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?IV Spectrinopathies Cause Profound Intellectual Disability, Congenital Hypotonia, and Motor Axonal Neuropathy.

ABSTRACT: ?IV 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 ?IV 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 ?I spectrin can cluster Na+ channels and partially compensate for the loss of AnkG and ?IV spectrin at nodes of Ranvier, AnkR and ?I 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.

SUBMITTER: Wang CC 

PROVIDER: S-EPMC5992132 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Wang Chih-Chuan CC   Ortiz-González Xilma R XR   Yum Sabrina W SW   Gill Sara M SM   White Amy A   Kelter Erin E   Seaver Laurie H LH   Lee Sansan S   Wiley Graham G   Gaffney Patrick M PM   Wierenga Klaas J KJ   Rasband Matthew N MN  

American journal of human genetics 20180531 6

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-f  ...[more]

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