PMID- 38050983
OWN - NLM
STAT- MEDLINE
DCOM- 20231207
LR  - 20231221
IS  - 1949-1042 (Electronic)
IS  - 1949-1034 (Print)
IS  - 1949-1034 (Linking)
VI  - 14
IP  - 1
DP  - 2023 Dec
TI  - The farnesyl transferase inhibitor (FTI) lonafarnib improves nuclear morphology 
      in ZMPSTE24-deficient fibroblasts from patients with the progeroid disorder 
      MAD-B.
PG  - 2288476
LID - 10.1080/19491034.2023.2288476 [doi]
LID - 2288476
AB  - Several related progeroid disorders are caused by defective post-translational 
      processing of prelamin A, the precursor of the nuclear scaffold protein lamin A, 
      encoded by LMNA. Prelamin A undergoes farnesylation and additional modifications 
      at its C-terminus. Subsequently, the farnesylated C-terminal segment is cleaved 
      off by the zinc metalloprotease ZMPSTE24. The premature aging disorder Hutchinson 
      Gilford progeria syndrome (HGPS) and a related progeroid disease, mandibuloacral 
      dysplasia (MAD-B), are caused by mutations in LMNA and ZMPSTE24, respectively, 
      that result in failure to process the lamin A precursor and accumulate 
      permanently farnesylated forms of prelamin A. The farnesyl transferase inhibitor 
      (FTI) lonafarnib is known to correct the aberrant nuclear morphology of HGPS 
      patient cells and improves lifespan in children with HGPS. Importantly, and in 
      contrast to a previous report, we show here that FTI treatment also improves the 
      aberrant nuclear phenotypes in MAD-B patient cells with mutations in ZMPSTE24 
      (P248L or L425P). As expected, lonafarnib does not correct nuclear defects for 
      cells with lamin A processing-proficient mutations. We also examine prelamin A 
      processing in fibroblasts from two individuals with a prevalent laminopathy 
      mutation LMNA-R644C. Despite the proximity of residue R644 to the prelamin A 
      cleavage site, neither R644C patient cell line shows a prelamin A processing 
      defect, and both have normal nuclear morphology. This work clarifies the prelamin 
      A processing status and role of FTIs in a variety of laminopathy patient cells 
      and supports the FDA-approved indication for the FTI Zokinvy for patients with 
      processing-deficient progeroid laminopathies, but not for patients with 
      processing-proficient laminopathies.
FAU - Odinammadu, Kamsi O
AU  - Odinammadu KO
AUID- ORCID: 0000-0003-0243-2395
AD  - Department of Cell Biology, The Johns Hopkins School of Medicine, Baltimore, MD, 
      USA.
FAU - Shilagardi, Khurts
AU  - Shilagardi K
AD  - Department of Cell Biology, The Johns Hopkins School of Medicine, Baltimore, MD, 
      USA.
FAU - Tuminelli, Kelsey
AU  - Tuminelli K
AD  - The Progeria Research Foundation, Peabody, MA, USA.
FAU - Judge, Daniel P
AU  - Judge DP
AD  - Department of Medicine, Medical University of South Carolina, Charleston, SC, 
      USA.
FAU - Gordon, Leslie B
AU  - Gordon LB
AD  - The Progeria Research Foundation, Peabody, MA, USA.
AD  - Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's 
      Hospital and Harvard Medical School, Boston, MA, USA.
AD  - Department of Pediatrics, Division of Genetics, Hasbro Children's Hospital and 
      Warren Alpert Medical School of Brown University, Providence, RI, USA.
FAU - Michaelis, Susan
AU  - Michaelis S
AD  - Department of Cell Biology, The Johns Hopkins School of Medicine, Baltimore, MD, 
      USA.
LA  - eng
GR  - R01 AG075047/AG/NIA NIH HHS/United States
GR  - R35 GM127073/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20231205
PL  - United States
TA  - Nucleus
JT  - Nucleus (Austin, Tex.)
JID - 101518322
RN  - IOW153004F (lonafarnib)
RN  - 0 (Lamin Type A)
RN  - 0 (Enzyme Inhibitors)
RN  - EC 2.- (Transferases)
RN  - EC 3.4.24.- (Metalloendopeptidases)
RN  - EC 3.4.24.84 (ZMPSTE24 protein, human)
RN  - 0 (Membrane Proteins)
SB  - IM
MH  - Child
MH  - Humans
MH  - Lamin Type A/genetics/metabolism
MH  - *Progeria/drug therapy/genetics/metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Mutation
MH  - *Lipodystrophy/metabolism
MH  - Fibroblasts/metabolism
MH  - Transferases/genetics/metabolism
MH  - Metalloendopeptidases/genetics/metabolism
MH  - Membrane Proteins/metabolism
PMC - PMC10730222
OTO - NOTNLM
OT  - Atypical progeroid syndrome
OT  - LMNA-C588R
OT  - LMNA-D325N
OT  - LMNA-E138K
OT  - LMNA-M540T
OT  - LMNA-R644C
OT  - ZMPSTE24-L425P
OT  - ZMPSTE24-P248L
OT  - mandibuloacral dysplasia-type B
OT  - prelamin A
COIS- No potential conflict of interest was reported by the authors.
EDAT- 2023/12/05 17:45
MHDA- 2023/12/07 12:42
PMCR- 2023/12/05
CRDT- 2023/12/05 08:13
PHST- 2023/12/07 12:42 [medline]
PHST- 2023/12/05 17:45 [pubmed]
PHST- 2023/12/05 08:13 [entrez]
PHST- 2023/12/05 00:00 [pmc-release]
AID - 2288476 [pii]
AID - 10.1080/19491034.2023.2288476 [doi]
PST - ppublish
SO  - Nucleus. 2023 Dec;14(1):2288476. doi: 10.1080/19491034.2023.2288476. Epub 2023 
      Dec 5.