Studies of the pathogenesis of human X-linked rare disease

We are interested to characterize the genetic aberrant mechanisms able to produce complex rearrangements in the NEMO/IKBKG locus, causing Incontinentia Pigmenti (IP, OMIM#308300) disease in different affected tissues of IP patients.

The IP locus has an intrinsic genomic instability able to predispose to the generation of novel rearrangements by different mechanisms during either meiotic or mitotic cellular division.

Mosaicism germinal and somatic, revealed in male patients affected by IP, has reinforced model that the IP pathogenesis based not only on the cellular effects of an impaired NEMO protein activity, but also derives from the context of the interaction of genetically different cells in the affected tissue.

Genetic and genomic aspects in genotype-phenotype correlation in human X-linked rare disease, Incontinentia pigmenti

This research line combines genomic/transcriptomic sequencing approaches and deep phenotyping analysis by IP family based-studies to identify rare or common variants associated to form of IP with neurological defects or with specific silent autoimmunity recently revealed in IP patients by SARS-CoV2 pandemic impact. We have built Incontinentia Pigmenti Genetic Biobank (IPGB genetic Biobank, http://www.igb.cnr.it/ipgb) located in CRB-IGB institute, that is the largest IP sample collection and one of the largest rare-disease-oriented collections in the world and including the clinical and genetic information. By improving our collaboration with national and international Association of IP patients we aim to collect samples and data of IP patients worldwide by high-quality procedures to facilitate comprehensive translational research and personalized treatment

IPGB biobank and historical collection of IP samples and data (Fusco et al., 2019)

1. Pescatore A, Spinosa E, Casale C, Lioi MB, Ursini MV, Fusco F.

Human Genetic Diseases Linked to the Absence of NEMO: An Obligatory Somatic Mosaic Disorder in Male.

Int J Mol Sci. 2022;23:1179. doi: 10.3390/ijms23031179.

2. Asano T, Boisson B, Onodi F, Matuozzo D, Moncada-Velez M, Maglorius Renkilaraj MRL, Zhang P, Meertens L, Bolze A, Materna M, Korniotis S, Gervais A, Talouarn E, Bigio B, Seeleuthner Y, Bilguvar K, Zhang Y, Neehus AL, Ogishi M, Pelham SJ, Le Voyer T, Rosain J, Philippot Q, Soler-Palacín P, Colobran R, Martin-Nalda A, Rivière JG, Tandjaoui-Lambiotte Y, Chaïbi K, Shahrooei M, Darazam IA, Olyaei NA, Mansouri D, Hatipoğlu N, Palabiyik F, Ozcelik T, Novelli G, Novelli A, Casari G, Aiuti A, Carrera P, Bondesan S, Barzaghi F, Rovere-Querini P, Tresoldi C, Franco JL, Rojas J, Reyes LF, Bustos IG, Arias AA, Morelle G, Christèle K, Troya J, Planas-Serra L, Schlüter A, Gut M, Pujol A, Allende LM, Rodriguez-Gallego C, Flores C, Cabrera-Marante O, Pleguezuelo DE, de Diego RP, Keles S, Aytekin G, Akcan OM, Bryceson YT, Bergman P, Brodin P, Smole D, Smith CIE, Norlin AC, Campbell TM, Covill LE, Hammarström L, Pan-Hammarström Q, Abolhassani H, Mane S, Marr N, Ata M, Al Ali F, Khan T, Spaan AN, Dalgard CL, Bonfanti P, Biondi A, Tubiana S, Burdet C, Nussbaum R, Kahn-Kirby A, Snow AL; COVID Human Genetic Effort; COVID-STORM Clinicians; COVID Clinicians; Imagine COVID Group; French COVID Cohort Study Group; CoV-Contact Cohort; Amsterdam UMC Covid-; Biobank; NIAID-USUHS COVID Study Group, Bustamante J, Puel A, Boisson-Dupuis S, Zhang SY, Béziat V, Lifton RP, Bastard P, Notarangelo LD, Abel L, Su HC, Jouanguy E, Amara A, Soumelis V, Cobat A, Zhang Q, Casanova JL.

