Details of Disease

General Information of Disease (ID: DISY55BU)

• Disease Name: Hutchinson-Gilford progeria syndrome
• Synonyms: Hutchinson Gilford progeria syndrome; progeria syndrome, childhood-onset; progeria; HGPS; Hutchinson-Gilford progeria; Hutchinson-Gilford progeria syndrome; Hutchinson-Gilford disease; Hutchinson Gilford syndrome; premature senility syndrome
• Disease Class: LD2B: Premature ageing appearance
• Definition: Hutchinson-Gilford progeria syndrome is a rare, fatal, autosomal dominant and premature aging disease, beginning in childhood and characterized by growth reduction, failure to thrive, a typical facial appearance (prominent forehead, protuberant eyes, thin nose with a beaked tip, thin lips, micrognathia and protruding ears) and distinct dermatologic features (generalized alopecia, aged-looking skin, sclerotic and dimpled skin over the abdomen and extremities, prominent cutaneous vasculature, dyspigmentation, nail hypoplasia and loss of subcutaneous fat).|Editor note: check wether subset prototype_pattern is appropriate
• Disease Hierarchy:
  DIS3GF09: Progeria
  DIS6SVEE: Syndromic disease
  DISCPWH9: Autosomal recessive disease
  DISFPEQA: Laminopathy
  DISOTEY1: Primary osteolysis
  DISY55BU: Hutchinson-Gilford progeria syndrome
• ICD Code: ICD-11: ICD-11: LD2B
• Disease Identifiers:
  MONDO ID: MONDO_0008310
  MESH ID: D011371
  UMLS CUI: C0033300
  OMIM ID: 176670
  MedGen ID: 46123
  Orphanet ID: 740
  SNOMED CT ID: 238870004

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 1 Approved Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Lonafarnib	DMGM2Z6	Approved	Small molecular drug	[1]

This Disease is Treated as An Indication in 1 Clinical Trial Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Progerinin	DM21RQ5	Phase 2	NA	[2]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 30 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
ZMPSTE24	OTUMYTEV	Supportive	Autosomal dominant	[3]
ALDH18A1	OT6W40XU	moderate	Genetic Variation	[13]
AMPD1	OTU17BCI	moderate	Biomarker	[14]
ANK3	OTJ3IRBP	Strong	Biomarker	[15]
BANF1	OTP7Z38L	Strong	Biomarker	[16]
BUB1B	OT8KME51	Strong	Biomarker	[17]
CTC1	OTRJY7QD	Strong	Genetic Variation	[18]
ERCC4	OTFIOPG1	Strong	Genetic Variation	[19]
GOLGA6A	OTHU9MRX	Strong	Altered Expression	[20]
GTF2H5	OTRL219S	Strong	Genetic Variation	[21]
H2AX	OT18UX57	Strong	Biomarker	[20]
HIP1	OT7AKCFQ	Strong	Altered Expression	[22]
ICMT	OT8CNKBO	Strong	Biomarker	[23]
ING1	OTEZBRKW	Strong	Genetic Variation	[24]
LEMD2	OT0YLT7L	Strong	Genetic Variation	[25]
MGME1	OTC5LPXX	Strong	Biomarker	[26]
PLB1	OTZ6TTYV	Strong	Genetic Variation	[27]
PRELP	OT9EEBUJ	Strong	Biomarker	[28]
PRPS1	OTN3A6CN	Strong	Altered Expression	[29]
PYCR1	OTQHB52T	Strong	Genetic Variation	[30]
ROBO3	OTPVG40S	Strong	Biomarker	[31]
SMURF2	OT3TRVL7	Strong	Biomarker	[32]
SRSF5	OTC5WP98	Strong	Altered Expression	[33]
SRSF6	OTGLOSYE	Strong	Biomarker	[34]
SUN1	OTIU8V4U	Strong	Biomarker	[35]
TNPO1	OT7W2CM8	Strong	Biomarker	[36]
TPR	OTUBBA4W	Strong	Biomarker	[20]
HFM1	OTHV3EFE	Definitive	Biomarker	[37]
LMNA	OT3SG7ZR	Definitive	Autosomal dominant	[38]
SPRTN	OT01D5CE	Definitive	Biomarker	[39]

This Disease Is Related to 8 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
SIRT6	TTUXYWF	Limited	Biomarker	[4]
ALPL	TTMR5UV	Strong	Biomarker	[5]
FDPS	TTIKWV4	Strong	Biomarker	[6]
GADD45B	TTMDW9L	Strong	Altered Expression	[7]
GGT1	TTZVT7O	Strong	Genetic Variation	[8]
PLA2R1	TTHKW7D	Strong	Biomarker	[9]
WRN	TT2H5WQ	Strong	Genetic Variation	[10]
XPA	TTGT87E	Strong	Biomarker	[11]

