CNPY3 variants associated with a recessive developmental and epileptic encephalopathy affect inflammasome and TLR function.

@article{garloff2026cnpy3,
  title = {{CNPY3 variants associated with a recessive developmental and epileptic encephalopathy affect inflammasome and TLR function.}},
  author = {Vera Garloff and Mona Grimmel and Reza Maroofian and Stephanie Efthymiou and Sven Stengel and Dolores Bello and Carolin Tille and Mohamed Ghait and Oliver Ohlenschläger and Andrea Dieckmann and Heike de Vries and Matthias Waginger and Seba Nadeef and Ehsan Barkhordari and Rauan Kaiyrzhanov and Sarah Bühler and Irisa Pjeci and Stefanie Beck-Wödl and Javeria Raza Alvi and Tipu Sultan and Anna Chassevent and Constance Smith-Hicks and Irina Mishina and Agustí Rodríguez-Palmero and Evangeline Wassmer and Julie Vogt and Christopher Manuel Meudt and Rami Abou Jamra and Mohammad Reza Abbaszadegan and Naser Ajami and Reza Azizimalamiri and Hamid Galehdari and Niloofar Chamanrou and Mina Zamani and Gholamreza Shariati and Pardis Nourbakhsh and Farhan Bahadar Ali and Ambrin Fatima and Sohana Nadeem Hashmi and Zafar Iqbal and Sidra Kaleem and Mathias Toft and Erum Afzal and Shazia Maqbool and Fatima Rahman and Vincenzo Salpietro and Margot Grisval and Caroline Racine and Louis Januel and David Cheillan and Cecile Acquaviva-Bourdain and Chadi Al Alam and Majid Alfadhel and Muhammad Umair and Barbara Oehl-Jaschkowitz and Shahzad Haider and Vivek Jain and Bhuvandeep Narang and Fawzia Amer and Nour Elkhateeb},
  journal = {EBioMedicine},
  year = {2026},
  month = oct,
  doi = {10.1016/j.ebiom.2026.106506},
  url = {https://europepmc.org/article/MED/42874293},
  note = {CC BY},
}

TY  - JOUR
TI  - CNPY3 variants associated with a recessive developmental and epileptic encephalopathy affect inflammasome and TLR function.
AU  - Vera Garloff
AU  - Mona Grimmel
AU  - Reza Maroofian
AU  - Stephanie Efthymiou
AU  - Sven Stengel
AU  - Dolores Bello
AU  - Carolin Tille
AU  - Mohamed Ghait
AU  - Oliver Ohlenschläger
AU  - Andrea Dieckmann
AU  - Heike de Vries
AU  - Matthias Waginger
AU  - Seba Nadeef
AU  - Ehsan Barkhordari
AU  - Rauan Kaiyrzhanov
AU  - Sarah Bühler
AU  - Irisa Pjeci
AU  - Stefanie Beck-Wödl
AU  - Javeria Raza Alvi
AU  - Tipu Sultan
AU  - Anna Chassevent
AU  - Constance Smith-Hicks
AU  - Irina Mishina
AU  - Agustí Rodríguez-Palmero
AU  - Evangeline Wassmer
AU  - Julie Vogt
AU  - Christopher Manuel Meudt
AU  - Rami Abou Jamra
AU  - Mohammad Reza Abbaszadegan
AU  - Naser Ajami
AU  - Reza Azizimalamiri
AU  - Hamid Galehdari
AU  - Niloofar Chamanrou
AU  - Mina Zamani
AU  - Gholamreza Shariati
AU  - Pardis Nourbakhsh
AU  - Farhan Bahadar Ali
AU  - Ambrin Fatima
AU  - Sohana Nadeem Hashmi
AU  - Zafar Iqbal
AU  - Sidra Kaleem
AU  - Mathias Toft
AU  - Erum Afzal
AU  - Shazia Maqbool
AU  - Fatima Rahman
AU  - Vincenzo Salpietro
AU  - Margot Grisval
AU  - Caroline Racine
AU  - Louis Januel
AU  - David Cheillan
AU  - Cecile Acquaviva-Bourdain
AU  - Chadi Al Alam
AU  - Majid Alfadhel
AU  - Muhammad Umair
AU  - Barbara Oehl-Jaschkowitz
AU  - Shahzad Haider
AU  - Vivek Jain
AU  - Bhuvandeep Narang
AU  - Fawzia Amer
AU  - Nour Elkhateeb
PY  - 2026
DA  - 2026/10/14
JO  - EBioMedicine
DO  - 10.1016/j.ebiom.2026.106506
UR  - https://europepmc.org/article/MED/42874293
