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TitleMutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
Journal, issue, pagesGenet Med, Page 102579, Year 2026
Publish dateApr 13, 2026
AuthorsAnna Lehman / Sana Ahmed / Arezoo Mohajeri / Alison M Berezuk / Dhiraj Mannar / Spencer Cholak / Katharine S Tuttle / James T Bennett / Jeanine Aparecida Magno / Mark Hannibal / Gordana Kovacevic / Vladimir Kuburović / M E Suzanne Lewis / Oana Moldovan / Zoe Nelson / Salmo Raskin / Anthony M Vandersteen / Jared C Roach / Sriram Subramaniam / Millan S Patel /
PubMed AbstractPURPOSE: Adams-Oliver syndrome (AOS) is a genetically heterogeneous disorder with cardinal features of aplasia cutis congenita and terminal limb reduction defects. A minority of individuals with AOS ...PURPOSE: Adams-Oliver syndrome (AOS) is a genetically heterogeneous disorder with cardinal features of aplasia cutis congenita and terminal limb reduction defects. A minority of individuals with AOS develop potentially lethal pulmonary hypertension (PH) in infancy, a subgroup that has been refractory to genetic explanation.
METHODS: We studied a cohort of individuals with AOS and no genetic diagnosis by genome and exome sequencing. We characterized rare identified substitution variants in valosin containing protein (VCP) in vitro using ATP hydrolysis, cryogenic-electron microscopy, thermal stability, and response to CB-5083, a VCP inhibitor.
RESULTS: We report a new genetic etiology for AOS in 6 families with PH and 1 family without it. We show that AOS-related VCP variants are hypermorphic with respect to ATP hydrolysis and cause N-terminal domain hyperflexibility with impairment of interdomain coupling. Additionally, we find that CB-5083 inhibits the overactive ATP hydrolysis. Review of published cases of AOS with PH suggests that pulmonary veno-occlusive disease is the most common mechanism. Clinical risk factors for PH in AOS include CMTC, prominent dilated subcutaneous veins and intra-uterine growth restriction.
CONCLUSION: We identify the prevalent genetic cause of pulmonary hypertension in AOS and highlight a potential therapeutic approach.
External linksGenet Med / PubMed:41979051
MethodsEM (single particle)
Resolution2.4 - 2.78 Å
Structure data

72383

9y03

EMDB-72383, PDB-9y03:
Cryo-EM structure of human VCP/p97-R89W mutant bound to ADP
Method: EM (single particle) / Resolution: 2.53 Å

72384

9y04

EMDB-72384, PDB-9y04:
Cryo-EM structure of human VCP/p97-R89W mutant bound to ATPgammaS
Method: EM (single particle) / Resolution: 2.55 Å

72385

9y05

EMDB-72385, PDB-9y05:
Cryo-EM structure of human VCP/p97-R89W mutant bound to CB-5083
Method: EM (single particle) / Resolution: 2.58 Å

72386

9y06

EMDB-72386, PDB-9y06:
Cryo-EM structure of human VCP/p97-T122P mutant bound to ADP
Method: EM (single particle) / Resolution: 2.74 Å

72387

9y07

EMDB-72387, PDB-9y07:
Cryo-EM structure of human VCP/p97-T122P mutant bound to ATPgammaS
Method: EM (single particle) / Resolution: 2.41 Å

72388

9y08

EMDB-72388, PDB-9y08:
Cryo-EM structure of human VCP/p97-G128D mutant bound to ADP
Method: EM (single particle) / Resolution: 2.78 Å

72389

9y09

EMDB-72389, PDB-9y09:
Cryo-EM structure of human VCP/p97-G128D mutant bound to ATPgS
Method: EM (single particle) / Resolution: 2.4 Å

72390

9y0b

EMDB-72390, PDB-9y0b:
Cryo-EM structure of human VCP/p97-G156D mutant bound to ADP
Method: EM (single particle) / Resolution: 2.61 Å

72391

9y0c

EMDB-72391, PDB-9y0c:
Cryo-EM structure of human VCP/p97-G156D mutant bound to ATPgammaS
Method: EM (single particle) / Resolution: 2.61 Å

Chemicals

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

ChemComp-AGS:
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogue*YM

ChemComp-MG:
Unknown entry

ChemComp-JDP:
1-[4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide

Source
  • homo sapiens (human)
KeywordsHYDROLASE / AAA ATPase / Unfoldase / ERAD

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