Abstract
Homozygous or compound heterozygous mutations in the GJC2 gene, encoding the gap junction protein connexin47 (Cx47), cause the autosomal recessive hypomyelinating Pelizaeus–Merzbacher-like disease (PMLD1, MIM# 608804). Although clinical and neuroradiological findings resemble those of the classic Pelizaeus–Merzbacher disease, PMLD patients usually show a greater level of cognitive and motor functions. Unpredictably a homozygous missense GJC2 mutation (p.Glu260Lys) was found in a patient presenting with a very severe clinical picture characterised by congenital nystagmus and severe neurological impairment. Also magnetic resonance imaging was unusually severe, showing an abnormal supra- and infratentorial white matter involvement extending to the spinal cord. The novel p.Glu260Lys (c.778G>A) mutation, occurring in a highly conserved motif (SRPTEK) of the Cx47 extracellular loop-2 domain, was predicted, by modelling analysis, to break a ‘salt bridge network’, crucial for a proper connexin–connexin interaction to form a connexon, thus hampering the correct formation of the connexon pore. The same structural analysis, extended to the previously reported missense mutations, predicted that most changes were expected to have less severe impact on protein functions, correlating with the mild PMLD1 form of the patients. Our study expands the spectrum of PMLD1 and provides evidence that the extremely severe clinical and neuroradiological PMLD1 form of our patient likely correlates with the predicted impairment of gap junction channel assembly resulting from the detrimental effect of the new p.Glu260Lys mutant allele on Cx47 protein.
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Acknowledgements
The patient sample was obtained from the ‘Cell Line and DNA Biobank from Patients Affected by Genetic Diseases’ (G Gaslini Institute)—Telethon Genetic Biobank Network (Project No. GTB07001). The study was also supported by Italian Health Department ‘Finanziamento Ricerca Corrente (contributo per la ricerca intramurale)’ and FP7-HEALTH—LeukoTreat no.241622.
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Biancheri, R., Rosano, C., Denegri, L. et al. Expanded spectrum of Pelizaeus–Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form. Eur J Hum Genet 21, 34–39 (2013). https://doi.org/10.1038/ejhg.2012.93
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DOI: https://doi.org/10.1038/ejhg.2012.93
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