Point mutations in KAL1 and the mitochondrial gene MT-tRNA(cys) synergize to produce Kallmann syndrome phenotype.
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.
Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China.
Fei
F
Wang
Center for Circadian Clocks, Medical College, Soochow University, Suzhou 215123, Jiangsu, China.|School of Biology &Basic Medical Sciences, Medical College, Soochow University, Suzhou 215123, Jiangsu, China.
Guo-Dong
GD
Huang
Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China.
Hui
H
Tian
Center for Circadian Clocks, Medical College, Soochow University, Suzhou 215123, Jiangsu, China.|School of Biology &Basic Medical Sciences, Medical College, Soochow University, Suzhou 215123, Jiangsu, China.
Ying-Bin
YB
Zhong
National Population and Family Planning Key Laboratory of Contraceptive Drugs and Devices, Shanghai Institute of Planned Parenthood Research, Shanghai, China.
Hui-Juan
HJ
Shi
Department of Urology, Shanghai Human Sperm Bank, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
Zheng
Z
Li
Departments of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230032, China.
Xian-Sheng
XS
Zhang
Center for Circadian Clocks, Medical College, Soochow University, Suzhou 215123, Jiangsu, China.|School of Biology &Basic Medical Sciences, Medical College, Soochow University, Suzhou 215123, Jiangsu, China.
Han
H
Wang
Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China.
Fei
F
Sun
D000604:Amino Acyl-tRNA Synthetases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D002465:Cell Movement; D002681:China; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D017436:Kallmann Syndrome / Q000235:genetics / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009690:Nucleic Acid Conformation; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D034622:RNA Interference; D012350:RNA, Transfer, Cys / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish / Q000378:metabolism
C076266:ANOS1 protein, human; D004272:DNA, Mitochondrial; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D012350:RNA, Transfer, Cys; D007987:Gonadotropin-Releasing Hormone; D000604:Amino Acyl-tRNA Synthetases; C000595892:CARS2 protein, human