βIV Spectrinopathies Cause Profound Intellectual Disability, Congenital Hypotonia, and Motor Axonal Neuropathy

Abstract

βIV 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 βIV 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 βI spectrin can cluster Na channels and partially compensate for the loss of AnkG and βIV spectrin at nodes of Ranvier, AnkR and βI 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.

βIV-Spectrin/STAT3 complex regulates fibroblast phenotype, fibrosis, and cardiac function

“…Going forward, it will be equally important to determine how our findings in the mouse translate to human disease. Recently, several loss-of-function variants in β IV -spectrin have been identified in human patients with neuropathy, myopathy, and congenital deafness (34,35). We anticipate that our findings will have important implications for human patients with both acquired and inherited forms of disease, given: (a) conservation of the β IV -spectrin/STAT3 complex across mouse and humans; (b) our previous studies showing loss of β IV -spectrin in human heart failure (36); and (c) results from this study showing transcriptional changes in human fibroblasts with acute spectrin knockdown (Supplemental Figure 5).…”

βII-spectrin promotes mouse brain connectivity through stabilizing axonal plasma membranes and enabling axonal organelle transport

“…βIV-spectrin similarly exhibits cell-type-specific expression in neurons and pancreatic β-cells (1,2,22). Consistent with these restricted expression patterns, mice and humans lacking these β-spectrins are viable, although with serious phenotypes, including severe anemia for βI-spectrin (23), cerebellar ataxia for βIII-spectrin (24), and abnormal neural development for βIV-spectrin (25). βII-spectrin, in contrast to other members of the β-spectrin family, is expressed in most cell types (although not in mature erythrocytes), and whole-body βII-spectrin knockout (KO) mice die by embryonic day (E)12 (26).…”

Cargo hold and delivery: Ankyrins, spectrins, and their functional patterning of neurons

“…Given the wide‐ranging functionality of ankyrins and spectrins in scaffolding the neuron, transporting and delivering essential cargo along the axon, and enabling the proper and stable localization of membrane protein complexes in neuronal processes, it is not surprising that their deficiencies underlie several neurodevelopmental, neurogenerative, and psychiatric disorders (De Rubeis et al, ; Ikeda et al, ; Iossifov et al, ; Kloth et al, ; Saitsu et al, ; Wang et al, ; Wirgenes et al, ). However, despite considerable progress in decoding the molecular underpinnings of neuronal ankyrins and spectrins over four decades, our present understanding is far from complete.…”