Partial loss of FITM2 function causes hereditary spastic paraplegia

Area of Science:

• Genetics
• Molecular Biology
• Neuroscience

Background:

• The FITM2 gene encodes fat-storage inducing transmembrane protein 2 (FIT2), an ER-localized lipid diphosphatase vital for ER homeostasis.
• Homozygous null mutations in FITM2 are previously associated with a syndrome of deafness and dystonia.
• Hereditary spastic paraplegia (HSP) is a group of inherited neurological disorders affecting the spinal cord.

Purpose of the Study:

• To investigate the genetic basis of hereditary spastic paraplegia (HSP) in two families.
• To identify novel mutations in the FITM2 gene associated with neurological disorders.
• To characterize the functional impact of identified FITM2 mutations.

Main Methods:

• Exome sequencing was performed on individuals from two families with HSP.
• Genetic analysis identified compound heterozygosity for FITM2 mutations in affected probands.
• Functional studies were conducted to assess the enzymatic activity and protein levels of the mutant FIT2.

Main Results:

• Two families with HSP were found to carry compound heterozygous mutations in FITM2.
• Affected individuals harbored one putative null allele and one G100R missense allele.
• The G100R mutation was identified as hypomorphic, reducing FIT2 protein levels to 20% and enzyme activity proportionally.

Conclusions:

• The G100R FITM2 mutation, leading to reduced enzyme activity, represents a newly recognized cause of hereditary spastic paraplegia (HSP).
• These findings expand the known clinical spectrum of FITM2-associated disorders beyond deafness and dystonia.
• FITM2 mutations are implicated in a broader range of neurological conditions, highlighting its importance in neuronal health.