ESPE Abstracts (2014) 82 FC5.3

aDepartment of Pediatric Endocrinology, Faculty of Medicine, Cukurova University, Adana, Turkey; bDivision of Neuroscience, Oregon National Primate Research Centre, Oregon, USA; cCentre for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Oregon, USA; dDepartment of Biotechnology, Institute of Sciences, Cukurova University, Adana, Turkey; eLaboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, UK; fDepartment of Neurology, Faculty of Medicine, Cukurova University, Adana, Turkey; gDepartment of Human Genetics, Nijmegen Medical Centre, Radboud University, Nijmegen, The Netherlands; hDepartment of Endocrinology and Metabolism, School of Medicine, Uludag University, Bursa, Turkey; iDepartment of Pediatric Endocrinology and Metabolism, School of Medicine, Uludag University, Bursa, Turkey; jDepartment of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain

Background: 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.

Patients and methods: We studied a cohort of multiplex families with GHS through autozygosity mapping and whole exome sequencing.

Results: We identified 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. WT 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: Thus NTE-dependent alteration of lipid homeostasis in GHS causes both neurodegeneration and nHH, the latter is due to impaired LH release from pituitary gonadotropes.

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