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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, <jats:italic>KAL1<\/jats:italic> c.146G&gt;T (p.Cys49Phe) and mitochondrial <jats:italic>tRNA<\/jats:italic><jats:sup><jats:italic>cys<\/jats:italic><\/jats:sup> (m.5800A&gt;G). Although two variants can\u2019t 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 <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/srep13050","type":"journal-article","created":{"date-parts":[[2015,8,17]],"date-time":"2015-08-17T09:40:30Z","timestamp":1439804430000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Point mutations in KAL1 and the mitochondrial gene MT-tRNAcys synergize to produce Kallmann syndrome phenotype"],"prefix":"10.1038","volume":"5","author":[{"given":"Fei","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guo-dong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Tian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying-bin","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui-juan","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xian-sheng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fei","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,8,17]]},"reference":[{"key":"BFsrep13050_CR1","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/0165-3806(89)90295-2","volume":"46","author":"S Wray","year":"1989","unstructured":"Wray, S., Nieburgs, A. & Elkabes, S. 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