This Disease Is Related to 1 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
NAT10	DEZV4AP	Strong	Biomarker	[12]

References

• [1] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [2] ClinicalTrials.gov (NCT05847179) A Phase 2, Open-Label Study to Evaluate the Safety and Tolerability of Progerinin for the Treatment of Bone Mineral Density (BMD) Loss in Subjects With Typical Werner Syndrome. U.S.National Institutes of Health.
• [3] A homozygous ZMPSTE24 null mutation in combination with a heterozygous mutation in the LMNA gene causes Hutchinson-Gilford progeria syndrome (HGPS): insights into the pathophysiology of HGPS. Hum Mutat. 2006 Jun;27(6):524-31. doi: 10.1002/humu.20315.
• [4] Enhanced insulin sensitivity in skeletal muscle and liver by physiological overexpression of SIRT6.Mol Metab. 2015 Sep 25;4(11):846-56. doi: 10.1016/j.molmet.2015.09.003. eCollection 2015 Nov.
• [5] ATP-based therapy prevents vascular calcification and extends longevity in a mouse model of Hutchinson-Gilford progeria syndrome.Proc Natl Acad Sci U S A. 2019 Nov 19;116(47):23698-23704. doi: 10.1073/pnas.1910972116. Epub 2019 Nov 5.
• [6] Drug screening on Hutchinson Gilford progeria pluripotent stem cells reveals aminopyrimidines as new modulators of farnesylation.Cell Death Dis. 2016 Feb 18;7(2):e2105. doi: 10.1038/cddis.2015.374.
• [7] Are There Common Mechanisms Between the Hutchinson-Gilford Progeria Syndrome and Natural Aging?.Front Genet. 2019 May 15;10:455. doi: 10.3389/fgene.2019.00455. eCollection 2019.
• [8] Absence of Lamin A/C gene mutations in four Wiedemann-Rautenstrauch syndrome patients.Am J Med Genet A. 2009 Dec;149A(12):2695-9. doi: 10.1002/ajmg.a.33090.
• [9] Targeting the phospholipase A2 receptor ameliorates premature aging phenotypes.Aging Cell. 2018 Dec;17(6):e12835. doi: 10.1111/acel.12835. Epub 2018 Sep 14.
• [10] Differential stem cell aging kinetics in Hutchinson-Gilford progeria syndrome and Werner syndrome.Protein Cell. 2018 Apr;9(4):333-350. doi: 10.1007/s13238-018-0517-8. Epub 2018 Feb 23.
• [11] Progerin sequestration of PCNA promotes replication fork collapse and mislocalization of XPA in laminopathy-related progeroid syndromes.FASEB J. 2017 Sep;31(9):3882-3893. doi: 10.1096/fj.201700014R. Epub 2017 May 17.
• [12] Recent Advances on the Structure and Function of RNA Acetyltransferase Kre33/NAT10.Cells. 2019 Sep 5;8(9):1035. doi: 10.3390/cells8091035.
• [13] Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature.Eur J Paediatr Neurol. 2014 Jul;18(4):511-5. doi: 10.1016/j.ejpn.2014.01.003. Epub 2014 Feb 28.
• [14] ZMPSTE24 missense mutations that cause progeroid diseases decrease prelamin A cleavage activity and/or protein stability.Dis Model Mech. 2018 Jul 13;11(7):dmm033670. doi: 10.1242/dmm.033670.
• [15] Mood, stress and longevity: convergence on ANK3.Mol Psychiatry. 2016 Aug;21(8):1037-49. doi: 10.1038/mp.2016.65. Epub 2016 May 24.
• [16] Nuclear Organization in Stress and Aging.Cells. 2019 Jul 1;8(7):664. doi: 10.3390/cells8070664.
• [17] BubR1 allelic effects drive phenotypic heterogeneity in mosaic-variegated aneuploidy progeria syndrome.J Clin Invest. 2020 Jan 2;130(1):171-188. doi: 10.1172/JCI126863.
• [18] CTC1 mutations in a Brazilian family with progeroid features and recurrent bone fractures.Mol Genet Genomic Med. 2018 Nov;6(6):1148-1156. doi: 10.1002/mgg3.495. Epub 2018 Nov 4.
• [19] Physical interaction between SLX4 (FANCP) and XPF (FANCQ) proteins and biological consequences of interaction-defective missense mutations.DNA Repair (Amst). 2015 Nov;35:48-54. doi: 10.1016/j.dnarep.2015.09.022. Epub 2015 Sep 30.
