Hutchinson-Gilford Progeria Syndrome

Mendelian MONDO:0008310 Pathograph 11 Show in embeddings browser hereditary disease premature aging syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare, fatal, segmental premature-aging disorder caused by a recurrent de novo synonymous LMNA point mutation (classically c.1824C>T, p.Gly608Gly) that activates a cryptic splice donor site in exon 11, producing a farnesylated, internally-truncated lamin A protein called progerin. Progerin accumulates at the nuclear lamina and disrupts nuclear architecture, driving a convergent set of aging hallmarks - genomic instability and impaired DNA repair, telomere shortening, heterochromatin loss/epigenetic dysregulation, progerin proteotoxicity, cellular senescence, and an ATM-NF-kB systemic inflammatory response. Children develop failure to thrive, alopecia, sclerodermatous skin, joint contractures, bone abnormalities, and, most consequentially, rapidly accelerated atherosclerosis, usually dying in their early teens of myocardial infarction or stroke. As the archetypal accelerated-aging disease, HGPS is a worked multi-hallmark conformer for the hallmarks-of-aging mechanism modules and a proving ground for geroprotective interventions (the farnesyltransferase inhibitor lonafarnib; rapamycin-induced autophagic progerin clearance).

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8
Pathophys.
5
Phenotypes
11
Pathograph
1
Genes
2
Medical Actions
⚙

Pathophysiology

8
LMNA cryptic splice activation and progerin accumulation
A recurrent de novo LMNA point mutation activates a cryptic splice donor site in exon 11, producing progerin, a permanently farnesylated, internally-truncated lamin A. Progerin accumulates at the nuclear lamina and adversely affects the integrity of the nuclear scaffold, the primary molecular lesion from which the downstream aging hallmarks emanate.
LMNA hgnc:6636
Downstream
Genomic instability and impaired DNA repair
Telomere shortening
Heterochromatin loss and epigenetic dysregulation
Progerin proteotoxic aggregation
Cellular senescence
ATM-NF-kB systemic inflammation
Vascular smooth muscle cell loss and accelerated atherosclerosis
Show evidence (2 references)
PMID:12714972 SUPPORT Human Clinical
"Here, we present evidence of mutations in lamin A (LMNA) as the cause of this disorder."
Identifies LMNA mutation as the cause of HGPS, the primary molecular lesion modeled here. Evidence source is HUMAN_CLINICAL (patient genetic study).
PMID:23012407 SUPPORT Human Clinical
"Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA that produces the farnesylated aberrant lamin A protein, progerin."
Establishes the LMNA mutation and farnesylated progerin as the cause of HGPS. Evidence source is HUMAN_CLINICAL (clinical trial report describing the disease).
Genomic instability and impaired DNA repair
Progerin accumulation compromises genome maintenance: HGPS and related laminopathy cells show defective DNA repair, accumulating DNA damage, and chromosomal aberrations, a genome-instability phenotype that limits cellular proliferative capacity.
DNA Repair GO:0006281 ↓ DECREASED DNA Damage Response GO:0006974 ↑ INCREASED
Downstream
Vascular smooth muscle cell loss and accelerated atherosclerosis
Show evidence (2 references)
PMID:15980864 SUPPORT In Vitro
"We found that Zmpste24-deficient mouse embryonic fibroblasts (MEFs) show increased DNA damage and chromosome aberrations and are more sensitive to"
Prelamin-A-accumulating (Zmpste24-deficient) fibroblasts show increased DNA damage and chromosome aberrations, supporting genomic instability in the laminopathy/HGPS mechanism. Evidence source is IN_VITRO (cultured mouse embryonic fibroblasts).
PMID:27374873 SUPPORT Other
"progerin accumulation elicits nuclear morphological abnormalities, misregulated gene expression, defects in DNA repair, telomere shortening, and genomic instability, all of which limit cellular proliferative capacity."
Review enumerating defects in DNA repair and genomic instability among the consequences of progerin accumulation. Evidence source is OTHER (review).
