Premium
Hereditary Spastic Paraplegia Type 43 ( SPG 43) is Caused by Mutation in C19orf12
Author(s) -
Landouré Guida,
Zhu PengPeng,
Lourenço Charles M.,
Johnson Janel O.,
Toro Camilo,
Bricceno Katherine V.,
Rinaldi Carlo,
Meilleur Katherine G.,
Sangaré Modibo,
Diallo Oumarou,
Pierson Tyler M.,
Ishiura Hiroyuki,
Tsuji Shoji,
Hein Nichole,
Fink John K.,
Stoll Marion,
Nicholson Garth,
Gonzalez Michael A.,
Speziani Fiorella,
Dürr Alexandra,
Stevanin Giovanni,
Biesecker Leslie G.,
Accardi John,
Landis Dennis M. D.,
Gahl William A.,
Traynor Bryan J.,
Marques Wilson,
Züchner Stephan,
Blackstone Craig,
Fischbeck Kenneth H.,
Burnett Barrington G.
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22378
Subject(s) - missense mutation , biology , hereditary spastic paraplegia , mutation , genetics , haplotype , exome sequencing , gene , phenotype , allele
We report here the genetic basis for a form of progressive hereditary spastic paraplegia ( SPG 43) previously described in two M alian 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 B razilian 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 M alian SPG 43 subjects. Heterologous expression of these SPG 43 and NBIA variants resulted in similar alterations in the subcellular distribution of C19orf12. The SPG 43 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.