Heyne, Henrike O., Baez-Nieto, David, Iqbal, Sumaiya ORCID: 0000-0001-7700-4374, Palmer, Duncan S., Brunklaus, Andreas ORCID: 0000-0002-7728-6903, May, Patrick ORCID: 0000-0001-8698-3770, Johannesen, Katrine M., Lauxmann, Stephan, Lemke, Johannes R., Moller, Rikke S., Perez-Palma, Eduardo, Scholl, Ute, I, Syrbe, Steffen, Lerche, Holger, Lal, Dennis, Campbell, Arthur J., Wang, Hao-Ran, Pan, Jen and Daly, Mark J. (2020). Predicting functional effects of missense variants in voltage-gated sodium and calcium channels. Sci. Transl. Med., 12 (556). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 1946-6242

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Abstract

Malfunctions of voltage-gated sodium and calcium channels (encoded by SCNxA and CACNA1x family genes, respectively) have been associated with severe neurologic, psychiatric, cardiac, and other diseases. Altered channel activity is frequently grouped into gain or loss of ion channel function (GOF or LOF, respectively) that often corresponds not only to clinical disease manifestations but also to differences in drug response. Experimental studies of channel function are therefore important, but laborious and usually focus only on a few variants at a time. On the basis of known gene-disease mechanisms of 19 different diseases, we inferred LOF (n = 518) and GOF (n = 309) likely pathogenic variants from the disease phenotypes of variant carriers. By training a machine learning model on sequence- and structure-based features, we predicted LOF or GOF effects [area under the receiver operating characteristics curve (ROC) = 0.85] of likely pathogenic missense variants. Our LOF versus GOF prediction corresponded to molecular LOF versus GOF effects for 87 functionally tested variants in SCN1/2/8A and CACNA1/(ROC = 0.73) and was validated in exome-wide data from 21,703 cases and 128,957 controls. We showed respective regional clustering of inferred LOF and GOF nucleotide variants across the alignment of the entire gene family, suggesting shared pathomechanisms in the SCNxA/CACNA1x family genes.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Heyne, Henrike O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baez-Nieto, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iqbal, SumaiyaUNSPECIFIEDorcid.org/0000-0001-7700-4374UNSPECIFIED
Palmer, Duncan S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brunklaus, AndreasUNSPECIFIEDorcid.org/0000-0002-7728-6903UNSPECIFIED
May, PatrickUNSPECIFIEDorcid.org/0000-0001-8698-3770UNSPECIFIED
Johannesen, Katrine M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lauxmann, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lemke, Johannes R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moller, Rikke S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perez-Palma, EduardoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scholl, Ute, IUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Syrbe, SteffenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lerche, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lal, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campbell, Arthur J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, Hao-RanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pan, JenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Daly, Mark J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-323437
DOI: 10.1126/scitranslmed.aay6848
Journal or Publication Title: Sci. Transl. Med.
Volume: 12
Number: 556
Date: 2020
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication: WASHINGTON
ISSN: 1946-6242
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
FAMILIAL HEMIPLEGIC MIGRAINE; AUTISM SPECTRUM DISORDER; DE-NOVO MUTATIONS; MOLECULAR-BASIS; PRECISION MEDICINE; NA+-CHANNEL; MUSCLE; INACTIVATION; ACTIVATION; EPILEPSYMultiple languages
Cell Biology; Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/32343

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