Telomere shortening
Progerin accumulation accelerates telomere shortening in HGPS cells, contributing to the loss of proliferative capacity and premature replicative senescence characteristic of the disease.
Telomere Maintenance GO:0000723 ↓ DECREASED
Downstream
Cellular senescence
Show evidence (1 reference)
PMID:27374873 SUPPORT Other
"progerin accumulation elicits nuclear morphological abnormalities, misregulated gene expression, defects in DNA repair, telomere shortening, and genomic instability, all of which limit cellular proliferative capacity."
Review identifying telomere shortening as a direct consequence of progerin accumulation, supporting the telomere-attrition conformance. Evidence source is OTHER (review).
Heterochromatin loss and epigenetic dysregulation
Cells expressing mutant lamin A show abnormally shaped nuclei with a loss of heterochromatin and progressive alterations of epigenetic control, including loss of the facultative-heterochromatin mark H3K27me3 and constitutive marks, producing misregulated gene expression.
Chromatin Organization GO:0006325 ⚠ ABNORMAL
Show evidence (2 references)
PMID:16738054 SUPPORT In Vitro
"Nuclei in cells expressing LADelta50 are abnormally shaped and display a loss of heterochromatin."
Demonstrates heterochromatin loss in HGPS (LADelta50/progerin) cells, the epigenetic alteration modeled here. Evidence source is IN_VITRO (patient and expression cell systems).
PMID:16738054 SUPPORT In Vitro
"In cells from a female HGPS patient, histone H3 trimethylated on lysine 27 (H3K27me3), a mark for facultative heterochromatin, is lost on the inactive X chromosome (Xi)."
Documents loss of the H3K27me3 heterochromatin mark in HGPS patient cells, supporting epigenetic dysregulation. Evidence source is IN_VITRO (patient cells).
Progerin proteotoxic aggregation
Farnesylated progerin resists normal turnover and forms insoluble aggregates that adversely affect the nuclear scaffold and cause nuclear blebbing; enhancing autophagic clearance of these aggregates is therapeutically beneficial.
Downstream
Cellular senescence
Show evidence (1 reference)
PMID:21715679 SUPPORT In Vitro
"Rapamycin also decreased the formation of insoluble progerin aggregates and induced clearance through autophagic mechanisms in normal fibroblasts."
Establishes insoluble progerin aggregates cleared by autophagy, supporting the proteostasis/aggregation conformance. Evidence source is IN_VITRO (fibroblast cultures).
Cellular senescence
HGPS fibroblasts undergo premature cellular senescence; progerin is likewise produced in senescent cells and cells from old individuals, linking HGPS to physiological aging. Rapamycin delays the onset of this senescence in HGPS cells.
Fibroblast CL:0000057
Cellular Senescence GO:0090398 ↑ INCREASED
Downstream
Vascular smooth muscle cell loss and accelerated atherosclerosis
Show evidence (2 references)
PMID:21715679 SUPPORT In Vitro
"Treatment with rapamycin abolished nuclear blebbing, delayed the onset of cellular senescence, and enhanced the degradation of progerin in HGPS cells."
Shows premature cellular senescence in HGPS cells (delayed by rapamycin), supporting the senescence conformance. Evidence source is IN_VITRO (HGPS fibroblasts).
PMID:27374873 SUPPORT Other
"progerin is also produced in senescent cells and cells from old individuals, suggesting that progerin accumulation might be a factor in physiological aging."
Links progerin to physiological cellular senescence and aging. Evidence source is OTHER (review).
ATM-NF-kB systemic inflammation
Accumulation of aberrant prelamin A / progerin at the nuclear lamina triggers an ATM- and NEMO-dependent signaling pathway that activates NF-kB and drives secretion of proinflammatory cytokines, linking accelerated aging to a chronic systemic inflammatory response (inflammaging).
Inflammatory Response GO:0006954 ↑ INCREASED
Downstream
Vascular smooth muscle cell loss and accelerated atherosclerosis
Show evidence (1 reference)
PMID:23019125 SUPPORT Model Organism
"Here we report that the accumulation of prelamin A isoforms at the nuclear lamina triggers an ATM- and NEMO-dependent signaling pathway that leads to NF-κB activation and secretion of high levels of proinflammatory cytokines in two different mouse models of accelerated aging (Zmpste24(-/-) and..."