• [20] A nuclear lamina-chromatin-Ran GTPase axis modulates nuclear import and DNA damage signaling.Aging Cell. 2019 Feb;18(1):e12851. doi: 10.1111/acel.12851. Epub 2018 Dec 19.
• [21] An Xpd mouse model for the combined xeroderma pigmentosum/Cockayne syndrome exhibiting both cancer predisposition and segmental progeria.Cancer Cell. 2006 Aug;10(2):121-32. doi: 10.1016/j.ccr.2006.05.027.
• [22] Increased expression of the Huntingtin interacting protein-1 gene in cells from Hutchinson Gilford Syndrome (Progeria) patients and aged donors.J Gerontol A Biol Sci Med Sci. 2003 Oct;58(10):B873-8. doi: 10.1093/gerona/58.10.b873.
• [23] Atomic structure of the eukaryotic intramembrane RAS methyltransferase ICMT.Nature. 2018 Jan 25;553(7689):526-529. doi: 10.1038/nature25439. Epub 2018 Jan 17.
• [24] The emerging role of alternative splicing in senescence and aging.Aging Cell. 2017 Oct;16(5):918-933. doi: 10.1111/acel.12646. Epub 2017 Jul 13.
• [25] The Discovery of a LEMD2-Associated Nuclear Envelopathy with Early Progeroid Appearance Suggests Advanced Applications for AI-Driven Facial Phenotyping.Am J Hum Genet. 2019 Apr 4;104(4):749-757. doi: 10.1016/j.ajhg.2019.02.021. Epub 2019 Mar 21.
• [26] Mice lacking the mitochondrial exonuclease MGME1 accumulate mtDNA deletions without developing progeria.Nat Commun. 2018 Mar 23;9(1):1202. doi: 10.1038/s41467-018-03552-x.
• [27] The role of lipid metabolism in aging, lifespan regulation, and age-related disease.Aging Cell. 2019 Dec;18(6):e13048. doi: 10.1111/acel.13048. Epub 2019 Sep 27.
• [28] PRELP, collagen, and a theory of Hutchinson-Gilford progeria.Ageing Res Rev. 2003 Jan;2(1):95-105. doi: 10.1016/s1568-1637(02)00044-2.
• [29] Next-Generation Sequencing and Quantitative Proteomics of Hutchinson-Gilford progeria syndrome-derived cells point to a role of nucleotide metabolism in premature aging.PLoS One. 2018 Oct 31;13(10):e0205878. doi: 10.1371/journal.pone.0205878. eCollection 2018.
• [30] Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations.Hum Genet. 2018 Dec;137(11-12):921-939. doi: 10.1007/s00439-018-1957-1. Epub 2018 Nov 19.
• [31] Loss of VHL promotes progerin expression, leading to impaired p14/ARF function and suppression of p53 activity.Cell Cycle. 2013 Jul 15;12(14):2277-90. doi: 10.4161/cc.25371.
• [32] Smurf2 regulates stability and the autophagic-lysosomal turnover of lamin A and its disease-associated form progerin.Aging Cell. 2018 Apr;17(2):e12732. doi: 10.1111/acel.12732. Epub 2018 Feb 5.
• [33] Enhanced SRSF5 Protein Expression Reinforces Lamin A mRNA Production in HeLa Cells and Fibroblasts of Progeria Patients.Hum Mutat. 2016 Mar;37(3):280-91. doi: 10.1002/humu.22945. Epub 2016 Jan 12.
• [34] A conserved splicing mechanism of the LMNA gene controls premature aging.Hum Mol Genet. 2011 Dec 1;20(23):4540-55. doi: 10.1093/hmg/ddr385. Epub 2011 Aug 29.
• [35] Dysregulated interactions between lamin A and SUN1 induce abnormalities in the nuclear envelope and endoplasmic reticulum in progeric laminopathies.J Cell Sci. 2014 Apr 15;127(Pt 8):1792-804. doi: 10.1242/jcs.139683. Epub 2014 Feb 12.
• [36] Inhibition of the acetyltransferase NAT10 normalizes progeric and aging cells by rebalancing the Transportin-1 nuclear import pathway.Sci Signal. 2018 Jul 3;11(537):eaar5401. doi: 10.1126/scisignal.aar5401.
• [37] Computational image analysis of nuclear morphology associated with various nuclear-specific aging disorders.Nucleus. 2011 Nov-Dec;2(6):570-9. doi: 10.4161/nucl.2.6.17798. Epub 2011 Nov 1.
• [38] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [39] Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features. Nat Genet. 2014 Nov;46(11):1239-44. doi: 10.1038/ng.3103. Epub 2014 Sep 28.