 X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19.

Sci Immunol. 2021;6:eabl4348. doi: 10.1126/sciimmunol.abl4348.

3. Bastard P, Gervais A, Le Voyer T, Rosain J, Philippot Q, Manry J, Michailidis E, Hoffmann HH, Eto S, Garcia-Prat M, Bizien L, Parra-Martínez A, Yang R, Haljasmägi L, Migaud M, Särekannu K, Maslovskaja J, de Prost N, Tandjaoui-Lambiotte Y, Luyt CE, Amador-Borrero B, Gaudet A, Poissy J, Morel P, Richard P, Cognasse F, Troya J, Trouillet-Assant S, Belot A, Saker K, Garçon P, Rivière JG, Lagier JC, Gentile S, Rosen LB, Shaw E, Morio T, Tanaka J, Dalmau D, Tharaux PL, Sene D, Stepanian A, Megarbane B, Triantafyllia V, Fekkar A, Heath JR, Franco JL, Anaya JM, Solé-Violán J, Imberti L, Biondi A, Bonfanti P, Castagnoli R, Delmonte OM, Zhang Y, Snow AL, Holland SM, Biggs C, Moncada-Vélez M, Arias AA, Lorenzo L, Boucherit S, Coulibaly B, Anglicheau D, Planas AM, Haerynck F, Duvlis S, Nussbaum RL, Ozcelik T, Keles S, Bousfiha AA, El Bakkouri J, Ramirez-Santana C, Paul S, Pan-Hammarström Q, Hammarström L, Dupont A, Kurolap A, Metz CN, Aiuti A, Casari G, Lampasona V, Ciceri F, Barreiros LA, Dominguez-Garrido E, Vidigal M, Zatz M, van de Beek D, Sahanic S, Tancevski I, Stepanovskyy Y, Boyarchuk O, Nukui Y, Tsumura M, Vidaur L, Tangye SG, Burrel S, Duffy D, Quintana-Murci L, Klocperk A, Kann NY, Shcherbina A, Lau YL, Leung D, Coulongeat M, Marlet J, Koning R, Reyes LF, Chauvineau-Grenier A, Venet F, Monneret G, Nussenzweig MC, Arrestier R, Boudhabhay I, Baris-Feldman H, Hagin D, Wauters J, Meyts I, Dyer AH, Kennelly SP, Bourke NM, Halwani R, Sharif-Askari NS, Dorgham K, Sallette J, Sedkaoui SM, AlKhater S, Rigo-Bonnin R, Morandeira F, Roussel L, Vinh DC, Ostrowski SR, Condino-Neto A, Prando C, Bonradenko A, Spaan AN, Gilardin L, Fellay J, Lyonnet S, Bilguvar K, Lifton RP, Mane S; HGID Lab; COVID Clinicians; COVID-STORM Clinicians; NIAID Immune Response to COVID Group; NH-COVAIR Study Group; Danish CHGE; Danish Blood Donor Study; St. James's Hospital; SARS CoV2 Interest group; French COVID Cohort Study Group; Imagine COVID-Group; Milieu Intérieur Consortium; CoV-Contact Cohort; Amsterdam UMC Covid-19; Biobank Investigators; COVID Human Genetic Effort; CONSTANCES cohort; 3C-Dijon Study; Cerba Health-Care; Etablissement du Sang study group, Anderson MS, Boisson B, Béziat V, Zhang SY, Vandreakos E, Hermine O, Pujol A, Peterson P, Mogensen TH, Rowen L, Mond J, Debette S, de Lamballerie X, Duval X, Mentré F, Zins M, Soler-Palacin P, Colobran R, Gorochov G, Solanich X, Susen S, Martinez-Picado J, Raoult D, Vasse M, Gregersen PK, Piemonti L, Rodríguez-Gallego C, Notarangelo LD, Su HC, Kisand K, Okada S, Puel A, Jouanguy E, Rice CM, Tiberghien P, Zhang Q, Cobat A, Abel L, Casanova JL.

Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths.

Sci Immunol. 2021;6:eabl4340. doi: 10.1126/sciimmunol.abl4340.

4. Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Zhang Y, Dorgham K, Philippot Q, Rosain J, Béziat V, Manry J, Shaw E, Haljasmägi L, Peterson P, Lorenzo L, Bizien L, Trouillet-Assant S, Dobbs K, de Jesus AA, Belot A, Kallaste A, Catherinot E, Tandjaoui-Lambiotte Y, Le Pen J, Kerner G, Bigio B, Seeleuthner Y, Yang R, Bolze A, Spaan AN, Delmonte OM, Abers MS, Aiuti A, Casari G, Lampasona V, Piemonti L, Ciceri F, Bilguvar K, Lifton RP, Vasse M, Smadja DM, Migaud M, Hadjadj J, Terrier B, Duffy D, Quintana-Murci L, van de Beek D, Roussel L, Vinh DC, Tangye SG, Haerynck F, Dalmau D, Martinez-Picado J, Brodin P, Nussenzweig MC, Boisson-Dupuis S, Rodríguez-Gallego C, Vogt G, Mogensen TH, Oler AJ, Gu J, Burbelo PD, Cohen JI, Biondi A, Bettini LR, D'Angio M, Bonfanti P, Rossignol P, Mayaux J, Rieux-Laucat F, Husebye ES, Fusco F, Ursini MV, Imberti L, Sottini A, Paghera S, Quiros-Roldan E, Rossi C, Castagnoli R, Montagna D, Licari A, Marseglia GL, Duval X, Ghosn J; HGID Lab; NIAID-USUHS Immune Response to COVID Group; COVID Clinicians; COVID-STORM Clinicians; Imagine COVID Group; French COVID Cohort Study Group; Milieu Intérieur Consortium; CoV-Contact Cohort; Amsterdam UMC Covid-19 Biobank; COVID Human Genetic Effort, Tsang JS, Goldbach-Mansky R, Kisand K, Lionakis MS, Puel A, Zhang SY, Holland SM, Gorochov G, Jouanguy E, Rice CM, Cobat A, Notarangelo LD, Abel L, Su HC, Casanova JL.

 Autoantibodies against type I IFNs in patients with life-threatening COVID-19.

Science. 2020; 370(6515):eabd4585. doi: 10.1126/science.abd4585. Epub 2020 Sep 24. PMID: 32972996.

5. Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, Ogishi M, Sabli IKD, Hodeib S, Korol C, Rosain J, Bilguvar K, Ye J, Bolze A, Bigio B, Yang R, Arias AA, Zhou Q, Zhang Y, Onodi F, Korniotis S, Karpf L, Philippot Q, Chbihi M, Bonnet-Madin L, Dorgham K, Smith N, Schneider WM, Razooky BS, Hoffmann HH, Michailidis E, Moens L, Han JE, Lorenzo L, Bizien L, Meade P, Neehus AL, Ugurbil AC, Corneau A, Kerner G, Zhang P, Rapaport F, Seeleuthner Y, Manry J, Masson C, Schmitt Y, Schlüter A, Le Voyer T, Khan T, Li J, Fellay J, Roussel L, Shahrooei M, Alosaimi MF, Mansouri D, Al-Saud H, Al-Mulla F, Almourfi F, Al-Muhsen SZ, Alsohime F, Al Turki S, Hasanato R, van de Beek D, Biondi A, Bettini LR, D'Angio' M, Bonfanti P, Imberti L, Sottini A, Paghera S, Quiros-Roldan E, Rossi C, Oler AJ, Tompkins MF, Alba C, Vandernoot I, Goffard JC, Smits G, Migeotte I, Haerynck F, Soler-Palacin P, Martin-Nalda A, Colobran R, Morange PE, Keles S, Çölkesen F, Ozcelik T, Yasar KK, Senoglu S, Karabela ŞN, Rodríguez-Gallego C, Novelli G, Hraiech S, Tandjaoui-Lambiotte Y, Duval X, Laouénan C; COVID-STORM Clinicians; COVID Clinicians; Imagine COVID Group; French COVID Cohort Study Group; CoV-Contact Cohort; Amsterdam UMC Covid-19 Biobank; COVID Human Genetic Effort; NIAID-USUHS/TAGC COVID Immunity Group, Snow AL, Dalgard CL, Milner JD, Vinh DC, Mogensen TH, Marr N, Spaan AN, Boisson B, Boisson-Dupuis S, Bustamante J, Puel A, Ciancanelli MJ, Meyts I, Maniatis T, Soumelis V, Amara A, Nussenzweig M, García-Sastre A, Krammer F, Pujol A, Duffy D, Lifton RP, Zhang SY, Gorochov G, Béziat V, Jouanguy E, Sancho-Shimizu V, Rice CM, Abel L, Notarangelo LD, Cobat A, Su HC, Casanova JL.

