title: Protein tyrosine phosphatase PTPN14 is a regulator of lymphatic function and choanal development in humans.
abstract: The lymphatic vasculature is essential for the recirculation of extracellular fluid, fat absorption, and immune function and as a route of tumor metastasis. The dissection of molecular mechanisms underlying lymphangiogenesis has been accelerated by the identification of tissue-specific lymphatic endothelial markers and the study of congenital lymphedema syndromes. We report the results of genetic analyses of a kindred inheriting a unique autosomal-recessive lymphedema-choanal atresia syndrome. These studies establish linkage of the trait to chromosome 1q32-q41 and identify a loss-of-function mutation in PTPN14, which encodes a nonreceptor tyrosine phosphatase. The causal role of PTPN14 deficiency was confirmed by the generation of a murine Ptpn14 gene trap model that manifested lymphatic hyperplasia with lymphedema. Biochemical studies revealed a potential interaction between PTPN14 and the vascular endothelial growth factor receptor 3 (VEGFR3), a receptor tyrosine kinase essential for lymphangiogenesis. These results suggest a unique and conserved role for PTPN14 in the regulation of lymphatic development in mammals and a nonconserved role in choanal development in humans.
authors.affiliation: Department of Genetics & Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Audrey C
authors.initials: AC
authors.lastname: Au
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Hernandez
authors.forename: Ernest
authors.initials: E
authors.lastname: Lieber
authors.forename: Ali M
authors.initials: AM
authors.lastname: Nadroo
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Shen
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Kelley
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
authors.forename: George A
authors.initials: GA
authors.lastname: Diaz
mesh_terms: D000818:Animals; D001483:Base Sequence; D002754:Choanal Atresia / Q000201:enzymology / Q000235:genetics; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D004789:Enzyme Activation; D005260:Female; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D042601:Lymphatic Vessels / Q000201:enzymology* / Q000473:pathology / Q000502:physiology* / Q000503:physiopathology; D008209:Lymphedema / Q000201:enzymology / Q000235:genetics; D008297:Male; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009305:Nasopharynx / Q000196:embryology* / Q000201:enzymology*; D010375:Pedigree; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D040321:Vascular Endothelial Growth Factor Receptor-3; C093261:PTPN14 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor
references.citation: EMBO J. 2001 Mar 15;20(6):1223-31
references.pmid: 11250889
references.citation: Mol Cell Biol. 2008 Mar;28(5):1792-801
references.pmid: 18160720
references.citation: Am J Hum Genet. 2000 Dec;67(6):1382-8
references.pmid: 11078474
references.citation: Biochem Biophys Res Commun. 1995 Apr 26;209(3):959-65
references.pmid: 7733990
references.citation: Nat Genet. 1995 Jun;10(2):235-7
references.pmid: 7663521
references.citation: Science. 1997 May 30;276(5317):1423-5
references.pmid: 9162011
references.citation: Hum Mol Genet. 2003 May 15;12(10):1179-85
references.pmid: 12719382
references.citation: Lymphat Res Biol. 2008;6(3-4):109-22
references.pmid: 19093783
references.citation: J Biol Chem. 2008 Apr 18;283(16):10919-29
references.pmid: 18223254
references.citation: Nucleic Acids Res. 2003 Jan 1;31(1):278-81
references.pmid: 12520002
references.citation: Am J Hum Genet. 2000 Aug;67(2):295-301
references.pmid: 10856194
references.citation: Hum Mol Genet. 2006 Oct 15;15 Spec No 2:R220-6
references.pmid: 16987887
references.citation: Dev Dyn. 1998 Jun;212(2):258-66
references.pmid: 9626500
references.citation: Methods Mol Biol. 2000;132:365-86
references.pmid: 10547847
references.citation: Mol Biol Cell. 2003 Jun;14(6):2520-9
references.pmid: 12808048
references.citation: Dev Dyn. 1998 Jun;212(2):171-80
references.pmid: 9626493
references.citation: Annu Rev Pathol. 2008;3:367-97
references.pmid: 18039141
references.citation: Ann Otol Rhinol Laryngol. 1991 Aug;100(8):661-4
references.pmid: 1872518
references.citation: Nat Genet. 2003 Jun;34(2):148-50
references.pmid: 12717436
references.citation: Nat Genet. 2000 Jun;25(2):153-9
references.pmid: 10835628
references.citation: Nat Genet. 2005 Dec;37(12):1317-9
references.pmid: 16273109
references.citation: Nat Rev Mol Cell Biol. 2006 Nov;7(11):833-46
references.pmid: 17057753
references.citation: EMBO J. 2002 Apr 2;21(7):1505-13
references.pmid: 11927535
references.citation: J Med Genet. 2005 Feb;42(2):98-102
references.pmid: 15689446
references.citation: Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7477-81
references.pmid: 7519780
references.citation: Nat Genet. 2001 Mar;27(3):277-85
references.pmid: 11242109
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12677-82
references.pmid: 11592985
references.citation: J Cell Sci. 2000 Sep;113 ( Pt 17):3117-23
references.pmid: 10934049
references.citation: Hum Mol Genet. 2009 Jan 1;18(1):193-201
references.pmid: 18849586
references.citation: Eur J Hum Genet. 2008 Nov;16(11):1289-300
references.pmid: 18781191
references.citation: Nat Med. 2004 Sep;10(9):974-81
references.pmid: 15322537
references.citation: Ann N Y Acad Sci. 2008;1131:203-5
references.pmid: 18519972
references.citation: Nat Genet. 2009 Dec;41(12):1272-4
references.pmid: 19935664
references.citation: Cell. 2010 Feb 19;140(4):460-76
references.pmid: 20178740
references.citation: Hum Mol Genet. 1998 Dec;7(13):2073-8
references.pmid: 9817924
references.citation: Nat Genet. 2001 Dec;29(4):465-8
references.pmid: 11704759
references.citation: Science. 2004 May 21;304(5674):1164-6
references.pmid: 15155950
references.citation: Development. 2010 Mar;137(6):1003-13
references.pmid: 20179099
references.citation: Mol Cell Biol. 2004 Jun;24(11):4613-26
references.pmid: 15143158
references.citation: J Biol Chem. 1999 Jul 16;274(29):20717-24
references.pmid: 10400706
references.citation: Development. 1996 Dec;122(12):3829-37
references.pmid: 9012504
references.citation: Am J Hum Genet. 1996 Jun;58(6):1347-63
references.pmid: 8651312
references.citation: J Biol Chem. 1999 Apr 30;274(18):12905-9
references.pmid: 10212280
references.citation: Am J Med Genet. 1982 Dec;13(4):413-6
references.pmid: 7158640
references.citation: Biochem Biophys Res Commun. 1994 Aug 30;203(1):479-84
references.pmid: 8074693
references.citation: Am J Hum Genet. 2003 Jun;72(6):1470-8
references.pmid: 12740761
references.citation: Lymphology. 1983 Mar;16(1):27-30
references.pmid: 6843174