CNPY3 variants associated with a recessive developmental and epileptic encephalopathy affect inflammasome and TLR function.
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Garloff Vera, Grimmel Mona, Maroofian Reza, Efthymiou Stephanie, Stengel Sven, Bello Dolores, Tille Carolin, Ghait Mohamed, Ohlenschläger Oliver, Dieckmann Andrea, de Vries Heike, Waginger Matthias, Nadeef Seba, Barkhordari Ehsan, Kaiyrzhanov Rauan, Bühler Sarah, Pjeci Irisa, Beck-Wödl Stefanie, Alvi Javeria Raza, Sultan Tipu, Chassevent Anna, Smith-Hicks Constance, Mishina Irina, Rodríguez-Palmero Agustí, Wassmer Evangeline, Vogt Julie, Meudt Christopher Manuel, Jamra Rami Abou, Abbaszadegan Mohammad Reza, Ajami Naser, Azizimalamiri Reza, Galehdari Hamid, Chamanrou Niloofar, Zamani Mina, Shariati Gholamreza, Nourbakhsh Pardis, Ali Farhan Bahadar, Fatima Ambrin, Hashmi Sohana Nadeem, Iqbal Zafar, Kaleem Sidra, Toft Mathias, Afzal Erum, Maqbool Shazia, Rahman Fatima, Salpietro Vincenzo, Grisval Margot, Racine Caroline, Januel Louis, Cheillan David, Acquaviva-Bourdain Cecile, Al Alam Chadi, Alfadhel Majid, Umair Muhammad, Oehl-Jaschkowitz Barbara, Haider Shahzad, Jain Vivek, Narang Bhuvandeep, Amer Fawzia, Elkhateeb Nour, Alvarez Carolina, Pérez-Palma Eduardo, Ríos-Pohl Loreto, Møller Rikke S, Baruah Debangana, Lingappa Lokesh, Farooq Ahmad, Zaki Maha S, Svyatova Gulnara, Murtazalieva Alexandra, Burabayeva Asem, Salayev Kamran, Guliyeva Ulviyya, Kahrizi Kimia, Najmabadi Hossein, Revah-Politi Anya, Mulhern Maureen S, Sands Tristan Timothy, Mustafa Hafiz Muhammad, Rao Hani Akbar, Oprea Gabriela, Rad Aboulfazl, Miryounesi Mohammad, Mardi Ali, Gowda Vykuntaraju K, Srinivasan Varunvenkat M, Alanazi Rola Mohammed, Abumansour Iman Sabri, Alhaddad Bader, Bakur Khadijah, Bauer Michael, Alkuraya Fowzan S, Huppke Peter, Houlden Henry, Haack Tobias B, Rubio Ignacio, Husain Ralf A
Аннотация
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.