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Peer-reviewedCC BYHuman mutation

Partial Loss of FITM2 Function Causes Hereditary Spastic Paraplegia.

  • Ainara Salazar-Villacorta1,2,3
  • Laura M Bond4,5
  • Leehyeon Kim6
  • Katherine Anagnostopoulou7
  • Annarita Scardamaglia1
  • Eugenia Filippakopoulou8
  • Athina Ververi9
  • Stephanie Efthymiou1
  • Argirios Dinopoulos10
  • David Murphy11
  • Chrisoula Kartanou8
  • Dimitrios M Vrachnos12
9 more authors
  • Theodoros Loupis13
  • Perilikis Makrythanasis14,15,16
  • Leonidas Stefanis17
  • Georgia Karadima8
  • Georgios Koutsis8
  • Marios Kaliakatsos2,3
  • Henry Houlden1
  • Tobias C Walther6,18
  • Robert V Farese6
18 affiliations
  1. 1Neuromuscular Disorders Department UCL Queen Square Institute of Neurology London UK.
  2. 2Department of Neurology Great Ormond Street Hospital for Children London UK nhs.uk.
  3. 3Developmental Neurosciences Department UCL GOS Institute of Child Health London UK.
  4. 4Department of Molecular Metabolism Harvard T.H. Chan School of Public Health Boston USA harvard.edu.
  5. 5Department of Cell Biology Harvard Medical School Boston USA harvard.edu.
  6. 6Cell Biology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York USA mskcc.org.
  7. 7Department of Molecular Genetics Genomedica Piraeus Greece.
  8. 8Neurogenetics Unit First Department of Neurology School of Medicine National and Kapodistrian University of Athens Eginition University Hospital Athens Greece uoa.gr.
  9. 9Department of Genetics for Rare Diseases Papageorgiou General Hospital Thessaloniki Greece papageorgiou-hospital.gr.
  10. 10Third Department of Pediatrics University General Hospital "Attikon" Athens Greece attikonhospital.gr.
  11. 11Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology London UK.
  12. 12Biomedical Research Foundation of the Academy of Athens (BRFAA) Athens Greece.
  13. 13Hematology Research Lab Clinical Experimental and Translational Research Center Biomedical Research Foundation Academy of Athens Athens Greece academyofathens.gr.
  14. 14Laboratory of Medical Genetics Medical School National and Kapodistrian University of Athens Athens Greece uoa.gr.
  15. 15Greek Genome Center Biomedical Research Foundation of the Academy of Athens Athens Greece academyofathens.gr.
  16. 16Department of Genetic Medicine and Development Medical School University of Geneva Geneva Switzerland unige.ch.
  17. 171st Department of Neurology Eginitio Hospital National and Kapodistrian University of Athens Athens Greece uoa.gr.
  18. 18Howard Hughes Medical Institute New York USA hhmi.org.
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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 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.

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Cite

BibTeXRIS
BibTeX
@article{salazarvillacorta2026partial,
  title = {{Partial Loss of FITM2 Function Causes Hereditary Spastic Paraplegia.}},
  author = {Ainara Salazar-Villacorta and Laura M Bond and Leehyeon Kim and Katherine Anagnostopoulou and Annarita Scardamaglia and Eugenia Filippakopoulou and Athina Ververi and Stephanie Efthymiou and Argirios Dinopoulos and David Murphy and Chrisoula Kartanou and Dimitrios M Vrachnos and Theodoros Loupis and Perilikis Makrythanasis and Leonidas Stefanis and Georgia Karadima and Georgios Koutsis and Marios Kaliakatsos and Henry Houlden and Tobias C Walther and Robert V Farese},
  journal = {Human mutation},
  year = {2026},
  month = oct,
  doi = {10.1155/humu/5893503},
  url = {https://europepmc.org/article/MED/42920715},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Partial Loss of FITM2 Function Causes Hereditary Spastic Paraplegia.
AU  - Ainara Salazar-Villacorta
AU  - Laura M Bond
AU  - Leehyeon Kim
AU  - Katherine Anagnostopoulou
AU  - Annarita Scardamaglia
AU  - Eugenia Filippakopoulou
AU  - Athina Ververi
AU  - Stephanie Efthymiou
AU  - Argirios Dinopoulos
AU  - David Murphy
AU  - Chrisoula Kartanou
AU  - Dimitrios M Vrachnos
AU  - Theodoros Loupis
AU  - Perilikis Makrythanasis
AU  - Leonidas Stefanis
AU  - Georgia Karadima
AU  - Georgios Koutsis
AU  - Marios Kaliakatsos
AU  - Henry Houlden
AU  - Tobias C Walther
AU  - Robert V Farese
PY  - 2026
DA  - 2026/10/22
JO  - Human mutation
DO  - 10.1155/humu/5893503
UR  - https://europepmc.org/article/MED/42920715
AB  - 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.
SN  - 1059-7794
SN  - 1098-1004
ER  -