Establishes ATM-NF-kB-driven systemic proinflammatory cytokine secretion in progeroid (Lmna) mouse models, supporting the inflammaging conformance. Evidence source is MODEL_ORGANISM (mouse models of accelerated aging).
Vascular smooth muscle cell loss and accelerated atherosclerosis
The convergent hallmark burden - genomic instability, senescence, and inflammation - is especially destructive in the vasculature, where it drives progressive loss of vascular smooth muscle cells and rapidly accelerated atherosclerosis. This cardiovascular disease is the principal cause of death in HGPS, typically from myocardial infarction or stroke in the early teens.
vascular smooth muscle cell CL:0000359
Show evidence (1 reference)
PMID:23012407 SUPPORT Human Clinical
"This multisystem disorder causes failure to thrive and accelerated atherosclerosis leading to early death."
States accelerated atherosclerosis as the cause of early death in HGPS, the consequence modeled here. Evidence source is HUMAN_CLINICAL (clinical trial report).
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hutchinson-Gilford Progeria Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

5
Cardiovascular 1
Accelerated coronary atherosclerosis Coronary artery atherosclerosis HP:0001677
Show evidence (1 reference)
PMID:18256394 SUPPORT Human Clinical
"Hutchinson-Gilford progeria syndrome is a rare, sporadic, autosomal dominant syndrome that involves premature aging, generally leading to death at approximately 13 years of age due to myocardial infarction or stroke."
Cardiovascular disease (myocardial infarction or stroke) from accelerated atherosclerosis is the leading cause of death, supporting this phenotype.
Integument 1
Alopecia Alopecia HP:0001596
Show evidence (1 reference)
PMID:18256394 SUPPORT Human Clinical
"Clinical investigations confirmed sclerotic skin, joint contractures, bone abnormalities, alopecia, and growth impairment in all 15 patients; cardiovascular and central nervous system sequelae were also documented."
Alopecia was confirmed in all patients in the NIH HGPS cohort.
Musculoskeletal 1
Joint contractures Joint contracture HP:0034392
Show evidence (1 reference)
PMID:18256394 SUPPORT Human Clinical
"Clinical investigations confirmed sclerotic skin, joint contractures, bone abnormalities, alopecia, and growth impairment in all 15 patients; cardiovascular and central nervous system sequelae were also documented."
Joint contractures were confirmed in all patients in the NIH HGPS cohort.
Growth 1
Failure to thrive Failure to thrive HP:0001508
Show evidence (1 reference)
PMID:18256394 SUPPORT Human Clinical
"Clinical investigations confirmed sclerotic skin, joint contractures, bone abnormalities, alopecia, and growth impairment in all 15 patients; cardiovascular and central nervous system sequelae were also documented."
Growth impairment was confirmed in all patients in the NIH HGPS cohort.
Other 1
Sclerodermatous skin Scleroderma HP:0100324
Show evidence (1 reference)
PMID:18256394 SUPPORT Human Clinical
"Clinical investigations confirmed sclerotic skin, joint contractures, bone abnormalities, alopecia, and growth impairment in all 15 patients; cardiovascular and central nervous system sequelae were also documented."
Sclerotic skin was confirmed in all patients in the NIH HGPS cohort.
🧬

Genetic Associations

1
LMNA (Causal variant)
Show evidence (2 references)
PMID:12714972 SUPPORT Human Clinical
"Here, we present evidence of mutations in lamin A (LMNA) as the cause of this disorder."
Identifies LMNA mutation as the genetic cause of HGPS.
PMID:18256394 SUPPORT Human Clinical
"The genetic basis of most cases of this syndrome is a change from glycine GGC to glycine GGT in codon 608 of the lamin A (LMNA) gene, which activates a cryptic splice donor site to produce abnormal lamin A"
Specifies the recurrent codon-608 LMNA splice mutation producing abnormal lamin A.
