2. Academic Validation
  3. Mutations in FEZF1 cause Kallmann syndrome

Mutations in FEZF1 cause Kallmann syndrome

  • Am J Hum Genet. 2014 Sep 4;95(3):326-31. doi: 10.1016/j.ajhg.2014.08.006.
L Damla Kotan 1,  B Ian Hutchins 2,  Yusuf Ozkan 3,  Fatma Demirel 4,  Hudson Stoner 2,  Paul J Cheng 2,  Ihsan Esen 4,  Fatih Gurbuz 5,  Y Kenan Bicakci 6,  Eda Mengen 5,  Bilgin Yuksel 5,  Susan Wray 7,  A Kemal Topaloglu 8
Affiliations

Affiliations

  • 1 Department of Biotechnology, Institute of Sciences, Cukurova University, 01330 Adana, Turkey.
  • 2 Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
  • 3 Department of Endocrinology, Faculty of Medicine, Fırat University, 23119 Elazıg, Turkey.
  • 4 Division of Pediatric Endocrinology, Ankara Pediatric Hematology and Oncology Training Hospital, 06200 Ankara, Turkey.
  • 5 Division of Pediatric Endocrinology, Faculty of Medicine, Cukurova University, 01330 Adana, Turkey.
  • 6 Department of Radiology, Faculty of Medicine, Cukurova University, 01330 Adana, Turkey.
  • 7 Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA. Electronic address: [email protected].
  • 8 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: [email protected].
PMID: 25192046 DOI: 10.1016/j.ajhg.2014.08.006
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.

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