Partial loss of FITM2 function causes hereditary spastic paraplegia
Salazar-Villacorta, A.; Bond, L. M.; Kim, L.; Anagnostopoulou, K.; Scardamaglia, A.; Filippakopoulou, E.; Ververi, A.; Efthymiou, S.; Dinopoulos, A.; Murphy, D.; Karadima, G.; Koutsis, G.; Kaliakatsos, M.; Houlden, H.; C. Walther, T.; Farese, R. V.
Show abstract
FITM2 encodes fat-storage inducing transmembrane protein 2 (FIT2), a lipid diphosphatase in the ER that cleaves acyl-CoAs and is crucial for ER homeostasis. In humans, homozygous null mutations in FITM2 are associated with a syndrome characterized by deafness and dystonia. Here, we report two families with hereditary spastic paraplegia (HSP) in whom exome sequencing revealed compound heterozygosity for FITM2 mutations. In each family, the affected probands carry one putative null allele and one G100R missense allele. Functional analyses demonstrated that the G100R allele is hypomorphic, with FIT2 protein levels reduced to 20% of wild type, leading to proportionately decreased enzyme activity. The occurrence of similar HSP disease phenotypes and the same hypomorphic mutation in these families suggests that the G100R mutation and its associated reduced enzyme activity represent a newly recognized clinical manifestation of FITM2 mutations, expanding the spectrum of conditions associated with this gene.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Loss of C2orf69 defines a fatal auto-inflammatory mitochondriopathy in Humans and Zebrafish 97%
- De novo EIF2AK1 and EIF2AK2 variants are associated with developmental delay, leukoencephalopathy, and neurologic decompensation 96%
- Missense variants affecting the actin-binding domains of PLS3 cause X-linked congenital diaphragmatic hernia and body wall defects 95%
Similar papers in this journal
- Unveiling the crucial neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies 96%
- Brain development mutations in the β-tubulin TUBB result in defective ciliogenesis 95%
- Specific heterozygous frameshift variants in hnRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy 95%
Similar papers in this journal
- Full-length isoform sequencing for resolving the molecular basis of Charcot-Marie-Tooth 2A 94%
- Immune cell mitochondrial phenotypes are largely preserved in mitochondrial diseases and do not reflect disease severity 92%
- Association of genetic variation at the GJA5/ACP6 locus with motor progression in Parkinson’s 91%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.