💊

Medical Actions

2
Lonafarnib
Action: Pharmacotherapy NCIT:C15986
Agent: lonafarnib CHEBI:47097
Lonafarnib is a farnesyltransferase inhibitor that blocks farnesylation of progerin, reducing its toxic association with the nuclear membrane. It is the first (and only FDA-approved) disease-directed therapy for HGPS; the pivotal trial showed improvements in weight gain, vascular stiffness, and other outcomes.
Mechanism Target:
INHIBITS LMNA cryptic splice activation and progerin accumulation — Farnesyltransferase inhibition blocks progerin farnesylation, reducing its pathogenic accumulation at the nuclear lamina.
Show evidence (1 reference)
PMID:23012407 SUPPORT Human Clinical
"Secondary outcomes included decreases in arterial pulse wave velocity and carotid artery echodensity and increases in skeletal rigidity and sensorineural hearing within patient subgroups. All patients improved in one or more of these outcomes."
The pivotal lonafarnib clinical trial showed measurable benefit in vascular and other outcomes in HGPS. Evidence source is HUMAN_CLINICAL (clinical trial).
Rapamycin
Action: Pharmacotherapy NCIT:C15986
Agent: sirolimus CHEBI:9168
Rapamycin (sirolimus), an mTOR inhibitor and caloric-restriction mimetic, enhances autophagic clearance of progerin, abolishes nuclear blebbing, and delays cellular senescence in HGPS cells - the geroprotective nutrient-sensing/autophagy intervention repurposed for progeria.
Mechanism Target:
INHIBITS Progerin proteotoxic aggregation — Rapamycin induces autophagic clearance of insoluble progerin aggregates, reducing progerin proteotoxicity.
Show evidence (1 reference)
PMID:21715679 SUPPORT In Vitro
"Treatment with rapamycin abolished nuclear blebbing, delayed the onset of cellular senescence, and enhanced the degradation of progerin in HGPS cells."
Rapamycin enhances progerin degradation and delays senescence in HGPS cells, the mechanistic basis for its use. Evidence source is IN_VITRO (HGPS fibroblasts).
{ }

Source YAML

click to show 
name: Hutchinson-Gilford Progeria Syndrome
creation_date: "2026-07-01T00:00:00Z"
description: >-
  Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare, fatal,
  segmental premature-aging disorder caused by a recurrent de novo synonymous
  LMNA point mutation (classically c.1824C>T, p.Gly608Gly) that activates a
  cryptic splice donor site in exon 11, producing a farnesylated,
  internally-truncated lamin A protein called progerin. Progerin accumulates at
  the nuclear lamina and disrupts nuclear architecture, driving a convergent set
  of aging hallmarks - genomic instability and impaired DNA repair, telomere
  shortening, heterochromatin loss/epigenetic dysregulation, progerin
  proteotoxicity, cellular senescence, and an ATM-NF-kB systemic inflammatory
  response. Children develop failure to thrive, alopecia, sclerodermatous skin,
  joint contractures, bone abnormalities, and, most consequentially, rapidly
  accelerated atherosclerosis, usually dying in their early teens of myocardial
  infarction or stroke. As the archetypal accelerated-aging disease, HGPS is a
  worked multi-hallmark conformer for the hallmarks-of-aging mechanism modules
  and a proving ground for geroprotective interventions (the
  farnesyltransferase inhibitor lonafarnib; rapamycin-induced autophagic
  progerin clearance).
category: Mendelian
parents:
- hereditary disease
- premature aging syndrome
synonyms:
- HGPS
- Progeria
- Hutchinson-Gilford syndrome
disease_term:
  preferred_term: Hutchinson-Gilford progeria syndrome
  term:
    id: MONDO:0008310
    label: Hutchinson-Gilford progeria syndrome
pathophysiology:
- name: LMNA cryptic splice activation and progerin accumulation
  description: >-
    A recurrent de novo LMNA point mutation activates a cryptic splice donor
    site in exon 11, producing progerin, a permanently farnesylated,
    internally-truncated lamin A. Progerin accumulates at the nuclear lamina and
    adversely affects the integrity of the nuclear scaffold, the primary
    molecular lesion from which the downstream aging hallmarks emanate.
