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

• Published in: American journal of human genetics 2018-06, Vol.102 (6), p.1158-1168
• Main Authors: Wang, Chih-Chuan, Ortiz-González, Xilma R., Yum, Sabrina W., Gill, Sara M., White, Amy, Kelter, Erin, Seaver, Laurie H., Lee, Sansan, Wiley, Graham, Gaffney, Patrick M., Wierenga, Klaas J., Rasband, Matthew N.
• Format: Article
• Language: English
• Subjects: Alleles; Animals; axon initial segment; Axons - metabolism; Axons - pathology; Child; Child, Preschool; Chlorocebus aethiops; COS Cells; cytoskeleton; Female; HEK293 Cells; Humans; Infant; Intellectual Disability - complications; Intellectual Disability - genetics; Intellectual Disability - physiopathology; Lipids; Male; Mice, Knockout; Motor Neuron Disease - complications; Motor Neuron Disease - genetics; Motor Neuron Disease - physiopathology; Muscle Hypotonia - complications; Muscle Hypotonia - congenital; Muscle Hypotonia - genetics; Muscle Hypotonia - physiopathology; Mutant Proteins - metabolism; Mutation - genetics; Nerve Tissue Proteins - genetics; node of Ranvier; Rats, Sprague-Dawley; Spectrin - genetics
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2018.04.012

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.