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 (Academic Journal)peer-review

55 Citations (Scopus)

Abstract

Context: Gordon Holmessyndrome (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 in to the disease mechanism in GHS. Methods: We studied a cohort of six multiplex families with GHS through autozygosity mapping and whole exome sequencing. Results: We identified six patients from three 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 (LPC) 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 phosholipid homeostasis in GHS causes both neurodegeneration and impaired LH release from pituitary gonadotropes leading to nHH.

Original languageEnglish
Pages (from-to)E2067-E2075
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume99
Issue number10
Early online date17 Jul 2014
DOIs
Publication statusPublished - 1 Oct 2014

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