  gene:
    preferred_term: LMNA
    description: Lamin A/C, a core intermediate-filament protein of the nuclear lamina.
    term:
      id: hgnc:6636
      label: LMNA
  role: trigger
  evidence:
  - reference: PMID:12714972
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we present evidence of mutations in lamin A (LMNA) as the cause of
      this disorder.
    explanation: >-
      Identifies LMNA mutation as the cause of HGPS, the primary molecular lesion
      modeled here. Evidence source is HUMAN_CLINICAL (patient genetic study).
  - reference: PMID:23012407
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare, fatal,
      segmental premature aging syndrome caused by a mutation in LMNA that
      produces the farnesylated aberrant lamin A protein, progerin.
    explanation: >-
      Establishes the LMNA mutation and farnesylated progerin as the cause of
      HGPS. Evidence source is HUMAN_CLINICAL (clinical trial report describing
      the disease).
  downstream:
  - target: Genomic instability and impaired DNA repair
  - target: Telomere shortening
  - target: Heterochromatin loss and epigenetic dysregulation
  - target: Progerin proteotoxic aggregation
  - target: Cellular senescence
  - target: ATM-NF-kB systemic inflammation
  - target: Vascular smooth muscle cell loss and accelerated atherosclerosis
- name: Genomic instability and impaired DNA repair
  conforms_to: "genomic_instability_aging#Declining Genome Maintenance and Erroneous Repair"
  description: >-
    Progerin accumulation compromises genome maintenance: HGPS and related
    laminopathy cells show defective DNA repair, accumulating DNA damage, and
    chromosomal aberrations, a genome-instability phenotype that limits cellular
    proliferative capacity.
  role: effector
  biological_processes:
  - preferred_term: DNA Repair
    term:
      id: GO:0006281
      label: DNA repair
    modifier: DECREASED
  - preferred_term: DNA Damage Response
    term:
      id: GO:0006974
      label: DNA damage response
    modifier: INCREASED
  evidence:
  - reference: PMID:15980864
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found that Zmpste24-deficient mouse embryonic fibroblasts (MEFs) show
      increased DNA damage and chromosome aberrations and are more sensitive to
    explanation: >-
      Prelamin-A-accumulating (Zmpste24-deficient) fibroblasts show increased DNA
      damage and chromosome aberrations, supporting genomic instability in the
      laminopathy/HGPS mechanism. Evidence source is IN_VITRO (cultured mouse
      embryonic fibroblasts).
  - reference: PMID:27374873
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      progerin accumulation elicits nuclear morphological abnormalities,
      misregulated gene expression, defects in DNA repair, telomere shortening,
      and genomic instability, all of which limit cellular proliferative
      capacity.
    explanation: >-
      Review enumerating defects in DNA repair and genomic instability among the
      consequences of progerin accumulation. Evidence source is OTHER (review).
  downstream:
  - target: Vascular smooth muscle cell loss and accelerated atherosclerosis
- name: Telomere shortening
  conforms_to: "telomere_attrition#Progressive Telomere Attrition"
  description: >-
    Progerin accumulation accelerates telomere shortening in HGPS cells,
    contributing to the loss of proliferative capacity and premature replicative
    senescence characteristic of the disease.
  role: effector
  biological_processes:
  - preferred_term: Telomere Maintenance
    term:
      id: GO:0000723
      label: telomere maintenance
    modifier: DECREASED
  evidence:
  - reference: PMID:27374873
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      progerin accumulation elicits nuclear morphological abnormalities,
      misregulated gene expression, defects in DNA repair, telomere shortening,
      and genomic instability, all of which limit cellular proliferative
      capacity.
    explanation: >-
      Review identifying telomere shortening as a direct consequence of progerin
      accumulation, supporting the telomere-attrition conformance. Evidence
      source is OTHER (review).
