Hereditary spastic paraplegia Type 43 (SPG43) is caused by mutation in C19orf12

Guida Landouré, Peng Peng Zhu, Charles M. Lourenço, Janel O. Johnson, Camilo Toro, Katherine V. Bricceno, Carlo Rinaldi, Katherine G. Meilleur, Modibo Sangaré, Oumarou Diallo, Tyler M. Pierson, Hiroyuki Ishiura, Shoji Tsuji, Nichole Hein, John K. Fink, Marion Stoll, Garth Nicholson, Michael A. Gonzalez, Fiorella Speziani, Alexandra DürrGiovanni Stevanin, Leslie G. Biesecker, John Accardi, Dennis M.D. Landis, William A. Gahl, Bryan J. Traynor, Wilson Marques, Stephan Züchner, Craig Blackstone, Kenneth H. Fischbeck, Barrington G. Burnett

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

We report here the genetic basis for a form of progressive hereditary spastic paraplegia (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous missense variant (c.187G>C; p.Ala63Pro) in C19orf12, a gene recently implicated in neurodegeneration with brain iron accumulation (NBIA). The same mutation was subsequently also found in a Brazilian family with features of NBIA, and we identified another NBIA patient with a three-nucleotide deletion (c.197_199del; p.Gly66del). Haplotype analysis revealed that the p.Ala63Pro mutations have a common origin, but MRI scans showed no brain iron deposition in the Malian SPG43 subjects. Heterologous expression of these SPG43 and NBIA variants resulted in similar alterations in the subcellular distribution of C19orf12. The SPG43 and NBIA variants reported here as well as the most common C19orf12 missense mutation reported in NBIA patients are found within a highly conserved, extended hydrophobic domain in C19orf12, underscoring the functional importance of this domain.

Original languageEnglish (US)
Pages (from-to)1357-1360
Number of pages4
JournalHuman mutation
Volume34
Issue number10
DOIs
StatePublished - Oct 2013

Keywords

  • C19orf12
  • Hereditary spastic paraplegia
  • NBIA
  • SPG43

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Landouré, G., Zhu, P. P., Lourenço, C. M., Johnson, J. O., Toro, C., Bricceno, K. V., Rinaldi, C., Meilleur, K. G., Sangaré, M., Diallo, O., Pierson, T. M., Ishiura, H., Tsuji, S., Hein, N., Fink, J. K., Stoll, M., Nicholson, G., Gonzalez, M. A., Speziani, F., ... Burnett, B. G. (2013). Hereditary spastic paraplegia Type 43 (SPG43) is caused by mutation in C19orf12. Human mutation, 34(10), 1357-1360. https://doi.org/10.1002/humu.22378