ArticleThe Journal of clinical endocrinology and metabolism2014
Loss-of-function mutations in PNPLA6 encoding neuropathy target esterase underlie pubertal failure and neurological deficits in Gordon Holmes syndrome.
Article in The Journal of clinical endocrinology and metabolism, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
66 citing papers in PubMed, 1 synthesis or guideline pooled it, 103 citations in OpenAlex.
- Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders.Brain : a journal of neurology · 2024Pooled it
- A novel PNPLA6 compound heterozygous mutation identified in a Chinese patient with Boucher‑Neuhäuser syndrome.Molecular medicine reports · 2018Trial
- Genetics of Idiopathic Hypogonadotropic HypogonadismJournal of clinical research in pediatric endocrinology · 2026Review
- Article
- Clinical and Genetic Profile of Gordon-Holmes Syndrome: A Review of Published Cases : Original Article.Cerebellum (London, England) · 2026Review
- Transcriptome-wide association study of prostate cancer in the Chinese population.Asian journal of urology · 2026Article
- Homozygous PNPLA6 Mutation (p.Arg1183Trp) Associated With Isolated Cerebellar Ataxia: A Familial Case Report.Cureus · 2026Article
- Compound Heterozygous Variants in the Phospholipase Gene PNPLA6 Cause Hypopituitarism and Vision Loss.Human mutation · 2026Article
- NovelJCEM case reports · 2026Article
- The cyclic nucleotide binding sites of Swiss-Cheese, thebioRxiv : the preprint server for biology · 2025Article
- Article
- A direct solubilization approach to purify active full-length human neuropathy target esterase.Protein expression and purification · 2025Article
- Novel variant inFrontiers in genetics · 2025Article
- Case Report: Novel compound heterozygous mutations inFrontiers in genetics · 2025Article
- Disorders of puberty and neurodevelopment: A shared etiology?Annals of the New York Academy of Sciences · 2024Review
- Article
- Review
- Lipid Profile Altered in Phenanthrene Exposed Zebrafish Embryos with Implications for Neurological Development and Early Life Nutritional Status.Environment & health (Washington, D.C.) · 2023Article
- Novel phenotype with prominent cerebellar oculomotor dysfunction in spastic paraplegia type 39.Journal of neurology · 2022Article
- Lipid Dyshomeostasis and Inherited Cerebellar Ataxia.Molecular neurobiology · 2022Review
6 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
19 authors at 7 institutions in 5 countries.
Funding
Abstract
contextGordon 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.
objectiveWe aimed to provide insight into the disease mechanism in GHS.
methodsWe studied a cohort of 6 multiplex families with GHS through autozygosity mapping and whole-exome sequencing.
resultsWe 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 gonadotrope cell line diminished LH response to GnRH by reducing GnRH-stimulated LH exocytosis, without affecting GnRH receptor signaling or LHβ synthesis.
conclusionThese 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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.