title: A mutation abolishing the ZMPSTE24 cleavage site in prelamin A causes a progeroid disorder.
abstract: In 1994 in the Journal of Cell Science, Hennekes and Nigg reported that changing valine to arginine at the endoproteolytic cleavage site in chicken prelamin A abolishes its conversion to lamin A. The consequences of this mutation in an organism have remained unknown. We now report that the corresponding mutation in a human subject leads to accumulation of prelamin A and causes a progeroid disorder. Next generation sequencing of the subject and her parents' exomes identified a de novo mutation in the lamin A/C gene (LMNA) that resulted in a leucine to arginine amino acid substitution at residue 647 in prelamin A. The subject's fibroblasts accumulated prelamin A, a farnesylated protein, which led to an increased percentage of cultured cells with morphologically abnormal nuclei. Treatment with a protein farnesyltransferase inhibitor improved abnormal nuclear morphology. This case demonstrates that accumulation of prelamin A, independent of the loss of function of ZMPSTE24 metallopeptidase that catalyzes processing of prelamin A, can cause a progeroid disorder and that a cell biology assay could be used in precision medicine to identify a potential therapy.
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Yuexia
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Uta
authors.initials: U
authors.lastname: Lichter-Konecki
authors.affiliation: Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Kwame
authors.initials: K
authors.lastname: Anyane-Yeboa
authors.affiliation: Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Shaw
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Lu
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Östlund
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Shin
authors.affiliation: Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Lorraine N
authors.initials: LN
authors.lastname: Clark
authors.affiliation: Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Gregg G
authors.initials: GG
authors.lastname: Gundersen
authors.affiliation: Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Nagy
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA hjw14@columbia.edu.
authors.forename: Howard J
authors.identifier: 0000-0002-7063-7889
authors.initials: HJ
authors.lastname: Worman
mesh_terms: D000293:Adolescent; D019943:Amino Acid Substitution / Q000235:genetics; D005260:Female; D005347:Fibroblasts; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008666:Metalloendopeptidases / Q000235:genetics*; D009154:Mutation; D011371:Progeria / Q000235:genetics*; D017368:Protein Prenylation
chemical_list: D034904:Lamin Type A; D008565:Membrane Proteins; C090764:prelamin A; D008666:Metalloendopeptidases; C120130:ZMPSTE24 protein, human
keywords: Lamin; Mandibuloacral dysplasia; Nuclear envelope; Progeria; ZMPSTE24