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.

Male infertility due to germ cell apoptosis in mice lacking the thiamin carrier, Tht1. A new insight into the critical role of thiamin in spermatogenesis.

A mouse model of thiamin-responsive megaloblastic anemia (diabetes mellitus, deafness, megaloblastic anemia) lacking functional Slc19a2 has been generated and unexpectedly found to have a male-specific sterility phenotype. We describe here the characterization of the testis-specific effects of absence of the high-affinity thiamin transporter, Tht1. Null males were found to have hypoplastic testes secondary to germ cell depletion. Morphologic and expression analysis revealed that under conditions of standard thiamin intake, tissues affected in the syndrome (pancreatic beta-cell, hematopoietic cells, auditory nerve) maintained normal function but pachytene stage spermatocytes underwent apoptosis. Under conditions of thiamin challenge, the apoptotic cell loss extended to earlier stages of germ cells but spared Sertoli cells and Leydig cells. Injection of high-dose thiamin was effective in reversing the spermatogenic failure, suggesting that the absence of the thiamin carrier could be overcome by diffusion-mediated transport at supranormal thiamin concentrations. These observations demonstrated that male germ cells, particularly those with high thiamin transporter expression beyond the blood-testis barrier, were more susceptible to apoptosis triggered by intracellular thiamin deficiency than any other tissue type. The findings described here highlight an unexpected and critical role for thiamin transport and metabolism in spermatogenesis.