  downstream:
  - target: Cellular senescence
- name: Heterochromatin loss and epigenetic dysregulation
  conforms_to: "epigenetic_alterations#Age-Associated Epigenetic Drift"
  description: >-
    Cells expressing mutant lamin A show abnormally shaped nuclei with a loss of
    heterochromatin and progressive alterations of epigenetic control, including
    loss of the facultative-heterochromatin mark H3K27me3 and constitutive
    marks, producing misregulated gene expression.
  role: effector
  biological_processes:
  - preferred_term: Chromatin Organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:16738054
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Nuclei in cells expressing LADelta50 are abnormally shaped and display a
      loss of heterochromatin.
    explanation: >-
      Demonstrates heterochromatin loss in HGPS (LADelta50/progerin) cells, the
      epigenetic alteration modeled here. Evidence source is IN_VITRO (patient
      and expression cell systems).
  - reference: PMID:16738054
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In cells from a female HGPS patient, histone H3 trimethylated on lysine 27
      (H3K27me3), a mark for facultative heterochromatin, is lost on the inactive
      X chromosome (Xi).
    explanation: >-
      Documents loss of the H3K27me3 heterochromatin mark in HGPS patient cells,
      supporting epigenetic dysregulation. Evidence source is IN_VITRO (patient
      cells).
- name: Progerin proteotoxic aggregation
  conforms_to: "loss_of_proteostasis#Misfolded-Protein Aggregation"
  description: >-
    Farnesylated progerin resists normal turnover and forms insoluble
    aggregates that adversely affect the nuclear scaffold and cause nuclear
    blebbing; enhancing autophagic clearance of these aggregates is
    therapeutically beneficial.
  role: effector
  evidence:
  - reference: PMID:21715679
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Rapamycin also decreased the formation of insoluble progerin aggregates
      and induced clearance through autophagic mechanisms in normal fibroblasts.
    explanation: >-
      Establishes insoluble progerin aggregates cleared by autophagy, supporting
      the proteostasis/aggregation conformance. Evidence source is IN_VITRO
      (fibroblast cultures).
  downstream:
  - target: Cellular senescence
- name: Cellular senescence
  conforms_to: "cellular_senescence#Senescence-Associated Cell Cycle Arrest"
  description: >-
    HGPS fibroblasts undergo premature cellular senescence; progerin is likewise
    produced in senescent cells and cells from old individuals, linking HGPS to
    physiological aging. Rapamycin delays the onset of this senescence in HGPS
    cells.
  role: effector
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: Cellular Senescence
    term:
      id: GO:0090398
      label: cellular senescence
    modifier: INCREASED
  evidence:
  - reference: PMID:21715679
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Treatment with rapamycin abolished nuclear blebbing, delayed the onset of
      cellular senescence, and enhanced the degradation of progerin in HGPS
      cells.
    explanation: >-
      Shows premature cellular senescence in HGPS cells (delayed by rapamycin),
      supporting the senescence conformance. Evidence source is IN_VITRO (HGPS
      fibroblasts).
  - reference: PMID:27374873
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      progerin is also produced in senescent cells and cells from old
      individuals, suggesting that progerin accumulation might be a factor in
      physiological aging.
    explanation: >-
      Links progerin to physiological cellular senescence and aging. Evidence
      source is OTHER (review).
  downstream:
  - target: Vascular smooth muscle cell loss and accelerated atherosclerosis
- name: ATM-NF-kB systemic inflammation
  conforms_to: "inflammaging#Chronic Low-Grade Sterile Inflammation"
  description: >-
    Accumulation of aberrant prelamin A / progerin at the nuclear lamina
    triggers an ATM- and NEMO-dependent signaling pathway that activates NF-kB
    and drives secretion of proinflammatory cytokines, linking accelerated aging
    to a chronic systemic inflammatory response (inflammaging).
  role: amplifier
  biological_processes:
  - preferred_term: Inflammatory Response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:23019125
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here we report that the accumulation of prelamin A isoforms at the nuclear
      lamina triggers an ATM- and NEMO-dependent signaling pathway that leads to
      NF-κB activation and secretion of high levels of proinflammatory cytokines
      in two different mouse models of accelerated aging (Zmpste24(-/-) and
      Lmna(G609G/G609G) mice).
    explanation: >-
      Establishes ATM-NF-kB-driven systemic proinflammatory cytokine secretion in
      progeroid (Lmna) mouse models, supporting the inflammaging conformance.