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.

Science. 2020;370(6515):eabd4570. doi: 10.1126/science.abd4570. Epub 2020 Sep 24. PMID: 32972995.

6. Fusco F, Pescatore A, Steffann J, Bonnefont JP, De Oliveira J, Lioi MB, Ursini MV.

Clinical utility gene card: for incontinentia pigmenti.

Eur J Hum Genet. 2019;27:1894-1900. doi: 10.1038/s41431-019-0463-9. Epub 2019 Jul 9. PMID: 31289372; PMCID: PMC6871521.

7. Fusco F, Valente V, Fergola D, Pescatore A, Lioi MB, Ursini MV.

The Incontinentia Pigmenti Genetic Biobank: study design and cohort profile to facilitate research into a rare disease worldwide.

Eur J Hum Genet. 2019;27:1509-1518. doi: 10.1038/s41431-019-0451-0. Epub 2019 Jun 23. PMID: 31231133; PMCID: PMC6777495.

8. Fusco F., Conte MI, Diociaiuti A., Bigoni S., Branda MF., Ferlini A., El Hachem M., Ursini MV.

Unusual Father-To-Daughter Transmission of Incontinentia Pigmenti due to Mosaicism in IP Males

Pediatrics. 2017: e20162950. doi: 10.1542/peds.2016-2950.

9. Fusco F, Pescatore A, Conte MI, Mirabelli P, Paciolla M, Esposito E, Lioi MB, Ursini MV.

EDA-ID and IP, Two Faces of the Same Coin: How the Same IKBKG/NEMO Mutation Affecting the NF-κB Pathway Can Cause Immunodeficiency and/or Inflammation.

Int Rev Immunol. 2015. 2;34:445-59.

10. Paciolla M, Pescatore A, Conte MI, Esposito E, Incoronato M, Fusco F*, Ursini MV*.

Rare Mendelian Primary Immunodeficiency diseases associated to impaired NF-kB signaling.

Genes and Immunity 2015; 16:239-46. Review.

*This Author should be considered Co-corresponding Authors.

11. Fusco F*, Paciolla M, Conte MI, Pescatore A, Esposito E, Mirabelli P, Lioi MB, Ursini MV. Incontinentia pigmenti: report on data from 2000 to 2013.

Orphanet J Rare Dis. 2014;9:93. doi: 10.1186/1750-1172-9-93.

*This Author should be considered First and corresponding Author.

12. Conte MI, Pescatore A, Paciolla M, Esposito E, Miano MG, Lioi MB, McAleer MA, Giardino G, Pignata C, Irvine AD, Scheuerle AE, Royer G, Hadj-Rabia S, Bodemer C, Bonnefont JP, Munnich A, Smahi A, Steffann J, Fusco F*, Ursini MV*.

Insight into IKBKG/NEMO locus: report of new mutations and complex genomic rearrangements leading to incontinentia pigmenti disease.

Hum Mutat. 2014; 35:165-177. doi: 10.1002/humu.22483. Epub 2013 Dec 12.

*These Authors contributed equally and should be considered joint corresponding and last Author.

13. Fusco F, Paciolla M, Napolitano F, Pescatore A, D'Addario I, Bal E, Lioi MB, Smahi A, Miano MG, Ursini MV.

Genomic architecture at the Incontinentia Pigmenti locus favours de novo pathological alleles through different mechanisms.

Hum Mol Genet 2012; 15;21:1260-1271.

