confirmatory radiographic lymphangiography in a Parkes-Weber syndrome (PKWS) patient with suspected RASA1 mutations and correlated the lymphatic abnormalities against that imaged in an inducible Rasa1 knockout mouse. Whole-exome sequencing (WES) analysis and validation by Sanger sequencing of DNA from the patient and unaffected biological parents enabled us to identify an early-frameshift deletion in RASA1 that was shared with the father, who possessed a capillary stain but otherwise no overt disease phenotype. Abnormal lymphatic vasculature was imaged in both affected and unaffected legs of the PKWS subject that transported injected indocyanine green dye to the inguinal lymph node and drained atypically into the abdomen and into dermal lymphocele-like vesicles on the groin. Dermal lymphatic hyperplasia and dilated vessels were observed in Rasa1-deficient mice, with subsequent development of chylous ascites. WES analyses did not identify potential gene modifiers that could explain the variability of penetrance between father and son. Nonetheless, we conclude that the RASA1 mutation is responsible for the aberrant lymphatic architecture and functional abnormalities, as visualized in the PKWS subject and in the animal model. Our unique method to combine investigatory near-infrared fluorescence lymphatic imaging and WES for accurate phenoptyping and unbiased genotyping allows the study of molecular mechanisms of lymphatic involvement of hemovascular disorders.
authors: Department of Diagnostic and Interventional Imaging, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors: Patricia E
authors: PE
authors: Burrows
authors: Manuel L
authors: ML
authors: Gonzalez-Garay
authors: John C
authors: JC
authors: Rasmussen
authors: Melissa B
authors: MB
authors: Aldrich
authors: Renie
authors: R
authors: Guilliod
authors: Erik A
authors: EA
authors: Maus
authors: Caroline E
authors: CE
authors: Fife
authors: Sunkuk
authors: S
authors: Kwon
authors: Philip E
authors: PE
authors: Lapinski
authors: Philip D
authors: PD
authors: King
authors: Eva M
authors: EM
authors: Sevick-Muraca
mesh_terms: D000818:Animals; D004396:Coloring Agents / Q000008:administration & dosage; D004195:Disease Models, Animal; D059472:Exome / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D006965:Hyperplasia; D007208:Indocyanine Green / Q000008:administration & dosage; D044148:Lymphatic Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013341:Sturge-Weber Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D020729:p120 GTPase Activating Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D004396:Coloring Agents; C557248:RASA1 protein, human; C581321:RASA1 protein, mouse; D020729:p120 GTPase Activating Protein; D007208:Indocyanine Green
keywords: CM-AVM; indocyanine green imaging; lymphatics; near-infrared fluorescence imaging
references: Sci Signal. 2013 Feb 26;6(264):re1
references: 23443682
references: Curr Opin Genet Dev. 2005 Jun;15(3):265-9
references: 15917201
references: Am J Hum Genet. 2003 Dec;73(6):1240-9
references: 14639529
references: Hum Mutat. 2008 Jul;29(7):959-65
references: 18446851
references: Nat Methods. 2010 Apr;7(4):248-9
references: 20354512
references: Vasc Cell. 2012 Nov 20;4(1):19
references: 23164092
references: Radiology. 2008 Mar;246(3):734-41
references: 18223125
references: Nat Protoc. 2009;4(7):1073-81
references: 19561590
references: Nat Med. 2011 Nov 07;17(11):1371-80
references: 22064427
references: Neurogastroenterol Motil. 2011 Sep;23(9):881-e344
references: 21624010
references: Annu Rev Med. 2012;63:217-31
references: 22034868
references: Curr Opin Biotechnol. 2009 Feb;20(1):74-82
references: 19233639
references: Genesis. 2007 Dec;45(12):762-7
references: 18064675
references: Br J Dermatol. 2008 May;158(5):1035-40
references: 18363760
references: Genome Res. 2010 Sep;20(9):1297-303
references: 20644199
references: Lymphat Res Biol. 2007;5(4):219-31
references: 18370912
references: Nucleic Acids Res. 2010 Sep;38(16):e164
references: 20601685
references: Arch Dermatol Res. 2008 Aug;300(7):385-8
references: 18327598
references: Nat Methods. 2010 Aug;7(8):575-6
references: 20676075
references: Am J Physiol Heart Circ Physiol. 2007 Jun;292(6):H3109-18
references: 17307997
references: J Immunol. 2011 Jul 1;187(1):151-63
references: 21646295
references: Development. 2010 Mar;137(6):1003-13
references: 20179099
references: Fly (Austin). 2012 Apr-Jun;6(2):80-92
references: 22728672
references: Transl Oncol. 2010 Dec 01;3(6):362-72
references: 21151475
references: Bioinformatics. 2009 Aug 15;25(16):2078-9
references: 19505943
references: Eur J Med Genet. 2012 Mar;55(3):191-5
references: 22342634
references: J Clin Invest. 2012 Feb;122(2):733-47
references: 22232212