1Department of Medical Genetics and Biotechnology, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
2Department of Medical Biotechnology, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
3Department of Biotechnology and Molecular Medicine, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran
4Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
5Department of Medical Biotechnology, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad, Ira
6Clinical Research Development Center, Imam Khomeini and Mohammad Kermanshahi and Farabi Hospitals, Kermanshah University of Medical Sciences, Kermanshah, Iran
7Madar Medical Genetics Center, Khorramabad, Iran
چکیده
Spastic paraplegia 50 (SPG50) is a rare autosomal recessive disorder caused by mutations in the AP4M1 gene (OMIM 602296). It is characterized by spasticity, severe intellectual disability, and delayed or absent speech. The present study reported a case from consanguineous parents, where the affected child presented with intellectual disability, seizures, muscle weakness, and deep white matter hyperintensity. Whole exome sequencing (WES) of the proband identified a novel, homozygous frameshift variant, c.258delG:p.A87Pfs*44, in the AP4M1 gene, which was confirmed by Sanger sequencing. This variant is predicted to cause a large truncation of the protein, leading to a loss of function. Molecular modeling and docking analyses further revealed that the loss of a substantial protein segment disrupts proper intramolecular interactions. A review of the literature on Iranian families with SPG50 yielded few reports, consistent with the disease’s rarity. This study expanded the knowledge of the clinical and genetic features of SPG50 and underscored the importance of this variant for genetic diagnosis and counseling in affected families.
Francisco S, Lamacchia L, Turco A, Ermondi G, Caron G, Rossi Sebastiano M. Restoring adapter protein complex 4 function with small molecules: an in silico approach to spastic paraplegia 50. Protein Sci. 2025;34:e70006. doi: 10.1002/pro.70006. PubMed PMID: 39723768; PubMed Central PMCID: PMCPMC11670165.
Brent JR, Deng HX. Paving a way to treat spastic paraplegia 50. J Clin Invest. 2023;133. doi: 10.1172/JCI170226. PubMed PMID: 37183815; PubMed Central PMCID: PMCPMC10178831
Dowling JJ, Pirovolakis T, Devakandan K, Stosic A, Pidsadny M, Nigro E, et al. AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient. Nat Med. 2024;30:1882-7. doi: 10.1038/s41591-024-03078-4. PubMed PMID: 38942994; PubMed Central PMCID: PMCPMC11271397
Mattera R, De Pace R, Bonifacino JS. The role of AP-4 in cargo export from the trans-Golgi network and hereditary spastic paraplegia. Biochem Soc Trans. 2020;48:1877-88. doi: 10.1042/BST20190664. PubMed PMID: 33084855.
Boehm M, Aguilar RC, Bonifacino JS. Functional and physical interactions of the adaptor protein complex AP-4 with ADP-ribosylation factors (ARFs). EMBO J. 2001;20:6265-76. doi: 10.1093/emboj/20.22.6265. PubMed PMID: 11707398; PubMed Central PMCID: PMCPMC125733.
Donaldson JG, Honda A, Weigert R. Multiple activities for Arf1 at the Golgi complex. Biochim Biophys Acta. 2005;1744:364-73. doi: 10.1016/j.bbamcr.2005.03.001. PubMed PMID: 15979507.
American College of Medical Genetics and Genomics [Internet]. Practice Guidelines. C2025. Available from: www.acmg.net/ACMG/Medical-Genetics-Practice-Resources/Practice-Guidelines.aspx
de Souza PVS, de Rezende Pinto WBV, de Rezende Batistella GN, Bortholin T, Oliveira ASB. Hereditary Spastic Paraplegia: Clinical and Genetic Hallmarks. Cerebellum. 2017;16:525-51. doi: 10.1007/s12311-016-0803-z. PubMed PMID: 27271711.
Bettencourt C, Salpietro V, Efthymiou S, Chelban V, Hughes D, Pittman AM, et al. Genotype-phenotype correlations and expansion of the molecular spectrum of AP4M1-related hereditary spastic paraplegia. Orphanet J Rare Dis. 2017;12:172. doi: 10.1186/s13023-017-0721-2. PubMed PMID: 29096665; PubMed Central PMCID: PMCPMC5669016.
Rossi V, Banfield DK, Vacca M, Dietrich LE, Ungermann C, D’Esposito M, et al. Longins and their longin domains: regulated SNAREs and multifunctional SNARE regulators. Trends Biochem Sci. 2004;29:682-8. doi: 10.1016/j.tibs.2004.10.002. PubMed PMID: 15544955.
Becker A, Felici C, Lambert L, de Saint Martin A, Abi-Warde MT, Schaefer E, et al. Putative founder effect of Arg338* AP4M1 (SPG50) variant causing severe intellectual disability, epilepsy and spastic paraplegia: Report of three families. Clin Genet. 2023;103:346-51. doi: 10.1111/cge.14264. PubMed PMID: 36371792; PubMed Central PMCID: PMCPMC10108251.
Zare Ashrafi F, Akhtarkhavari T, Fattahi Z, Asadnezhad M, Beheshtian M, Arzhangi S, et al. Emerging Epidemiological Data on Rare Intellectual Disability Syndromes from Analyzing the Data of a Large Iranian Cohort. Arch Iran Med. 2023;26:186-97. doi: 10.34172/aim.2023.29. PubMed PMID: 38301078; PubMed Central PMCID: PMCPMC10685746.
Miryounesi M, Tabei SMB, Dianatpour M, Fardaei M, Ghafouri-Fard S. Report of three cases with hereditary spastic paraplegia and investigation of the mutations. Meta Gene. 2018;16:105-7. doi: 10.1016/j.mgene.2018.02.009.
