Journal article
A De Novo Sequence Variant in Barrier-to-Autointegration Factor Is Associated with Dominant Motor Neuronopathy
Cells (Basel, Switzerland), Vol.12(6), 847
03/09/2023
DOI: 10.3390/cells12060847
PMCID: PMC10099716
PMID: 36980188
Abstract
Barrier-to-autointegration factor (BAF) is an essential component of the nuclear lamina. Encoded by
, this DNA binding protein contributes to the regulation of gene expression, cell cycle progression, and nuclear integrity. A rare recessive BAF variant, Ala12Thr, causes the premature aging syndrome, Néstor-Guillermo progeria syndrome (NGPS). Here, we report the first dominant pathogenic BAF variant, Gly16Arg, identified in a patient presenting with progressive neuromuscular weakness. Although disease variants carry nearby amino acid substitutions, cellular and biochemical properties are distinct. In contrast to NGPS, Gly16Arg patient fibroblasts show modest changes in nuclear lamina structure and increases in repressive marks associated with heterochromatin. Structural studies reveal that the Gly16Arg substitution introduces a salt bridge between BAF monomers, reducing the conformation ensemble available to BAF. We show that this structural change increases the double-stranded DNA binding affinity of BAF Gly16Arg. Together, our findings suggest that BAF Gly16Arg has an increased chromatin occupancy that leads to epigenetic changes and impacts nuclear functions. These observations provide a new example of how a missense mutation can change a protein conformational equilibrium to cause a dominant disease and extend our understanding of mechanisms by which BAF function impacts human health.
Details
- Title: Subtitle
- A De Novo Sequence Variant in Barrier-to-Autointegration Factor Is Associated with Dominant Motor Neuronopathy
- Creators
- Agathe Marcelot - Institut de Biologie Physico-ChimiqueFelipe Rodriguez-Tirado - Department of Biochemistry and Molecular Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAPhilippe Cuniasse - Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Saclay, 91198 Gif-sur-Yvette, FranceMei-Ling Joiner - Department of Biochemistry and Molecular Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USASimona Miron - Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Saclay, 91198 Gif-sur-Yvette, FranceAlexey A Soshnev - The University of Texas at San AntonioMimi Fang - University of IowaMiles A Pufall - University of IowaKatherine D Mathews - Wellstone Muscular Dystrophy Specialized Research Center, Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USASteven A Moore - Wellstone Muscular Dystrophy Specialized Research Center, Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USASophie Zinn-Justin - Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Saclay, 91198 Gif-sur-Yvette, FrancePamela K Geyer - Department of Biochemistry and Molecular Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Cells (Basel, Switzerland), Vol.12(6), 847
- DOI
- 10.3390/cells12060847
- PMID
- 36980188
- PMCID
- PMC10099716
- NLM abbreviation
- Cells
- eISSN
- 2073-4409
- Grant note
- ANR-10-INSB-05-01 / Agence Nationale de la Recherche CA234561 / NCR GM087341 / National Institute of Health P50NS053672 / NINDS NIH HHS Institutional funds / University of Texas San Antonio AG072397 / NIA NIH HHS
- Language
- English
- Date published
- 03/09/2023
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Biology; Obstetrics and Gynecology; Biochemistry and Molecular Biology; Neurology (Pediatrics)
- Record Identifier
- 9984381135402771
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