Found in 10 geographically diverse families worldwide
The diagnostic gap for rare neurodegenerative diseases is still considerable, despite continuous advances in gene identification. Many novel Mendelian genes have only been identified in a few families worldwide. Here we report the identification of an autosomal-dominant gene for hereditary spastic paraplegia (HSP) in 10 families that are of diverse geographic origin and whose affected members all carry unique truncating changes in a circumscript region of UBAP1 (ubiquitin-associated protein 1).
HSP is a neurodegenerative disease characterized by progressive lower-limb spasticity and weakness, as well as frequent bladder dysfunction. At least 40% of affected persons are currently undiagnosed after exome sequencing.
We identified pathological truncating variants in UBAP1 in affected persons from Iran, USA, Germany, Canada, Spain, and Bulgarian Roma. The genetic support ranges from linkage in the largest family (LOD = 8.3) to three confirmed de novo mutations. We show that mRNA in the fibroblasts of affected individuals escapes nonsense-mediated decay and thus leads to the expression of truncated proteins; in addition, concentrations of the full-length protein are reduced in comparison to those in controls. This suggests either a dominant-negative effect or haploinsufficiency. UBAP1 links endosomal trafficking to the ubiquitination machinery pathways that have been previously implicated in HSPs, and UBAP1 provides a bridge toward a more unified pathophysiology.
SOURCE: Am J Hum Genet. 2019 Apr 4;104(4):767-773. doi: 10.1016/j.ajhg.2019.03.001. Epub 2019 Mar 28. Copyright © 2019. Published by Elsevier Inc. PMID: 30929741
Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia.
Farazi Fard MA1, Rebelo AP2, Buglo E2, Nemati H3, Dastsooz H4, Gehweiler I5, Reich S5, Reichbauer J5, Quintáns B6, Ordóñez-Ugalde A6, Cortese A2, Courel S2, Abreu L2, Powell E7, Danzi MC2, Martuscelli NB8, Bis-Brewer DM2, Tao F2, Zarei F3, Habibzadeh P9, Yavarian M1, Modarresi F10, Silawi M1, Tabatabaei Z1, Yousefi M1, Farpour HR3, Kessler C5, Mangold E11, Kobeleva X12, Tournev I13, Chamova T14, Mueller AJ15, Haack TB15, Tarnopolsky M16, Gan-Or Z17, Rouleau GA17, Synofzik M5, Sobrido MJ6, Jordanova A18, Schüle R5, Zuchner S2, Faghihi MA19.
1 Persian BayanGene Research and Training Center, Shiraz, Iran.
2 John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL 33136, USA.
3 Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
4 Persian BayanGene Research and Training Center, Shiraz, Iran; Italian Institute for Genomic Medicine, University of Turin, Turin 10126 Italy.
5 Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen 72076, Germany; German Center for Neurodegenerative Diseases, Tübingen 72706, Germany.
6 Neurogenetics Group Instituto de Investigación Sanitaria, Hospital Clínico de Santiago, Santiago de Compostela 15706, Spain.
7 The Genesis Project foundation Miami, FL 33136, USA.
8 Department of Biology University of Miami, Miami, FL 33136, USA.
9 Persian BayanGene Research and Training Center, Shiraz, Iran; Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran.
10 Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136 USA.
11 Institute of Human Genetics University of Bonn, Bonn 53113, Germany.
12 Department of Neurology, University of Bonn, Bonn 53113, Germany.
13 Department of Neurology, Medical University-Sofia, Sofia 1431, Bulgaria; Department of Cognitive Science and Psychology, New Bulgarian University, Sofia 1618, Bulgaria.
14 Department of Neurology, Medical University-Sofia, Sofia 1431, Bulgaria.
15 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen 72706, Germany; Centre for Rare Diseases, University of Tübingen, Tübingen 72706, Germany.
16 Department of Pediatrics, McMaster University, Hamilton, Ontario L8S 4L8, Canada.
17 Department of Human Genetics, McGill University, Montréal, Quebec H3A 0G4, Canada; Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
18 Molecular Neurogenomics Group, VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Antwerpen 2610, Belgium; Molecular Medicine Center Department of Medical Chemistry and Biochemistry, Medical University-Sofia, Sofia 1431, Bulgaria.
19 Persian BayanGene Research and Training Center, Shiraz, Iran; Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136 USA. Electronic address: [email protected]
SPG80 HSP also found in unrelated Chinese families
Hereditary spastic paraplegias refer to a heterogeneous group of neurodegenerative disorders resulting from degeneration of the corticospinal tract. Clinical characterization of patients with hereditary spastic paraplegias represents progressive spasticity, exaggerated reflexes and muscular weakness. Here, to expand on the increasingly broad pools of previously unknown hereditary spastic paraplegia causative genes and subtypes, we performed whole exome sequencing for six affected and two unaffected individuals from two unrelated Chinese families with an autosomal dominant hereditary spastic paraplegia and lacking mutations in known hereditary spastic paraplegia implicated genes.
Exome sequencing revealed two stop-gain mutations, c.247_248insGTGAATTC (p.I83Sfs*11) and c.526G>T (p.E176*), in the ubiquitin-associated protein 1 (UBAP1) gene, which co-segregated with the spastic paraplegia. We also identified two UBAP1 frameshift mutations, c.324_325delCA (p.H108Qfs*10) and c.425_426delAG (p.K143Sfs*15), in two unrelated families from an additional 38 Chinese pedigrees with autosomal dominant hereditary spastic paraplegias and lacking mutations in known causative genes.
The primary disease presentation was a pure lower limb predominant spastic paraplegia. In vivo downregulation of UBAP1 in zebrafish causes abnormal organismal morphology, inhibited motor neuron outgrowth, decreased mobility, and shorter lifespan. UBAP1 is incorporated into endosomal sorting complexes required for transport complex I and binds ubiquitin to function in endosome sorting. Patient-derived truncated form(s) of UBAP1 cause aberrant endosome clustering, pronounced endosome enlargement, and cytoplasmic accumulation of ubiquitinated proteins in HeLa cells and wild-type mouse cortical neuron cultures.
Biochemical and immunocytochemical experiments in cultured cortical neurons derived from transgenic UBAP1flox mice confirmed that disruption of UBAP1 leads to dysregulation of both early endosome processing and ubiquitinated protein sorting. Strikingly, deletion of UBAP1 promotes neurodegeneration, potentially mediated by apoptosis. Our study provides genetic and biochemical evidence that mutations in UBAP1 can cause pure autosomal dominant spastic paraplegia.
SOURCE: Brain. 2019 Aug 1;142(8):2238-2252. doi: 10.1093/brain/awz158. © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. PMID: 31203368
Stop-gain mutations in UBAP1 cause pure autosomal-dominant spastic paraplegia.
1 Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China.
2 Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou 350005, China.
3 Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
4 Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL 60201, USA.
5 Department of Anatomy, Histology and Embryology, Shanghai Medical College, Fudan University, Shanghai 200032, China.