Hereditary Spastic Paraplegia Type 43 (SPG43) is Caused by Mutation inC19orf12

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.

A novel mutation in KIF5A in a Malian family with spastic paraplegia and sensory loss

“…While dominant HSPs are prevalent in northern Europe and North America, recessive cases are mostly seen in North Africa, the Middle East, and Mediterranean regions 1, 2, 3. Although prevalent in other populations, genetically confirmed HSP cases in sub‐Saharan Africa in general, and West Africa in particular, are rare 4. Here, we report here a novel mutation in an HSP gene in a previously unstudied population in Mali.…”

Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms

“…SPG43, previously described in two Malian sisters (Meilleur et al, 2010), is caused by missense mutation or nucleotides deletion in C19orf12 (Landouré et al, 2013). Mutations in the same gene are also reported in a series of patients with NBIA (Hartig et al, 2011).…”

“…In addition to Silver syndrome, patients may have bilateral optic atrophy or axonal sensory motor polyneuropathy and MRI evidenced iron deposits in the globus pallidus of Brazilian patients, linking with SPG43 and NBIA (Landouré et al, 2013).…”

Analysis of the C19orf12 and WDR45 genes in patients with neurodegeneration with brain iron accumulation

“…MPAN-3 showed the homozygous recurrent mutation p.Gly69Arg [2,5,6,14]. She presented at age 10 with gait impairment and repeated falls due to spasticity of the lower limbs.…”

“…The wide phenotypic spectrum of NBIA, as well as parallels to other disorders such as Parkinsonism or spastic paraplegia [1,2], can make diagnosis difficult and, in some cases, the underlying genetic mechanisms still remain unknown.…”