ZFIN ID: ZDB-PUB-170214-134
Point mutations in KAL1 and the mitochondrial gene MT-tRNA(cys) synergize to produce Kallmann syndrome phenotype
Wang, F., Huang, G.D., Tian, H., Zhong, Y.B., Shi, H.J., Li, Z., Zhang, X.S., Wang, H., Sun, F.
Date: 2015
Source: Scientific Reports   5: 13050 (Journal)
Registered Authors: Huang, Guodong, Li, Zheng, Sun, Fei, Wang, Han, Zhong, Yingbin
Keywords: Disease genetics, Endocrine reproductive disorders, Genetics of the nervous system
MeSH Terms:
  • Amino Acyl-tRNA Synthetases/antagonists & inhibitors
  • Amino Acyl-tRNA Synthetases/genetics
  • Amino Acyl-tRNA Synthetases/metabolism
  • Animals
  • Asian Continental Ancestry Group/genetics
  • Base Sequence
  • Cell Movement
  • China
  • DNA, Mitochondrial/chemistry
  • DNA, Mitochondrial/genetics*
  • Extracellular Matrix Proteins/genetics*
  • Extracellular Matrix Proteins/metabolism
  • Gonadotropin-Releasing Hormone/metabolism
  • HEK293 Cells
  • Humans
  • Kallmann Syndrome/genetics
  • Kallmann Syndrome/pathology*
  • Nerve Tissue Proteins/genetics*
  • Nerve Tissue Proteins/metabolism
  • Neurons/metabolism
  • Nucleic Acid Conformation
  • Pedigree
  • Phenotype
  • Point Mutation
  • RNA Interference
  • RNA, Transfer, Cys/genetics*
  • RNA, Transfer, Cys/metabolism
  • Zebrafish/metabolism
PubMed: 26278626 Full text @ Sci. Rep.
Kallmann syndrome (KS) is an inherited developmental disorder defined as the association of hypogonadotropic hypogonadism and anosmia or hyposmia. KS has been shown to be a genetically heterogeneous disease with different modes of inheritance. However, variants in any of the causative genes identified so far are only found in approximately one third of KS patients, thus indicating that other genes or pathways remain to be discovered. Here, we report a large Han Chinese family with inherited KS which harbors two novel variants, KAL1 c.146G>T (p.Cys49Phe) and mitochondrial tRNA(cys) (m.5800A>G). Although two variants can't exert obvious effects on the migration of GnRH neurons, they show the synergistic effect, which can account for the occurrence of the disorder in this family. Furthermore, the disturbance of the mitochondrial cysteinyl-tRNA pathway can significantly affect the migration of GnRH cells in vitro and in vivo by influencing the chemomigration function of anosmin-1. Our work highlights a new mode of inheritance underlay the genetic etiology of KS and provide valuable clues to understand the disease development.