Abstract
Benign familial neonatal convulsion (BFNC) is a rare autosomal dominant disorder caused by mutations in KCNQ2 and KCNQ3, two genes encoding for potassium channel subunits. A large family with nine members affected by BFNC is described in the present study. All affected members of this family carry a novel deletion/insertion mutation in the KCNQ2 gene (c.761_770del10insA), which determines a premature truncation of the protein. In addition, in the family of the proposita's father, a novel sequence variant (c.2687A>G) in KCNQ3 leading to the p.N821S amino acid change was detected. When heterologously expressed in Chinese hamster ovary cells, KCNQ2 subunits carrying the mutation failed to form functional potassium channels in homomeric configuration and did not affect channels formed by KCNQ2 and/or KCNQ3 subunits. On the other hand, homomeric and heteromeric potassium channels formed by KCNQ3 subunits carrying the p.N821S variant were indistinguishable from those formed by wild-type KCNQ3 subunits. Finally, the current density of the cells mimicking the double heterozygotic condition for both KCNQ2 and KCNQ3 alleles of the proband was decreased by approximately 25% when compared to cells expressing only wild-type alleles. Collectively, these results suggest that, in the family investigated, the KCNQ2 mutation is responsible for the BFNC phenotype, possibly because of haplo-insufficiency, whereas the KCNQ3 variant is functionally silent, a result compatible with its lack of segregation with the BFNC phenotype.
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Acknowledgements
The authors express their gratitude to T.J. Jentsch, Zentrum für Molekulare Neurobiologie Hamburg (ZMNH), Germany, for sharing KCNQ2 and KCNQ3 cDNAs. This work was supported by the European Union Specific Targeted Research Project (STREP) PL 503038; the Italian National Institute of Health (Ministero della Salute) grants RF/2002, RF/2003 and RC2004; the Italian Ministry of the University and Research (MIUR) FIRB RBNE01XMP4; the Fondazione Telethon Onlus (Project GGP030209) and the Regione Campania Regional Law n.5 of 28/3/2002 (year 2003). The described experiments comply with the current laws of Italy.
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Bassi, M.T., Balottin, U., Panzeri, C. et al. Functional analysis of novel KCNQ2 and KCNQ3 gene variants found in a large pedigree with benign familial neonatal convulsions (BFNC). Neurogenetics 6, 185–193 (2005). https://doi.org/10.1007/s10048-005-0012-2
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DOI: https://doi.org/10.1007/s10048-005-0012-2