title: Identification of a Large DNAJB2 Deletion in a Family with Spinal Muscular Atrophy and Parkinsonism.
abstract: In this study, we described the identification of a large DNAJB2 (HSJ1) deletion in a family with recessive spinal muscular atrophy and Parkinsonism. After performing homozygosity mapping and whole genome sequencing, we identified a 3.8 kb deletion, spanning the entire DnaJ domain of the HSJ1 protein, as the disease-segregating mutation. By performing functional assays, we showed that HSJ1b-related DnaJ domain deletion leads to loss of HSJ1b mRNA and protein levels, increased HSJ1a mRNA and protein expressions, increased cell death, protein aggregation, and enhanced autophagy. Given the role of HSJ1 proteins in the degradation of misfolded proteins, we speculated that enhanced autophagy might be promoted by the elevated HSJ1a expression seen in HSJ1b-deficient cells. We also observed a significant reduction in both tau and brain-derived neurotrophic factor levels, which may explain the dopaminergic deficits seen in one of the affected siblings. We concluded that HSJ1b deficiency leads to a complex neurological phenotype, possibly due to the accumulation of misfolded proteins, caused by the lack of the DnaJ domain activity. We thus expand the phenotypic and genotypic spectrums associated with DNAJB2 disease and suggest relevant disease-associated mechanisms.
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York City, New York.
authors.forename: Elena
authors.initials: E
authors.lastname: Sanchez
authors.affiliation: Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Darvish
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York City, New York.|The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York City, New York.
authors.forename: Roxana
authors.initials: R
authors.lastname: Mesias
authors.affiliation: Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Shaghyegh
authors.initials: S
authors.lastname: Taghavi
authors.affiliation: Genetics Research Centre, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Saghar Ghasemi
authors.initials: SG
authors.lastname: Firouzabadi
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York City, New York.|Department of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, New York City, New York.
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Walker
authors.affiliation: Department of Neurology, School of Medicine, Imam Khomeini Hospital and Iranian Center of Neurological Research, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Abbas
authors.initials: A
authors.lastname: Tafakhori
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York City, New York. coro.paisan-ruiz@mssm.edu.|Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York City, New York. coro.paisan-ruiz@mssm.edu.|Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York City, New York. coro.paisan-ruiz@mssm.edu.|Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York City, New York. coro.paisan-ruiz@mssm.edu.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York City, New York. coro.paisan-ruiz@mssm.edu.
authors.forename: Coro
authors.initials: C
authors.lastname: Paisán-Ruiz
mesh_terms: D000328:Adult; D001343:Autophagy; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002874:Chromosome Mapping; D015536:Down-Regulation; D005260:Female; D020022:Genetic Predisposition to Disease; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism*; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D016875:tau Proteins / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C121958:DNAJB2 protein, human; D050956:HSP40 Heat-Shock Proteins; C054369:MAPT protein, human; D018832:Molecular Chaperones; D016875:tau Proteins; C579455:BDNF protein, human
keywords: DNAJB2; DnaJ domain deletion; Parkinsonism; WGS; spinal muscular atrophy