title: Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12.
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.
authors.affiliation: 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.
authors.forename: Guida
authors.initials: G
authors.lastname: Landouré
authors.forename: Peng-Peng
authors.initials: PP
authors.lastname: Zhu
authors.forename: Charles M
authors.initials: CM
authors.lastname: Lourenço
authors.forename: Janel O
authors.initials: JO
authors.lastname: Johnson
authors.forename: Camilo
authors.initials: C
authors.lastname: Toro
authors.forename: Katherine V
authors.initials: KV
authors.lastname: Bricceno
authors.forename: Carlo
authors.initials: C
authors.lastname: Rinaldi
authors.forename: Katherine G
authors.initials: KG
authors.lastname: Meilleur
authors.forename: Modibo
authors.initials: M
authors.lastname: Sangaré
authors.forename: Oumarou
authors.initials: O
authors.lastname: Diallo
authors.forename: Tyler M
authors.initials: TM
authors.lastname: Pierson
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ishiura
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.forename: Nichole
authors.initials: N
authors.lastname: Hein
authors.forename: John K
authors.initials: JK
authors.lastname: Fink
authors.forename: Marion
authors.initials: M
authors.lastname: Stoll
authors.forename: Garth
authors.initials: G
authors.lastname: Nicholson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gonzalez
authors.forename: Fiorella
authors.initials: F
authors.lastname: Speziani
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dürr
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
authors.forename: John
authors.initials: J
authors.lastname: Accardi
authors.forename: Dennis M D
authors.initials: DM
authors.lastname: Landis
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.forename: Wilson
authors.initials: W
authors.lastname: Marques
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.forename: Craig
authors.initials: C
authors.lastname: Blackstone
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fischbeck
authors.forename: Barrington G
authors.initials: BG
authors.lastname: Burnett
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology; D006720:Homozygote; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D021381:Protein Transport; D016415:Sequence Alignment; D017384:Sequence Deletion; D015419:Spastic Paraplegia, Hereditary / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism
chemical_list: C568481:C19orf12 protein, human; D024101:Mitochondrial Proteins
keywords: C19orf12; NBIA; SPG43; hereditary spastic paraplegia