AB  - Background  Canopy FGF signalling regulator 3 (CNPY3) is an endoplasmic reticulum (ER)-resident chaperone essential for toll-like receptor (TLR) folding, trafficking and inflammasome activation. In rare paediatric cases, biallelic CNPY3 variants have been associated with developmental and epileptic encephalopathy (DEE), but available data remain sparse.Methods  50 individuals from 38 unrelated families with biallelic CNPY3 variants and DEE were evaluated for exome and genome findings, standardised clinical phenotype descriptions, EEG results, and neuroimaging data. A selection of variants underwent functional analysis focussing on protein stability and localisation, TLR2 function, NLPR3 inflammasome activation, and structural conformation.Findings  Disease onset occurred in early infancy (median age at onset 68 days), with a clinical phenotype comprising global developmental delay (100%) and intractable epilepsy (86%), accompanied by microcephaly (70%), spasticity (77%), growth faltering (63%), stridor (48%), and early mortality (38%). Epileptic spasms and tonic seizures (46% each) were the most frequent seizure types, and EEG findings included suppression-burst (37%) and hypsarrhythmia (28%). Phenotypic severity varied substantially, with most patients being severely affected (median score 16, range 2-20). Most variants occurred in the homozygous state (95%), including 13 missense changes and 7 truncating alleles. Variants were classified as of uncertain significance (71%), followed by likely pathogenic (23%) and pathogenic (6%) according to ACMG/AMP criteria. Genotype-phenotype correlation showed that individuals with truncating variants were, on average, more severely affected than those with non-truncating variants (median score 18 vs 14.5). Protein modelling predicted conformational effects for most missense variants. In cells, frameshift alleles abolished CNPY3 protein expression, whereas nonsense alleles markedly reduced protein levels. ER localisation of CNPY3 remained preserved across tested genotypes; however, capacity to support TLR2 maturation and processing varied substantially. Remarkably, some missense variants permitted TLR2 surface expression but impaired downstream signalling and inflammasome activation, uncoupling trafficking from signal transduction.Interpretation  CNPY3-associated DEE is a severe early-onset disorder with genotype-dependent phenotypic severity, accompanied by allele-specific disruption of innate immune pathways. Our findings reveal separable effects on TLR trafficking, downstream signalling and inflammasome activation, identifying CNPY3 as a key regulator of multiple cellular pathways involved in inflammatory responses and neurodevelopment.Funding  Interdisciplinary Center of Clinical Research and Jena School of Molecular Medicine, Jena University Hospital; Friedrich Schiller University Jena; The Wellcome Trust; The Medical Research Council; The MSA Trust; The National Institute for Health Research University College London Hospitals Biomedical Research Centre; The Michael J Fox Foundation; Biotechnology and Biological Sciences Research Council; The Fidelity Trust; Rosetrees Trust; Ataxia UK; Brain Research UK; Sparks GOSH Charity; Alzheimer's Research UK; CureDRPLA; UK Dementia Research Institute; Parkinson's UK; South-Eastern Norway Regional Health Authority, Norway; France Genomic Medicine Plan 2025; Deutsche Forschungsgemeinschaft; European Commission; Federal Government of Germany; State of Thuringia; Pakistan Science Foundation; King Abdullah International Medical Research Center; Science and Technology Development Fund; King Salman Center for Disability Research.
SN  - 2352-3964
ER  -