Identification and analyses of exonic and copy number variants in spastic paraplegia.
AP4B1
DDHD2
Exome
Pakistan
SPG11
Spasticity
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
21 Jun 2024
21 Jun 2024
Historique:
received:
25
03
2024
accepted:
14
06
2024
medline:
22
6
2024
pubmed:
22
6
2024
entrez:
21
6
2024
Statut:
epublish
Résumé
Hereditary spastic paraplegias are a diverse group of degenerative disorders that are clinically categorized as isolated; with involvement of lower limb spasticity, or symptomatic, where spastic paraplegia is complicated by further neurological features. We sought to identify the underlying genetic causes of these disorders in the participating patients. Three consanguineous families with multiple affected members were identified by visiting special schools in the Punjab Province. DNA was extracted from blood samples of the participants. Exome sequencing was performed for selected patients from the three families, and the data were filtered to identify rare homozygous variants. ExomeDepth was used for the delineation of the copy number variants. All patients had varying degrees of intellectual disabilities, poor speech development, spasticity, a wide-based gait or an inability to walk and hypertonia. In family RDHR07, a homozygous deletion involving multiple exons and introns of SPG11 (NC000015.9:g.44894055_449028del) was found and correlated with the phenotype of the patients who had spasticity and other complex movement disorders, but not those who exhibited ataxic or indeterminate symptoms as well. In families ANMD03 and RDFA06, a nonsense variant, c.985C > T;(p.Arg329Ter) in DDHD2 and a frameshift insertion‒deletion variant of AP4B1, c.965-967delACTinsC;p.(Tyr322SerfsTer14), were identified which were homozygous in the patients while the obligate carriers in the respective pedigrees were heterozygous. All variants were ultra-rare with none, or very few carriers identified in the public databases. The three loss of function variants are likely to cause nonsense-mediated decay of the respective transcripts. Our research adds to the genetic variability associated with the SPG11 and AP4B1 variants and emphasizes the genetic heterogeneity of hereditary spastic paraplegia.
Identifiants
pubmed: 38906889
doi: 10.1038/s41598-024-64922-8
pii: 10.1038/s41598-024-64922-8
doi:
Substances chimiques
SPG11 protein, human
0
Adaptor Protein Complex 4
0
Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
14331Subventions
Organisme : Higher Education Commision, Pakistan
ID : 2877
Informations de copyright
© 2024. The Author(s).
Références
Salinas, S., Proukakis, C., Crosby, A. & Warner, T. T. Hereditary spastic paraplegia: Clinical features and pathogenetic mechanisms. Lancet. Neurol. 7, 1127–1138. https://doi.org/10.1016/S1474-4422(08)70258-8 (2008).
doi: 10.1016/S1474-4422(08)70258-8
pubmed: 19007737
Erfanian Omidvar, M. et al. Genotype–phenotype associations in hereditary spastic paraplegia: A systematic review and meta-analysis on 13,570 patients. J. Neurol. 268, 2065–2082. https://doi.org/10.1007/s00415-019-09633-1 (2021).
doi: 10.1007/s00415-019-09633-1
pubmed: 31745725
Kara, E. et al. Genetic and phenotypic characterization of complex hereditary spastic paraplegia. Brain 139, 1904–1918. https://doi.org/10.1093/brain/aww111 (2016).
doi: 10.1093/brain/aww111
pubmed: 27217339
pmcid: 4939695
Anheim, M. et al. SPG11 spastic paraplegia: A new cause of juvenile parkinsonism. J. Neurol. 256, 104–108. https://doi.org/10.1007/s00415-009-0083-3 (2009).
doi: 10.1007/s00415-009-0083-3
pubmed: 19224311
Stevanin, G. Spastic paraplegia 11. GeneReviews® published by pubmed.ncbi.nlm.ncbi.gov Web (2019). https://pubmed.ncbi.nlm.nih.gov/20301389/ . Accessed 03 Jan 2024
Blackstone, C. Hereditary spastic paraplegia. Handb. Clin. Neurol. 148, 633–652 (2018).
