Journal
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Volume 99, Issue 10, Pages E2067-E2075Publisher
ENDOCRINE SOC
DOI: 10.1210/jc.2014-1836
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Funding
- Scientific and Technological Research Council of Turkey [109S455]
- Turkish Society for Pediatric Endocrinology and Diabetes
- European Society for Pediatric Endocrinology, Sabbatical Leave Programme
- National Science Foundation [IOS1121691]
- [NS061800]
- Biotechnology and Biological Sciences Research Council [BB/J014699/1] Funding Source: researchfish
- BBSRC [BB/J014699/1] Funding Source: UKRI
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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 L beta T2 gonadotrope cell line diminished LH response to GnRH by reducing GnRH-stimulated LH exocytosis, without affecting GnRH receptor signaling or LH beta 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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