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Am J Hum Genet. 2018 Jun 7;102(6):1158-1168. doi: 10.1016/j.ajhg.2018.04.012. Epub 2018 May 31.

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

Author information

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.

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

PMID:
29861105
PMCID:
PMC5992132
DOI:
10.1016/j.ajhg.2018.04.012
[Indexed for MEDLINE]
Free PMC Article

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