doi: 10.1016/B978-0-444-64076-5.00041-7
pubmed: 29478605
Tesson, C., Koht, J. & Stevanin, G. Delving into the complexity of hereditary spastic paraplegias: How unexpected phenotypes and inheritance modes are revolutionizing their nosology. Hum. Genet. 134, 511–538. https://doi.org/10.1007/s00439-015-1536-7 (2015).
doi: 10.1007/s00439-015-1536-7
pubmed: 25758904
pmcid: 4424374
Ruano, L., Melo, C., Silva, M. C. & Coutinho, P. The global epidemiology of hereditary ataxia and spastic paraplegia: A systematic review of prevalence studies. Neuroepidemiology 42, 174–183. https://doi.org/10.1159/000358801 (2014).
doi: 10.1159/000358801
pubmed: 24603320
Iskender, C. et al. Turkish families with juvenile motor neuron disease broaden the phenotypic spectrum of SPG11. Neurol. Genet. https://doi.org/10.1212/NXG.0000000000000025 (2015).
doi: 10.1212/NXG.0000000000000025
pubmed: 27066562
pmcid: 4809458
Castro-Fernández, C. et al. Targeted NGS meets expert clinical characterization: efficient diagnosis of spastic paraplegia type 11. Appl. Transl. Genom. 5, 33–36. https://doi.org/10.1016/j.atg.2015.05.005 (2015).
doi: 10.1016/j.atg.2015.05.005
pubmed: 26937357
pmcid: 4745395
Stevanin, G. et al. Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration. Brain 131, 772–784. https://doi.org/10.1093/brain/awm293 (2008).
doi: 10.1093/brain/awm293
pubmed: 18079167
Tüysüz, B. et al. Autosomal recessive spastic tetraplegia caused by AP4M1 and AP4B1 gene mutation: Expansion of the facial and neuroimaging features. Am. J. Med. Genet. A 164, 1677–1685. https://doi.org/10.1002/ajmg.a.36514 (2014).
doi: 10.1002/ajmg.a.36514
Manzoor, H. et al. Novel homozygous variants in ATCAY, MCOLN1, and SACS in complex neurological disorders. Parkinsonism Relat. Disord. 51, 91–95. https://doi.org/10.1016/j.parkreldis.2018.02.005 (2018).
doi: 10.1016/j.parkreldis.2018.02.005
pubmed: 29449188
Adzhubei, I. A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249. https://doi.org/10.1038/nmeth0410-248 (2010).
doi: 10.1038/nmeth0410-248
pubmed: 20354512
pmcid: 2855889
Ioannidis, N. M. et al. REVEL: An ensemble method for predicting the pathogenicity of rare missense variants. Am. J. Hum. Genet. 99, 877–885. https://doi.org/10.1016/j.ajhg.2016.08.016 (2016).
doi: 10.1016/j.ajhg.2016.08.016
pubmed: 27666373
pmcid: 5065685
Kircher, M. et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46, 310–315. https://doi.org/10.1038/ng.2892 (2014).
doi: 10.1038/ng.2892
pubmed: 24487276
pmcid: 3992975
Ng, P. C. & Henikoff, S. Predicting deleterious amino acid substitutions. Genome Res. 11, 863–874. https://doi.org/10.1101/gr.176601 (2001).
doi: 10.1101/gr.176601
pubmed: 11337480
pmcid: 311071
Plagnol, V. et al. A robust model for read count data in exome sequencing experiments and implications for copy number variant calling. Bioinformatics 28, 2747–2754. https://doi.org/10.1093/bioinformatics/bts526 (2012).
doi: 10.1093/bioinformatics/bts526
pubmed: 22942019
pmcid: 3476336
Méreaux, J.-L. et al. Clinical and genetic spectra of 1550 index patients with hereditary spastic paraplegia. Brain 145, 1029–1037. https://doi.org/10.1093/brain/awab386 (2022).
doi: 10.1093/brain/awab386
pubmed: 34983064
Merten, M. Keeping it in the family: consanguineous marriage and genetic disorders, from Islamabad to Bradford. Br. Med. J. 365, l1851. https://doi.org/10.1136/bmj.l1851 (2019).
