2. Academic Validation
  3. Loss-of-function mutations in PNPLA6 encoding neuropathy target esterase underlie pubertal failure and neurological deficits in Gordon Holmes syndrome

Loss-of-function mutations in PNPLA6 encoding neuropathy target esterase underlie pubertal failure and neurological deficits in Gordon Holmes syndrome

  • J Clin Endocrinol Metab. 2014 Oct;99(10):E2067-75. doi: 10.1210/jc.2014-1836.
A Kemal Topaloglu 1,  Alejandro Lomniczi,  Doris Kretzschmar,  Gregory A Dissen,  L Damla Kotan,  Craig A McArdle,  A Filiz Koc,  Ben C Hamel,  Metin Guclu,  Esra D Papatya,  Erdal Eren,  Eda Mengen,  Fatih Gurbuz,  Mandy Cook,  Juan M Castellano,  M Burcu Kekil,  Neslihan O Mungan,  Bilgin Yuksel,  Sergio R Ojeda
Affiliations

Affiliation

  • 1 Division of Pediatric Endocrinology (A.K.T., E.M., F.G., N.O.M., B.Y.) and Department of Neurology (A.F.K.), Faculty of Medicine, and Department of Biotechnology (A.K.T., L.D.K., M.B.K.), Institute of Sciences, Cukurova University, 01330 Adana, Turkey; Division of Neuroscience (A.L., G.A.D., S.R.O.), Oregon National Primate Research Centre, Beaverton, Oregon 97006; Oregon Institute of Occupational Health Sciences (D.K., M.C.), Oregon Health and Science University, Portland, Oregon 97239; Laboratories for Integrative Neuroscience and Endocrinology (C.A.M.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom BS1 3NY; Department of Human Genetics (B.C.H.), Nijmegen Medical Centre, Radboud University, Nijmegen, The Netherlands 6525 GA; Departments of Endocrinology and Metabolism (M.G.) and Pediatric Endocrinology and Metabolism (E.D.P., E.E.), School of Medicine, Uludag University, Bursa, Turkey 16110; and Department of Cell Biology, Physiology, and Immunology (J.M.C.), University of Cordoba, Cordoba, Spain 14071.
PMID: 25033069 DOI: 10.1210/jc.2014-1836
Abstract

Context: Gordon Holmes syndrome (GHS) is characterized by cerebellar ataxia/atrophy and normosmic hypogonadotropic hypogonadism (nHH). The underlying pathophysiology of this combined neurodegeneration and nHH remains unknown.

Objective: We aimed to provide insight into the disease mechanism in GHS.

Methods: We studied a cohort of 6 multiplex families with GHS through autozygosity mapping and whole-exome sequencing.

Results: We identified 6 patients from 3 independent families carrying loss-of-function mutations in PNPLA6, which encodes neuropathy target esterase (NTE), a lysophospholipase that maintains intracellular phospholipid homeostasis by converting lysophosphatidylcholine to glycerophosphocholine. Wild-type PNPLA6, but not PNPLA6 bearing these mutations, rescued a well-established Drosophila neurodegenerative phenotype caused by the absence of sws, the fly ortholog of mammalian PNPLA6. Inhibition of NTE activity in the LβT2 gonadotrope cell line diminished LH response to GnRH by reducing GnRH-stimulated LH exocytosis, without affecting GnRH Receptor signaling or LHβ synthesis.

Conclusion: These results suggest that NTE-dependent alteration of phospholipid homeostasis in GHS causes both neurodegeneration and impaired LH release from pituitary gonadotropes, leading to nHH.

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