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

A. Kemal Topaloglu, 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

Research output: Contribution to journalArticle

51 Scopus citations

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 gonadotropecell 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.

Original languageEnglish (US)
Pages (from-to)E2067-E2075
JournalJournal of Clinical Endocrinology and Metabolism
Volume99
Issue number10
DOIs
StatePublished - Oct 1 2014

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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    Topaloglu, A. K., Lomniczi, A., Kretzschmar, D., Dissen, G. A., Kotan, L. D., McArdle, C. A., Koc, A. F., Hamel, B. C., Guclu, M., Papatya, E. D., Eren, E., Mengen, E., Gurbuz, F., Cook, M., Castellano, J. M., Kekil, M. B., Mungan, N. O., Yuksel, B., & Ojeda, S. R. (2014). Loss-of-function mutations in PNPLA6 encoding neuropathy target esterase underlie pubertal failure and neurological deficits in Gordon Holmes syndrome. Journal of Clinical Endocrinology and Metabolism, 99(10), E2067-E2075. https://doi.org/10.1210/jc.2014-1836