doi: 10.1136/bmj.l1851
Khan, T. N. et al. Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation. Eur. J. Hum. Genet. 22, 1180–1184. https://doi.org/10.1038/ejhg.2014.5 (2014).
doi: 10.1038/ejhg.2014.5
pubmed: 24473461
pmcid: 4169543
Gros-Louis, F. et al. An ALS2 gene mutation causes hereditary spastic paraplegia in a Pakistani kindred. Ann. Neurol. 53, 144–145. https://doi.org/10.1002/ana.10422 (2003).
doi: 10.1002/ana.10422
pubmed: 12509863
Lemire, G. et al. ABHD16A deficiency causes a complicated form of hereditary spastic paraplegia associated with intellectual disability and cerebral anomalies. Am. J. Hum. Genet. 108, 2017–2023. https://doi.org/10.1016/j.ajhg.2021.09.005 (2021).
doi: 10.1016/j.ajhg.2021.09.005
pubmed: 34587489
pmcid: 8546048
Tariq, H. & Naz, S. TFG associated hereditary spastic paraplegia: An addition to the phenotypic spectrum. Neurogenetics 18, 105–109. https://doi.org/10.1007/s10048-017-0508-6 (2017).
doi: 10.1007/s10048-017-0508-6
pubmed: 28124177
Deng, R. et al. AMFR dysfunction causes autosomal recessive spastic paraplegia in human that is amenable to statin treatment in a preclinical model. Acta Neuropathol. 146, 353–368. https://doi.org/10.1007/s00401-023-02579-9 (2023).
doi: 10.1007/s00401-023-02579-9
pubmed: 37119330
pmcid: 10328903
Arif, B. et al. A novel homozygous KY variant causing a complex neurological disorder. Eur. J. Med. Genet 63, 104031. https://doi.org/10.1016/j.ejmg.2020.104031 (2020).
doi: 10.1016/j.ejmg.2020.104031
pubmed: 32818658
pmcid: 7554104
Neuser, S. et al. Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability. Hum. Mutation 42, 762–776. https://doi.org/10.1002/humu.24206 (2021).
doi: 10.1002/humu.24206
Bibi, F. et al. Rare novel CYP2U1 and ZFYVE26 variants identified in two Pakistani families with spastic paraplegia. J. Neurol. Sci. 411, 116669. https://doi.org/10.1016/j.jns.2020.116669 (2020).
doi: 10.1016/j.jns.2020.116669
pubmed: 32006740
Pereira, M. C. et al. Alu elements mediate large SPG11 gene rearrangements: Further spatacsin mutations. Genet. Med. 14, 143–151. https://doi.org/10.1038/gim.2011.7 (2012).
doi: 10.1038/gim.2011.7
Crimella, C. et al. Point mutations and a large intragenic deletion in SPG11 in complicated spastic paraplegia without thin corpus callosum. J. Med. Genet. 46, 345–351. https://doi.org/10.1136/jmg.2008.063321 (2009).
doi: 10.1136/jmg.2008.063321
pubmed: 19196735
Zulfiqar, S. et al. Whole exome sequencing identifies novel variant underlying hereditary spastic paraplegia in consanguineous Pakistani families. J. Clin. Neurosci. 67, 19–23. https://doi.org/10.1016/j.jocn.2019.06.039 (2019).
doi: 10.1016/j.jocn.2019.06.039
pubmed: 31281085
Paisan-Ruiz, C., Dogu, O., Yilmaz, A., Houlden, H. & Singleton, A. SPG11 mutations are common in familial cases of complicated hereditary spastic paraplegia. Neurology 70, 1384–1389. https://doi.org/10.1212/01.wnl.0000294327.66106.3d (2008).
doi: 10.1212/01.wnl.0000294327.66106.3d
pubmed: 18337587
Dwianingsih, E. K. et al. A novel splicing silencer generated by DMD exon 45 deletion junction could explain upstream exon 44 skipping that modifies dystrophinopathy. J. Hum. Genet. 59, 423–429. https://doi.org/10.1038/jhg.2014.36 (2014).
