2. Academic Validation
  3. βIV Spectrinopathies Cause Profound Intellectual Disability, Congenital Hypotonia, and Motor Axonal Neuropathy

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

  • Am J Hum Genet. 2018 Jun 7;102(6):1158-1168. doi: 10.1016/j.ajhg.2018.04.012.
Chih-Chuan Wang 1,  Xilma R Ortiz-González 2,  Sabrina W Yum 2,  Sara M Gill 3,  Amy White 3,  Erin Kelter 4,  Laurie H Seaver 5,  Sansan Lee 6,  Graham Wiley 7,  Patrick M Gaffney 7,  Klaas J Wierenga 8,  Matthew N Rasband 9
Affiliations

Affiliations

  • 1 Department of Neuroscience and Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA.
  • 2 Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Neurology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 3 Department of Audiology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 4 Women and Children's Hospital of Buffalo, Buffalo, NY 14203, USA.
  • 5 Spectrum Health Medical Genetics, MSU College of Human Medicine, Department of Pediatrics and Human Development, Grand Rapids, MI 49503, USA.
  • 6 Hawai'i Community Genetics, Honolulu, HI 96814, USA.
  • 7 Division of Genomics and Data Sciences, Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
  • 8 Department of Pediatrics, Oklahoma University Health Sciences Center, Oklahoma City, OK 73104, USA. Electronic address: klaas-wierenga@ouhsc.edu.
  • 9 Department of Neuroscience and Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: rasband@bcm.edu.
PMID: 29861105 DOI: 10.1016/j.ajhg.2018.04.012
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.

Keywords

axon initial segment; cytoskeleton; node of Ranvier.

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