      Evidence source is MODEL_ORGANISM (mouse models of accelerated aging).
  downstream:
  - target: Vascular smooth muscle cell loss and accelerated atherosclerosis
- name: Vascular smooth muscle cell loss and accelerated atherosclerosis
  description: >-
    The convergent hallmark burden - genomic instability, senescence, and
    inflammation - is especially destructive in the vasculature, where it drives
    progressive loss of vascular smooth muscle cells and rapidly accelerated
    atherosclerosis. This cardiovascular disease is the principal cause of death
    in HGPS, typically from myocardial infarction or stroke in the early teens.
  role: consequence
  cell_types:
  - preferred_term: vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  evidence:
  - reference: PMID:23012407
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This multisystem disorder causes failure to thrive and accelerated
      atherosclerosis leading to early death.
    explanation: >-
      States accelerated atherosclerosis as the cause of early death in HGPS, the
      consequence modeled here. Evidence source is HUMAN_CLINICAL (clinical trial
      report).
phenotypes:
- name: Failure to thrive
  category: Growth
  diagnostic: true
  description: Profound growth impairment and failure to thrive begin in infancy.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:18256394
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical investigations confirmed sclerotic skin, joint contractures, bone
      abnormalities, alopecia, and growth impairment in all 15 patients;
      cardiovascular and central nervous system sequelae were also documented.
    explanation: Growth impairment was confirmed in all patients in the NIH HGPS cohort.
- name: Alopecia
  category: Dermatologic
  diagnostic: true
  description: Progressive loss of scalp and body hair is an early, characteristic feature.
  phenotype_term:
    preferred_term: Alopecia
    term:
      id: HP:0001596
      label: Alopecia
  evidence:
  - reference: PMID:18256394
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical investigations confirmed sclerotic skin, joint contractures, bone
      abnormalities, alopecia, and growth impairment in all 15 patients;
      cardiovascular and central nervous system sequelae were also documented.
    explanation: Alopecia was confirmed in all patients in the NIH HGPS cohort.
- name: Sclerodermatous skin
  category: Dermatologic
  description: Sclerotic, sclerodermatous skin changes are characteristic of the progeroid habitus.
  phenotype_term:
    preferred_term: Scleroderma
    term:
      id: HP:0100324
      label: Scleroderma
  evidence:
  - reference: PMID:18256394
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical investigations confirmed sclerotic skin, joint contractures, bone
      abnormalities, alopecia, and growth impairment in all 15 patients;
      cardiovascular and central nervous system sequelae were also documented.
    explanation: Sclerotic skin was confirmed in all patients in the NIH HGPS cohort.
- name: Joint contractures
  category: Musculoskeletal
  description: Progressive joint contractures limit range of motion.
  phenotype_term:
    preferred_term: Joint contracture
    term:
      id: HP:0034392
      label: Joint contracture
  evidence:
  - reference: PMID:18256394
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical investigations confirmed sclerotic skin, joint contractures, bone
      abnormalities, alopecia, and growth impairment in all 15 patients;
      cardiovascular and central nervous system sequelae were also documented.
    explanation: Joint contractures were confirmed in all patients in the NIH HGPS cohort.
