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.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology