ArticleBrain : a journal of neurology2014
PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum.
Article in Brain : a journal of neurology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 122 papers, 1 of them a synthesis that pooled it.
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Who cites it
122 citing papers in PubMed, 1 synthesis or guideline pooled it, 222 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
- Splenial corpus callosum lesions in Boucher-Neuhäuser syndrome: a case series and comprehensive literature review with exploratory analysis of disease duration.Neuroradiology · 2026Article
- 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
- Outer retinal tubulation associated with photoreceptor degeneration.Progress in retinal and eye research · 2026Review
- 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
- A direct solubilization approach to purify active full-length human neuropathy target esterase.Protein expression and purification · 2025Article
- Hereditary Spastic Paraplegia in Alberta: Lessons from a Well-Defined Cohort Including the Indigenous Population.Movement disorders clinical practice · 2025Observational
- A comprehensive genetic landscape of inherited retinal diseases in a large Pakistani cohort.NPJ genomic medicine · 2025Article
- PNPLA6 regulates retinal homeostasis by choline through phospholipid turnover.Nature communications · 2025Article
- Glycerophospholipids: Roles in Cell Trafficking and Associated Inborn Errors.Journal of inherited metabolic disease · 2025Review
- Globalizing newborn screening: bridging gaps in genetic diagnosis and treatment.Frontiers in pediatrics · 2025Article
- Case Report: Novel compound heterozygous mutations inFrontiers in genetics · 2025Article
- Novel PNPLA8 variants associated with primary ovarian insufficiency, tremors, cerebellar ataxia and limb weakness: a case report and literature review.Journal of neurology · 2024Review
- Two case reports of a novel missense mutation in the PNPLA6 gene in two siblings with chorioretinal dystrophy, hypogonadotropic hypogonadism, and cerebellar ataxia.Molecular biology reports · 2024Article
62 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 13 institutions in 7 countries.
Funding
Abstract
Boucher-Neuhäuser and Gordon Holmes syndromes are clinical syndromes defined by early-onset ataxia and hypogonadism plus chorioretinal dystrophy (Boucher-Neuhäuser syndrome) or brisk reflexes (Gordon Holmes syndrome). Here we uncover the genetic basis of these two syndromes, demonstrating that both clinically distinct entities are allelic for recessive mutations in the gene PNPLA6. In five of seven Boucher-Neuhäuser syndrome/Gordon Holmes syndrome families, we identified nine rare conserved and damaging mutations by applying whole exome sequencing. Further, by dissecting the complex clinical presentation of Boucher-Neuhäuser syndrome and Gordon Holmes syndrome into its neurological system components, we set out to analyse an additional 538 exomes from families with ataxia (with and without hypogonadism), pure and complex hereditary spastic paraplegia, and Charcot-Marie-Tooth disease type 2. We identified four additional PNPLA6 mutations in spastic ataxia and hereditary spastic paraplegia families, revealing that Boucher-Neuhäuser and Gordon Holmes syndromes in fact represent phenotypic clusters on a spectrum of neurodegenerative diseases caused by mutations in PNPLA6. Structural analysis indicates that the majority of mutations falls in the C-terminal phospholipid esterase domain and likely inhibits the catalytic activity of PNPLA6, which provides the precursor for biosynthesis of the neurotransmitter acetylcholine. Our findings show that PNPLA6 influences a manifold of neuronal systems, from the retina to the cerebellum, upper and lower motor neurons and the neuroendocrine system, with damage of this protein causing an extraordinarily broad continuous spectrum of associated neurodegenerative disease.
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