- name: Accelerated coronary atherosclerosis
  category: Cardiovascular
  diagnostic: true
  description: >-
    Rapidly progressive atherosclerosis, especially coronary, is the leading
    cause of death (myocardial infarction or stroke) in the early teens.
  phenotype_term:
    preferred_term: Coronary artery atherosclerosis
    term:
      id: HP:0001677
      label: Coronary artery atherosclerosis
  evidence:
  - reference: PMID:18256394
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hutchinson-Gilford progeria syndrome is a rare, sporadic, autosomal
      dominant syndrome that involves premature aging, generally leading to death
      at approximately 13 years of age due to myocardial infarction or stroke.
    explanation: >-
      Cardiovascular disease (myocardial infarction or stroke) from accelerated
      atherosclerosis is the leading cause of death, supporting this phenotype.
genetic:
- name: LMNA
  association: Causal variant
  notes: >-
    HGPS is caused by a recurrent de novo LMNA mutation (classically
    c.1824C>T, p.Gly608Gly) that activates a cryptic exon-11 splice donor site,
    producing the truncated, farnesylated lamin A isoform progerin.
  evidence:
  - reference: PMID:12714972
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we present evidence of mutations in lamin A (LMNA) as the cause of
      this disorder.
    explanation: Identifies LMNA mutation as the genetic cause of HGPS.
  - reference: PMID:18256394
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The genetic basis of most cases of this syndrome is a change from glycine
      GGC to glycine GGT in codon 608 of the lamin A (LMNA) gene, which activates
      a cryptic splice donor site to produce abnormal lamin A
    explanation: Specifies the recurrent codon-608 LMNA splice mutation producing abnormal lamin A.
treatments:
- name: Lonafarnib
  description: >-
    Lonafarnib is a farnesyltransferase inhibitor that blocks farnesylation of
    progerin, reducing its toxic association with the nuclear membrane. It is the
    first (and only FDA-approved) disease-directed therapy for HGPS; the pivotal
    trial showed improvements in weight gain, vascular stiffness, and other
    outcomes.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: lonafarnib
      term:
        id: CHEBI:47097
        label: lonafarnib
  target_mechanisms:
  - target: LMNA cryptic splice activation and progerin accumulation
    treatment_effect: INHIBITS
    description: >-
      Farnesyltransferase inhibition blocks progerin farnesylation, reducing its
      pathogenic accumulation at the nuclear lamina.
  evidence:
  - reference: PMID:23012407
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Secondary outcomes included decreases in arterial pulse wave velocity and
      carotid artery echodensity and increases in skeletal rigidity and
      sensorineural hearing within patient subgroups. All patients improved in
      one or more of these outcomes.
    explanation: >-
      The pivotal lonafarnib clinical trial showed measurable benefit in vascular
      and other outcomes in HGPS. Evidence source is HUMAN_CLINICAL (clinical
      trial).
- name: Rapamycin
  description: >-
    Rapamycin (sirolimus), an mTOR inhibitor and caloric-restriction mimetic,
    enhances autophagic clearance of progerin, abolishes nuclear blebbing, and
    delays cellular senescence in HGPS cells - the geroprotective
    nutrient-sensing/autophagy intervention repurposed for progeria.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
  target_mechanisms:
  - target: Progerin proteotoxic aggregation
    treatment_effect: INHIBITS
    description: >-
      Rapamycin induces autophagic clearance of insoluble progerin aggregates,
      reducing progerin proteotoxicity.
  evidence:
  - reference: PMID:21715679
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Treatment with rapamycin abolished nuclear blebbing, delayed the onset of
      cellular senescence, and enhanced the degradation of progerin in HGPS
      cells.
    explanation: >-
      Rapamycin enhances progerin degradation and delays senescence in HGPS
      cells, the mechanistic basis for its use. Evidence source is IN_VITRO (HGPS
      fibroblasts).
clinical_trials: []
datasets: []
notes: >-
  HGPS is curated as the flagship multi-hallmark conformer for the
  hallmarks-of-aging mechanism modules, declaring parallel conforms_to across
  genomic_instability_aging, telomere_attrition, epigenetic_alterations,
  loss_of_proteostasis, cellular_senescence, and inflammaging (the aging
  analog of the multi-hallmark cancer conformer Hepatocellular_Carcinoma).
  Mitochondrial-dysfunction and stem-cell-exhaustion arms are also reported in
  HGPS but are intentionally not asserted here pending primary evidence that
  passes snippet validation. The lonafarnib (farnesyltransferase inhibitor) and
  rapamycin (mTOR/autophagy) treatments tie HGPS to the geroprotector
  intervention-testing theme.