ZFIN ID: ZDB-PUB-130729-8
Mutations in DSTYK and Dominant Urinary Tract Malformations
Sanna-Cherchi, S., Sampogna, R.V., Papeta, N., Burgess, K.E., Nees, S.N., Perry, B.J., Choi, M., Bodria, M., Liu, Y., Weng, P.L., Lozanovski, V.J., Verbitsky, M., Lugani, F., Sterken, R., Paragas, N., Caridi, G., Carrea, A., Dagnino, M., Materna-Kiryluk, A., Santamaria, G., Murtas, C., Ristoska-Bojkovska, N., Izzi, C., Kacak, N., Bianco, B., Giberti, S., Gigante, M., Piaggio, G., Gesualdo, L., Vukic, D.K., Vukojevic, K., Saraga-Babic, M., Saraga, M., Gucev, Z., Allegri, L., Latos-Bielenska, A., Casu, D., State, M., Scolari, F., Ravazzolo, R., Kiryluk, K., Al-Awqati, Q., D'Agati, V.D., Drummond, I.A., Tasic, V., Lifton, R.P., Ghiggeri, G.M., and Gharavi, A.G.
Date: 2013
Source: New. Engl. J. Med.   369(7): 621-9 (Journal)
Registered Authors: Drummond, Iain, Liu, Yan
Keywords: none
MeSH Terms:
  • Adult
  • Animals
  • Base Sequence
  • Child
  • Exome
  • Female
  • Gene Knockdown Techniques
  • Genetic Linkage
  • Genome-Wide Association Study
  • Heterozygote
  • Humans
  • Infant
  • Kidney/abnormalities
  • Male
  • Mice
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • RNA, Small Interfering
  • Receptor-Interacting Protein Serine-Threonine Kinases/genetics*
  • Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
  • Urinary Tract/abnormalities*
  • Urinary Tract/growth & development
  • Urinary Tract/metabolism
  • Urogenital Abnormalities/genetics*
  • Young Adult
PubMed: 23862974 Full text @ New Engl. J. Med.

Linkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine–threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases.