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

Hum Mutat. 2013 Oct;34(10):1357-60. doi: 10.1002/humu.22378.

Guida Landouré ¹, 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 Dürr, Giovanni Stevanin, Leslie G Biesecker, NIH Intramural Sequencing Center, John Accardi, Dennis M D Landis, William A Gahl, Bryan J Traynor, Wilson Marques Jr, Stephan Züchner, Craig Blackstone, Kenneth H Fischbeck, Barrington G Burnett

Affiliations

Affiliation

1 Service de Neurologie, Centre Hospitalier Universitaire du Point "G", Bamako, Mali; Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.

PMID: 23857908 DOI: 10.1002/humu.22378

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.

Keywords

C19orf12; NBIA; SPG43; hereditary spastic paraplegia.

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