title: Mutations in FEZF1 cause Kallmann syndrome.
abstract: Gonadotropin-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.
authors.affiliation: Department of Biotechnology, Institute of Sciences, Cukurova University, 01330 Adana, Turkey.
authors.forename: L Damla
authors.initials: LD
authors.lastname: Kotan
authors.affiliation: Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
authors.forename: B Ian
authors.initials: BI
authors.lastname: Hutchins
authors.affiliation: Department of Endocrinology, Faculty of Medicine, Fırat University, 23119 Elazıg, Turkey.
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Ozkan
authors.affiliation: Division of Pediatric Endocrinology, Ankara Pediatric Hematology and Oncology Training Hospital, 06200 Ankara, Turkey.
authors.forename: Fatma
authors.initials: F
authors.lastname: Demirel
authors.affiliation: Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
authors.forename: Hudson
authors.initials: H
authors.lastname: Stoner
authors.affiliation: Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Cheng
authors.affiliation: Division of Pediatric Endocrinology, Ankara Pediatric Hematology and Oncology Training Hospital, 06200 Ankara, Turkey.
authors.forename: Ihsan
authors.initials: I
authors.lastname: Esen
authors.affiliation: Division of Pediatric Endocrinology, Faculty of Medicine, Cukurova University, 01330 Adana, Turkey.
authors.forename: Fatih
authors.initials: F
authors.lastname: Gurbuz
authors.affiliation: Department of Radiology, Faculty of Medicine, Cukurova University, 01330 Adana, Turkey.
authors.forename: Y Kenan
authors.initials: YK
authors.lastname: Bicakci
authors.affiliation: Division of Pediatric Endocrinology, Faculty of Medicine, Cukurova University, 01330 Adana, Turkey.
authors.forename: Eda
authors.initials: E
authors.lastname: Mengen
authors.affiliation: Division of Pediatric Endocrinology, Faculty of Medicine, Cukurova University, 01330 Adana, Turkey.
authors.forename: Bilgin
authors.initials: B
authors.lastname: Yuksel
authors.affiliation: Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA. Electronic address: wrays@ninds.nih.gov.
authors.forename: Susan
authors.initials: S
authors.lastname: Wray
authors.affiliation: Department 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.
authors.forename: A Kemal
authors.initials: AK
authors.lastname: Topaloglu
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics*; D005190:Family; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D006801:Humans; D007006:Hypogonadism; D007030:Hypothalamo-Hypophyseal System; D017436:Kallmann Syndrome / Q000235:genetics*; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D018034:Olfactory Receptor Neurons / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D011446:Prospective Studies; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C557090:FEZF2 protein, human; C560820:Fezf1 protein, mouse; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D007987:Gonadotropin-Releasing Hormone