doi: 10.1038/jhg.2014.36
pubmed: 24871807
Khajavi, M., Inoue, K. & Lupski, J. R. Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease. Eur. J. Hum. Genet. 14, 1074–1081. https://doi.org/10.1038/sj.ejhg.5201649 (2006).
doi: 10.1038/sj.ejhg.5201649
pubmed: 16757948
Martin, E. et al. Spatacsin and spastizin act in the same pathway required for proper spinal motor neuron axon outgrowth in zebrafish. Neurobiol. Dis. 48, 299–308. https://doi.org/10.1016/j.nbd.2012.07.003 (2012).
doi: 10.1016/j.nbd.2012.07.003
pubmed: 22801083
Pérez-Brangulí, F. et al. Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia. Hum. Mol. Genet. 23, 4859–4874. https://doi.org/10.1093/hmg/ddu200 (2014).
doi: 10.1093/hmg/ddu200
pubmed: 24794856
pmcid: 4140466
Schuurs-Hoeijmakers, J. H. et al. Mutations in DDHD2, encoding an intracellular phospholipase A1, cause a recessive form of complex hereditary spastic paraplegia. Am. J. Hum. Genet. 91, 1073–1081. https://doi.org/10.1016/j.ajhg.2012.10.017 (2012).
doi: 10.1016/j.ajhg.2012.10.017
pubmed: 23176823
pmcid: 3516595
Yahia, A. et al. Clinical phenotyping and genetic diagnosis of a large cohort of Sudanese families with hereditary spinocerebellar degenerations. Eur. J. Hum. Genet. https://doi.org/10.1038/s41431-023-01344-6 (2023).
doi: 10.1038/s41431-023-01344-6
pubmed: 37528188
Alrayes, N. et al. Truncating mutation in intracellular phospholipase A1 gene (DDHD2) in hereditary spastic paraplegia with intellectual disability (SPG54). BMC Res. Notes. 8, 1–5. https://doi.org/10.1186/s13104-015-1227-4 (2015).
doi: 10.1186/s13104-015-1227-4
Inloes, J. M. et al. The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase. Proc. Natl. Acad. Sci. 111, 14924–14929. https://doi.org/10.1073/pnas.1413706111 (2014).
doi: 10.1073/pnas.1413706111
pubmed: 25267624
pmcid: 4205627
Salayev, K. et al. AP4B1-associated hereditary spastic paraplegia: Expansion of clinico-genetic phenotype and geographic range. Eur. J. Med. Genet. 65, 104620. https://doi.org/10.1016/j.ejmg.2022.104620 (2022).
doi: 10.1016/j.ejmg.2022.104620
pubmed: 36122674
Matsuda, S. et al. Accumulation of AMPA receptors in autophagosomes in neuronal axons lacking adaptor protein AP-4. Neuron 57, 730–745. https://doi.org/10.1016/j.neuron.2008.02.012 (2008).
doi: 10.1016/j.neuron.2008.02.012
pubmed: 18341993
Abou Jamra, R. et al. Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. Am. J. Hum. Genet. 88, 788–795. https://doi.org/10.1016/j.ajhg.2011.04.019 (2011).
doi: 10.1016/j.ajhg.2011.04.019
pubmed: 21620353
pmcid: 3113253
Bauer, P. et al. Mutation in the AP4B1 gene cause hereditary spastic paraplegia type 47 (SPG47). Neurogenetics 13, 73–76. https://doi.org/10.1007/s10048-012-0314-0 (2012).
doi: 10.1007/s10048-012-0314-0
pubmed: 22290197
Ruan, W.-C. et al. Novel variants in AP4B1 cause spastic tetraplegia, moderate psychomotor development delay and febrile seizures in a Chinese patient: a case report. BMC Med. Genet. 21, 1–6. https://doi.org/10.1186/s12881-020-0988-3 (2020).
doi: 10.1186/s12881-020-0988-3