| First Author | Wang CC | Year | 2018 |
| Journal | Am J Hum Genet | Volume | 102 |
| Issue | 6 | Pages | 1158-1168 |
| PubMed ID | 29861105 | Mgi Jnum | J:269189 |
| Mgi Id | MGI:6272090 | Doi | 10.1016/j.ajhg.2018.04.012 |
| Citation | Wang CC, et al. (2018) betaIV Spectrinopathies Cause Profound Intellectual Disability, Congenital Hypotonia, and Motor Axonal Neuropathy. Am J Hum Genet 102(6):1158-1168 |
| abstractText | betaIV spectrin links ankyrinG (AnkG) and clustered ion channels at axon initial segments (AISs) and nodes of Ranvier to the axonal cytoskeleton. Here, we report bi-allelic pathogenic SPTBN4 variants (three homozygous and two compound heterozygous) that cause a severe neurological syndrome that includes congenital hypotonia, intellectual disability, and motor axonal and auditory neuropathy. We introduced these variants into betaIV spectrin, expressed these in neurons, and found that 5/7 were loss-of-function variants disrupting AIS localization or abolishing phosphoinositide binding. Nerve biopsies from an individual with a loss-of-function variant had reduced nodal Na(+) channels and no nodal KCNQ2 K(+) channels. Modeling the disease in mice revealed that although ankyrinR (AnkR) and betaI spectrin can cluster Na(+) channels and partially compensate for the loss of AnkG and betaIV spectrin at nodes of Ranvier, AnkR and betaI spectrin cannot cluster KCNQ2- and KCNQ3-subunit-containing K(+) channels. Our findings define a class of spectrinopathies and reveal the molecular pathologies causing nervous-system dysfunction. |
