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Hereditary Spastic Paraplegia Type 43 (SPG43) is Caused by Mutation in C19orf12

2013; Wiley; Volume: 34; Issue: 10 Linguagem: Inglês

10.1002/humu.22378

1098-1004

Guida Landouré, Peng-Peng Zhu, Charles Marques Lourenço, Janel O. Johnson, Camilo Toro, Katherine V. Bricceno, Carlo Rinaldi, Katherine G. Meilleur, Modibo Sangaré, Oumarou Diallo, Tyler Mark Pierson, Hiroyuki Ishiura, Shoji Tsuji, Nichole D. Hein, John K. Fink, Marion Stoll, Garth A. Nicholson, Michael Gonzalez, Fiorella Speziani, Alexandra Dürr, Giovanni Stévanin, 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,

Amyotrophic Lateral Sclerosis Research

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.