Protein tyrosine phosphatase PTPN14 is a regulator of lymphatic function and choanal development in humans.
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.
Au
Audrey C
AC
Department of Genetics & Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
Hernandez
Paolo A
PA
Lieber
Ernest
E
Nadroo
Ali M
AM
Shen
Yu-Ming
YM
Kelley
Kevin A
KA
Gelb
Bruce D
BD
Diaz
George A
GA
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
D018076:DNA, Complementary; D040321:Vascular Endothelial Growth Factor Receptor-3; C093261:PTPN14 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor
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