01At a glance
02What it is
Children with HGPS age ~8x faster than normal. Growth failure, hair loss, skin changes, and premature atherosclerosis lead to death from heart attack or stroke at a median age of ~14.5 years.
03What goes wrong
Gain-of-function / toxic protein. The c.1824C>T (p.Gly608Gly) variant activates a cryptic splice donor in LMNA exon 11, causing an in-frame deletion of 50 codons of prelamin A. The resulting isoform 'progerin' retains its C-terminal CAAX box and is farnesylated, but lacks the ZMPSTE24 cleavage site (which lies within the deleted region), so it remains permanently farnesylated and anchors at the nuclear lamina, disrupting nuclear architecture.
04How NIGHTINGALE routes it
Recommended modality: degrader (selective progerin) + farnesyltransferase inhibitor (approved)
Progerin is a toxic gain-of-function protein; selective degradation is mechanistically appropriate (in principle). NOTE: the approved drug lonafarnib is NOT an AUTOTAC — see treatment.
05Treatment today
Lonafarnib (Zokinvy)
2020-11-20 (Eiger BioPharmaceuticals)Inhibits farnesyltransferase, blocking the farnesylation step required for progerin to anchor at the nuclear envelope — thereby reducing toxic progerin accumulation. It does NOT bind LMNA/progerin directly.
06In the pipeline
- CRISPR base editing to correct the c.1824C>T splice variant (preclinical)
- Progerin-targeting PROTAC/AUTOTAC degraders (investigational, not yet clinical)
Combination studied: Lonafarnib + pravastatin + zoledronic acid (farnesylation inhibitor triple, Circulation 2016, PMID 27400896)
Key reference: PMID 27400896 · PubMed
07Verification
Every line below is the registry's own verification record — what was checked, against which source, and what is still open.
- uniprot: P02545 = LMNA (Prelamin-A/C), 664 aa — VERIFIED via UniProt REST API (live)
- gene mutation: c.1824C>T (p.Gly608=) — VERIFIED via ClinVar RCV000015593 (live)
- inheritance: Autosomal dominant de novo — VERIFIED via ClinVar + Orphanet API (live)
- orpha code: 740 = Hutchinson-Gilford progeria syndrome (Active) — VERIFIED via Orphanet API (live, 2026-07-02)
- drug mw: 638.8 Da, CID 148195, C27H31Br2ClN4O2 — VERIFIED via PubChem REST API (live)
- fda date: 2020-11-20 (NDA 213969, Eiger BioPharmaceuticals) — VERIFIED via FDA accessdata (live)
08Sources
| Fact | Source | Accession | Retrieved |
|---|---|---|---|
| Gene/protein identity | UniProt | P02545 (LMNA, Prelamin-A/C, 664 aa) | 2026-10-04 |
| Disease classification & definition | Orphanet | ORPHAcode 740 (Hutchinson-Gilford progeria syndrome) | 2026-10-04 |
| Causative mutation | ClinVar | RCV000015593 (NM_170707.4(LMNA):c.1824C>T p.Gly608=) | 2026-10-04 |
| Drug molecular weight | PubChem | CID 148195 (lonafarnib, 638.8 Da, C27H31Br2ClN4O2) | 2026-10-04 |
| FDA approval | FDA | NDA 213969 (Zokinvy/lonafarnib, 2020-11-20) | 2026-10-04 |
| Triple farnesylation-inhibitor therapy | Circulation (Gordon et al. 2016) | PMID 27400896 | 2026-10-04 |
Corrections carried into registry v2 (5)
- FIXED: inheritance was wrongly listed 'autosomal recessive / X-linked HPRT1' — correct is autosomal dominant de novo c.1824C>T (now double-confirmed via ClinVar + Orphanet).
- FIXED: lonafarnib was described as 'binding LMNA' — correct mechanism is farnesyltransferase inhibition (blocks progerin farnesylation).
- FIXED: 'Lonafarnib-AUTOTAC' conflated the approved farnesyltransferase inhibitor with a hypothetical autophagy degrader — the two are now separated.
- FIXED (double-check 2026-10-04): protein name corrected to 'Prelamin-A/C'; mechanism made precise (50-codon deletion, retained farnesylation, missing ZMPSTE24 site).
- VERIFIED (2026-10-04): ORPHAcode 740 confirmed live via Orphanet API. Prevalence/median-age still UNVERIFIED (Orphanet nomenclature API does not carry epidemiology figures).