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A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions.
Coste de Bagneaux, Pierre; von Elsner, Leonie; Bierhals, Tatjana; Campiglio, Marta; Johannsen, Jessika; Obermair, Gerald J; Hempel, Maja; Flucher, Bernhard E; Kutsche, Kerstin.
Afiliación
  • Coste de Bagneaux P; Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria.
  • von Elsner L; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Bierhals T; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Campiglio M; Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria.
  • Johannsen J; Childrens Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Obermair GJ; Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria.
  • Hempel M; Division Physiology, Karl Landsteiner University of Health Sciences, Krems, Austria.
  • Flucher BE; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Kutsche K; Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria.
PLoS Genet ; 16(3): e1008625, 2020 03.
Article en En | MEDLINE | ID: mdl-32176688
ABSTRACT
P/Q-type channels are the principal presynaptic calcium channels in brain functioning in neurotransmitter release. They are composed of the pore-forming CaV2.1 α1 subunit and the auxiliary α2δ-2 and ß4 subunits. ß4 is encoded by CACNB4, and its multiple splice variants serve isoform-specific functions as channel subunits and transcriptional regulators in the nucleus. In two siblings with intellectual disability, psychomotor retardation, blindness, epilepsy, movement disorder and cerebellar atrophy we identified rare homozygous variants in the genes LTBP1, EMILIN1, CACNB4, MINAR1, DHX38 and MYO15 by whole-exome sequencing. In silico tools, animal model, clinical, and genetic data suggest the p.(Leu126Pro) CACNB4 variant to be likely pathogenic. To investigate the functional consequences of the CACNB4 variant, we introduced the corresponding mutation L125P into rat ß4b cDNA. Heterologously expressed wild-type ß4b associated with GFP-CaV1.2 and accumulated in presynaptic boutons of cultured hippocampal neurons. In contrast, the ß4b-L125P mutant failed to incorporate into calcium channel complexes and to cluster presynaptically. When co-expressed with CaV2.1 in tsA201 cells, ß4b and ß4b-L125P augmented the calcium current amplitudes, however, ß4b-L125P failed to stably complex with α1 subunits. These results indicate that p.Leu125Pro disrupts the stable association of ß4b with native calcium channel complexes, whereas membrane incorporation, modulation of current density and activation properties of heterologously expressed channels remained intact. Wildtype ß4b was specifically targeted to the nuclei of quiescent excitatory cells. Importantly, the p.Leu125Pro mutation abolished nuclear targeting of ß4b in cultured myotubes and hippocampal neurons. While binding of ß4b to the known interaction partner PPP2R5D (B56δ) was not affected by the mutation, complex formation between ß4b-L125P and the neuronal TRAF2 and NCK interacting kinase (TNIK) seemed to be disturbed. In summary, our data suggest that the homozygous CACNB4 p.(Leu126Pro) variant underlies the severe neurological phenotype in the two siblings, most likely by impairing both channel and non-channel functions of ß4b.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Canales de Calcio / Mutación Missense / Subunidades de Proteína / Trastornos del Neurodesarrollo Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: PLoS Genet Asunto de la revista: GENETICA Año: 2020 Tipo del documento: Article País de afiliación: Austria

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Canales de Calcio / Mutación Missense / Subunidades de Proteína / Trastornos del Neurodesarrollo Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: PLoS Genet Asunto de la revista: GENETICA Año: 2020 Tipo del documento: Article País de afiliación: Austria