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1537-66059532014Sep04American journal of human geneticsAm J Hum GenetMutations in FEZF1 cause Kallmann syndrome.326331326-3110.1016/j.ajhg.2014.08.006S0002-9297(14)00350-4Gonadotropin-releasing hormone (GnRH) neurons originate outside the CNS in the olfactory placode and migrate into the CNS, where they become integral components of the hypothalamic-pituitary-gonadal (HPG) axis. Disruption of this migration results in Kallmann syndrome (KS), which is characterized by anosmia and pubertal failure due to hypogonadotropic hypogonadism. Using candidate-gene screening, autozygosity mapping, and whole-exome sequencing in a cohort of 30 individuals with KS, we searched for genes newly associated with KS. We identified homozygous loss-of-function mutations in FEZF1 in two independent consanguineous families each with two affected siblings. The FEZF1 product is known to enable axons of olfactory receptor neurons (ORNs) to penetrate the CNS basal lamina in mice. Because a subset of axons in these tracks is the migratory pathway for GnRH neurons, in FEZF1 deficiency, GnRH neurons also fail to enter the brain. These results indicate that FEZF1 is required for establishment of the central component of the HPG axis in humans.Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.KotanL DamlaLDDepartment of Biotechnology, Institute of Sciences, Cukurova University, 01330 Adana, Turkey.HutchinsB IanBICellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.OzkanYusufYDepartment of Endocrinology, Faculty of Medicine, Fırat University, 23119 Elazıg, Turkey.DemirelFatmaFDivision of Pediatric Endocrinology, Ankara Pediatric Hematology and Oncology Training Hospital, 06200 Ankara, Turkey.StonerHudsonHCellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.ChengPaul JPJCellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.EsenIhsanIDivision of Pediatric Endocrinology, Ankara Pediatric Hematology and Oncology Training Hospital, 06200 Ankara, Turkey.GurbuzFatihFDivision of Pediatric Endocrinology, Faculty of Medicine, Cukurova University, 01330 Adana, Turkey.BicakciY KenanYKDepartment of Radiology, Faculty of Medicine, Cukurova University, 01330 Adana, Turkey.MengenEdaEDivision of Pediatric Endocrinology, Faculty of Medicine, Cukurova University, 01330 Adana, Turkey.YukselBilginBDivision of Pediatric Endocrinology, Faculty of Medicine, Cukurova University, 01330 Adana, Turkey.WraySusanSCellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA. Electronic address: wrays@ninds.nih.gov.TopalogluA KemalAKDepartment of Biotechnology, Institute of Sciences, Cukurova University, 01330 Adana, Turkey; Division of Pediatric Endocrinology, Faculty of Medicine, Cukurova University, 01330 Adana, Turkey. Electronic address: ktopaloglu@cu.edu.tr.engZ01 NS002824ImNIHIntramural NIH HHSUnited StatesNS002824-13NSNINDS NIH HHSUnited StatesJournal ArticleMulticenter StudyResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov't
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