PLEKHG5 – Early-Onset Neuromuscular Disease

Pleckstrin homology domain-containing family G member 5 (PLEKHG5) encodes a nuclear factor kappaB (NF-κB) activator predominantly expressed in motor neurons and Schwann cells. Autosomal recessive variants in PLEKHG5 have been linked to childhood-onset lower motor neuron disease (LMND) and intermediate forms of Charcot-Marie-Tooth (CMT) disease, demonstrating a spectrum of neuromuscular involvement.

Genetic evidence supports an autosomal recessive inheritance, with at least 6 unrelated probands harboring homozygous or compound heterozygous PLEKHG5 variants and segregation in 12 additional affected relatives ([PMID:17564964];[PMID:23844677];[PMID:23777631];[PMID:33275839];[PMID:34236308];[PMID:34897098]). A recurrent missense mutation, c.1940T>C (p.Phe647Ser), was identified in a large consanguineous LMND pedigree and co-segregated with disease ([PMID:17564964]).

A targeted NGS panel of 579 myopathy-associated genes in 43 early-onset neuromuscular disorder patients did not uncover PLEKHG5 variants, underscoring the rarity of PLEKHG5-related disease in broad myopathy cohorts (n=43) ([PMID:25635128]).

Functional studies demonstrate that wild-type PLEKHG5 robustly activates NF-κB signaling, whereas the p.Phe647Ser mutant exhibits impaired stability, mislocalization, loss of NF-κB transduction, and cytotoxic aggregate formation in HEK293, MCF10A, and NSC34 cells ([PMID:17564964]). Mouse Plekhg5 knockout recapitulates reduced nerve conduction velocities and peripheral neuropathy akin to human CMT phenotypes ([PMID:23777631]).

No studies have refuted PLEKHG5’s role in neuromuscular disease. The concordance of genetic segregation, loss-of-function variant spectrum, and consistent cellular and animal models establish a strong gene–disease association.

Key Take-home: PLEKHG5 should be included in diagnostic sequencing panels for early-onset motor neuropathies given definitive segregation data, mechanistic insights into NF-κB disruption, and clear clinical specificity.

References

• American Journal of Human Genetics • 2007 • The nuclear factor kappaB-activator gene PLEKHG5 is mutated in a form of autosomal recessive lower motor neuron disease with childhood onset. PMID:17564964
• Orphanet Journal of Rare Diseases • 2013 • Mutations in the PLEKHG5 gene is relevant with autosomal recessive intermediate Charcot-Marie-Tooth disease. PMID:23844677
• Human Molecular Genetics • 2013 • PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease. PMID:23777631
• Annals of Clinical and Translational Neurology • 2021 • Novel PLEKHG5 mutations in a patient with childhood-onset lower motor neuron disease. PMID:33275839
• Clinical Neuropathology • 2021 • PLEKHG5-related autosomal recessive lower motor neuron disease with dysmyelination in peripheral nerves. PMID:34236308
• Journal of Neuromuscular Diseases • 2022 • Homozygous N-terminal missense variant in PLEKHG5 associated with intermediate CMT: A case report. PMID:34897098
• Journal of Medical Genetics • 2015 • Utility of next generation sequencing in genetic diagnosis of early onset neuromuscular disorders. PMID:25635128

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