Partial Loss of FITM2 Function Causes Hereditary Spastic Paraplegia

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 presenting with late childhood-onset, slowly progressive limb spasticity, cerebellar features, and relatively preserved cognition, consistent with a complex hereditary spastic paraplegia (HSP) phenotype 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.