ArticleBrain : a journal of neurology2009
Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations.
Article in Brain : a journal of neurology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers, 1 of them a synthesis that pooled it.
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Who cites it
58 citing papers in PubMed, 1 synthesis or guideline pooled it, 155 citations in OpenAlex.
- A novel homozygous variant in the POLR1A gene: a complicated hereditary spastic paraplegia (c-HSP) or a hypomyelinating leukodystrophy type-27 (HLD27) phenotype?Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026Pooled it
- Molecular dynamics simulation of GJC2 mutants reveal pathogenic mechanisms of PMLD1 and SPG44.The Journal of general physiology · 2025Article
- Overview of genetic variants in a cohort of Iranian patients with leukodystrophy.Scientific reports · 2025Article
- Expanding the phenotypic spectrum ofCurrent journal of neurology · 2025Article
- Prominent Head and Arm Tremor in Late-Onset Pelizaeus-Merzbacher-Like Disease 1.Movement disorders clinical practice · 2025Article
- Neurodevelopmental Implications Underpinning Hereditary Spastic Paraplegia.CNS neuroscience & therapeutics · 2025Review
- Hereditary spastic paraplegia and extensive leukoencephalopathy: a case report of a unique phenotype associated with a GJB1/Cx32 p.Pro174Ser variant.BMC neurology · 2024Article
- Metabolite profile in hereditary spastic paraplegia analyzed using magnetic resonance spectroscopy: a cross-sectional analysis in a longitudinal study.Frontiers in neuroscience · 2024Article
- Description of Phenotypic Heterogeneity in aMolecular syndromology · 2023Article
- Molecular Pathogenic Mechanisms of Hypomyelinating Leukodystrophies (HLDs).Neurology international · 2023Review
- A founder mutation in COQ7, p.(Leu111Pro), causes pure hereditary spastic paraplegia (HSP) in the Iranian population.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2023Article
- Mechanisms of Diseases Associated with Mutation in GJC2/Connexin 47.Biomolecules · 2023Review
- The Puzzle of Hereditary Spastic Paraplegia: From Epidemiology to Treatment.International journal of molecular sciences · 2022Review
- A novel mutation in GJC2 associated with hypomyelinating leukodystrophy type 2 disorder.Genomics & informatics · 2022Article
- Two distinct types of nodes of Ranvier support auditory nerve function in the mouse cochlea.Glia · 2022Article
- Exploring Motor Neuron Diseases Using iPSC Platforms.Stem cells (Dayton, Ohio) · 2022Article
- Hereditary Spastic Paraplegia: An Update.International journal of molecular sciences · 2022Review
- Gap Junction Channelopathies and Calmodulinopathies. Do Disease-Causing Calmodulin Mutants Affect Direct Cell-Cell Communication?International journal of molecular sciences · 2021Review
- Importance of lipids for upper motor neuron health and disease.Seminars in cell & developmental biology · 2021Review
- Hypomyelinating leukodystrophies - unravelling myelin biology.Nature reviews. Neurology · 2021Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
Recessive mutations in GJA12/GJC2, the gene that encodes the gap junction protein connexin47 (Cx47), cause Pelizaeus-Merzbacher-like disease (PMLD), an early onset dysmyelinating disorder of the CNS, characterized by nystagmus, psychomotor delay, progressive spasticity and cerebellar signs. Here we describe three patients from one family with a novel recessively inherited mutation, 99C>G (predicted to cause an Ile>Met amino acid substitution; I33M) that causes a milder phenotype. All three had a late-onset, slowly progressive, complicated spastic paraplegia, with normal or near-normal psychomotor development, preserved walking capability through adulthood, and no nystagmus. MRI and MR spectroscopy imaging were consistent with a hypomyelinating leukoencephalopathy. The mutant protein forms gap junction plaques at cell borders similar to wild-type (WT) Cx47 in transfected cells, but fails to form functional homotypic channels in scrape-loading and dual whole-cell patch clamp assays. I33M forms overlapping gap junction plaques and functional channels with Cx43, however, I33M/Cx43 channels open only when a large voltage difference is applied to paired cells. These channels probably do not function under physiological conditions, suggesting that Cx47/Cx43 channels between astrocytes and oligodendrocytes are disrupted, similar to the loss-of-function endoplasmic reticulum-retained Cx47 mutants that cause PMLD. Thus, GJA12/GJC2 mutations can result in a milder phenotype than previously appreciated, but whether I33M retains a function of Cx47 not directly related to forming functional gap junction channels is not known.
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