14. Fusco F, Paciolla M, Chen E, Li X, Genesio R, Conti A, Jones J, Poeta L, Lioi MB, Ursini MV, Miano MG.

Genetic and molecular analysis of a new unbalanced X;18 rearrangement: localization of the diminished ovarian reserve disease locus in the distal Xq POF1 region.

Hum Reprod. 2011; 26:3186-3196.

15. Fusco F, D'Urso M, Miano MG, Ursini MV.

The LCR at the IKBKG locus is prone to recombine.

Am J Hum Genet. 2010;86:650-652.

16. Fusco F., Paciolla M., Pescatore A., Lioi MB., Ayuso C., Faravelli F., Gentile M., Zollino M., D’Urso M., Miano MG., and Ursini MV.

Microdeletion/duplication at the Xq28 IP Locus causes de novo IKBKG/NEMO/IKKgamma exon4_10 deletion in Families with Incontinentia Pigmenti.

Human Mutation, 2009; 30:1284-1291.

EDUCATION

• 2006: post-degree in Food Sciences and Nutrition Federico II University of Naples,
• 2000: PhD in Molecular and Cellular Genetics Federico II University of Naples,
• 1995: Degree in Biological Science Naples, Federico II University of Naples

RESEARCH AND PROFESSIONAL EXPERIENCE

• 2010 -present CNR Researcher, IGB-CNR, Naples.
• 2002 -2010 Senior PostDoc fellow IGB- CNR, Naples.
• 2000-2002 Junior PostDoc fellow “Federico II” University of Naples
• 1996-2000 PhD student in Genetics Federico II” University of Naples
• 1993-1995 degree training, IGB-CNR, Naples

AWARDS AND HONORS

• 2019-present Moderator Human Disease Genes website for IKBKG gene (https://humandiseasegenes.nl/moderators/)
• 2017-2019 Member of BBRMI Working group ELSI for rare patients
• 2017- present Qualified as Associate Professor in Genetics (05/I1)
• 2016-present Manager for BBRMI of IPGB (Incontinentia Pigmenti Genetic Biobank) at the Institute IGB-CNR in Naples (http://www.igb.cnr.it/ipgb)
• 2015- present Manager of Incontinentia Pigmenti Genetic Biobank, IPGB -CNR
• 2015- present Responsible for managing records for the collection of genetic and clinical data of IP patients and principal investigator for the project "Establishment of a genetic biobank for Incontinentia pigmenti", at the Institute IGB-CNR in Naples.
• 2013- present Active database curator for the IKBKG/NEMO gene mutations in Leiden Open Variation Database (LOVD) (http://databases.lovd.nl/shared/genes/IKBKG).
• 2013 Selected delegate for the workshop on Implementation of Clinical Genetic Databases in Manchester, UK.
• 2011- present Responsible of diagnostic test: Molecular diagnosis of incontinentia pigmenti (IKBKG gene)(http://www.orpha.net/consor/cgibin/ClinicalLabs_Search.php?lng=EN&data_id=18677&search=ClinicalLabs_Search_Simple&data_type=Test&title=Diagnosi-molecolare-dell-incontinentia-pigmenti--gene-IKBKG-&MISSING%20CONTENT=Diagnosi-molecolare-dell-incontinentia-pigmenti--gene-IKBKG)

PATENTING

Patent n.PZ2014A00004, CNR: 10315; 10 April 2014, title "Diagnostic Kit and a method for the Incontinentia pigmenti genetic diagnosis” MV Ursini, M Paciolla, F Fusco (CNR), MB Lioi.

FUNDING

2017-2021              Funding Agency: IPASSI (Italian Association of Incontinentia  Pigmenti)  Project: Incontinentia pigmenti Research and diagnosis;

2017-2018              Funding Agency: Consiglio Nazionale delle Ricerche –Dipartimento di Scienze Biomediche Progetto Bandiera “Interomics: 2th Call for Proposal-Cell-based O mics for research applications in precision medicine”; Project: TranscriptOMIC strategy to identify the altered signal pathways in patients with severe forms of Incontinentia pigmenti.