Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia

Abstract

Our findings reinforce the suggested specific function of IBA57 in mitochondrial [4Fe-4S] protein maturation and provide additional evidence for its role in human disease. The less decreased IBA57 protein level in this family explains phenotypic differences compared with the previously described lethal encephalomyopathy with no functional IBA57.

Mutation of the iron‐sulfur cluster assembly gene IBA57 causes fatal infantile leukodystrophy

“…Brain MRI predominantly showed frontoparietal polymicrogyria, hypoplasia of the corpus callosum and the medulla oblongata (Ajit Bolar et al 2013). In contrast, a phenotypically rather mild IBA57 hypomorphic mutation was recently reported in association with a slowly progressive childhood-onset neurological appearance characterized by symptoms of a rare form of spastic paraparesis, optic atrophy and peripheral neuropathy (SPOAN) (Lossos et al 2015). The IBA57 patient presented here showed an intermediate phenotype.…”

“…Glycine concentration is typically increased in CSF from the patients with NFU1-related disease and also was significantly increased in the patients with the neonatal form of IBA57 deficiency (Ajit Bolar et al 2013). In contrast, the patients presenting with the SPOAN phenotype had normal glycine concentration in CSF (Lossos et al 2015). In the patient described here, despite clinical and radiological signs of severe leukodystrophy, glycine was only mildly increased in blood and CSF, indicating that multiple mitochondrial dysfunction syndrome (MMDS) should be considered even in the absence of a severe glycine increase.…”

“…However, the E. coli protein contains a phenylalanine residue instead of arginine in this position thus precluding mechanistic predictions of how the R146W mutation may impair protein functionality. Nevertheless, it is possible to estimate the degree of functional impairment of IBA57_R146W from a comparison of the current case with two previously described mutations which do not impair protein function but rather severely decrease the IBA57 protein levels (Ajit Bolar et al 2013;Lossos et al 2015). In these cases, hardly any or approximately 10 % Fig.…”

“…By now, several gene defects have been identified to be causative for such phenotypes including defects in NFU1 (MIM 608100), BOLA3 (MIM 613183), and IBA57 (MIM 615316) (Cameron et al 2011;Navarro-Sastre et al 2011;Ajit Bolar et al 2013). Interestingly, mutation of IBA57 can lead to drastically different phenotypes varying from a severe clinical phenotype with fatal outcome in the neonatal period (Ajit Bolar et al 2013), to relatively mild neurological symptoms starting in childhood (Lossos et al 2015). Here, we report yet another phenotype associated with a new mutation in IBA57 mainly characterized by fatal infantile leukodystrophy.…”

Desvendando as bases moleculares da síndrome SPOAN: deleção em homozigose em região regulatória leva à superexpressão do gene KLC2

“…A extração de RNA de sangue total de pacientes (n = 7), heterozigotos (n = 7) e controles familiares wild-type (n = 6) foi realizada utilizando o kit PAXgene Blood RNA (Qiagen Até o presente momento foram descritas variantes patogênicas em três genes associados à HSP localizadas na mesma região ou próxima a região mapeada da síndrome SPOAN (FLRT1, BSCL2 e CAPN1), porém nenhuma variante patogênica no WES dos dois pacientes foi detectada em homozigose nesses genes (Gan-Or et al, 2016). Recentemente foi identificada uma família consanguínea de origem árabe composta por 12 pacientes apresentando paraplegia espástica, atrofia ótica e neuropatia periférica, que os autores denominaram essa doença de SPOAN-like (Lossos et al, 2015). Estudos de ligação mapearam a variante patogênica dessa família na região cromossômica 1q e o sequenciamento do exoma identificou a variante c.678A>G (p.Q226Q) no IBA57 como causadora da doença.…”