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    Genetics of neurofibromatosis type 2 and schwannomatosis



    Principal Investigators

    Béatrice Parfait (MCU-PH, Université Paris Descartes)


    Dominique Lallemand (CR1, INSERM)




    Neurofibromatosis type 2 (MIM101000) is an autosomal-dominant disease with a frequency of 1/25000 livebirths. Patients are predisposed to develop bilateral vestibular schwannomas, although schwannomas in other cranial, spinal and peripheral nerves can also be observed. Additional clinical features include various type of nervous system tumors (meningiomas and ependymomas), ocular and cutaneous lesions. This tumor predisposition syndrome results from the loss of function of the NF2 tumour suppressor gene located on chromosome 22q12.2. Half of patients are sporadic cases and recent studies show the presence of mosaicism in 20 to 30% of de novo cases. Schwannomas are also observed in schwannomatosis (MIM162091) another tumor predisposition characterized by the development of multiple schwannomas. Germline mutations of SMARCB1 et LZTR1 genes localized in the proximity of the NF2 gene are involved in familial and sporadic forms of schwannomatosis.

    We aim to understand the molecular bases of schwannomas development in NF2 and schwannomatosis by studying the functional consequences of genetic alterations on tumorigenesis using tumor samples, primary Schwann cells or immortalized Schwann cells genetically modified with CRIPSR Cas9 to selectively target NF2, LZTR1 and SMARCB1.


    The group

    Eric Pasmant (MCU-PH, Université Paris Descartes)

    Ingrid Laurendeau (IE, Université Paris Descartes)

    Doriane Saintemarie (TCH, Université Paris Descartes)


    Research interests

    In accordance with results of other groups, we have recently shown that two thirds of NF2 patients’ schwannomas carry a germline mutation in the NF2 gene combined to the somatic inactivation of the second NF2 allele corresponding to the deletion of the NF2-SMARCB1-LZTR1 chromosomal region (Louvrier et al 2018).

    Furthermore, schwannomas development in patients with a germinal mutation of SMARCB1 or LZTR1 are linked to the bi-allelic inactivation of these genes. This one can be associated with a mono or bi-allelic inactivation of NF2 (Kehrer et al 2017 for review). Finally, a recent analysis of the exomes of sporadic schwannomas has revealed the involvement of bi-allelic somatic mutations of NF2 in 77% of the tumors, often associated with mutations of LZTR1 (Agnihotri S et al 2016).


    NF2 is primarily a major regulator of the Hippo signaling pathway. LZTR1 is a negative regulator of the Ras family of GTPases whereas SMARCB1 is involved in transcriptional regulation through chromatin remodeling. Although the main cellular functions of these three tumor suppressors are relatively well documented, the mechanisms of their functional synergies following co-inactivation are still poorly understood. Finally, additional yet uncharacterized cellular functions of NF2 and LZTR1 are likely to be involved in tumor development and require further investigation.

    Our group thus has two main objectives:

    (1) to understand the functional  consequences of the co-inactivation of NF2 and LZTR1 in Schwann cells, its impact on proliferation and transformation, its role in tumor development, and its consequences on the definition of potential therapeutic targets.

    (2) to identify potential new cellular functions for NF2 and LZTR1, likely to be implicated in tumor development and to influence the nature of therapeutic targets.




    Main publications

    Louvrier C, Pasmant E, Briand-Suleau A, Cohen J, Nitschké P, Nectoux J, Orhant L, Zordan C, Goizet C, Goutagny S, Lallemand D, Vidaud M, Vidaud D, Kalamarides M, Parfait B. Targeted next-generation sequencing for differential diagnosis of neurofibromatosis type 2, schwannomatosis, and meningiomatosis. Neuro Oncol. 2018;20:917-929. (

    Tauziede-Espariat A, Parfait B, Besnard A, Lacombe J, Pallud J, Tazi S, Puget S, Lot G, Terris B, Cohen J, Vidaud M, Figarella-Branger D, Monnien F, Polivka M, Adle-Biassette H, Varlet P. Loss of SMARCE1 expression is a specific diagnostic marker of clear cell meningioma: a comprehensive immunophenotypical and molecular analysis. Brain Pathol. 2018;28(4):466-474. (

    Pasmant E, Louvrier C, Luscan A, Cohen J, Laurendeau I, Vidaud M, Vidaud D, Goutagny S, Kalamarides M, Parfait B. Neurofibromatosis type 2 French cohort analysis using a comprehensive NF2 molecular diagnostic strategy. Neurochirurgie. 2018;64(5):335-341 (

    Sabra H, Brunner M, Mandati V, Wehrle-Haller B, Lallemand D, Ribba AS, Chevalier G, Guardiola P, Block MR, Bouvard D. β1 integrin-dependent Rac/group I PAK signaling mediates YAP activation of Yes-associated protein 1 (YAP1) via NF2/merlin. J Biol Chem. 2017;292(47):19179-19197. (

    Couderc C, Boin A, Fuhrmann L, Vincent-Salomon A, Mandati V, Kieffer Y, Mechta-Grigoriou F, Del Maestro L, Chavrier P, Vallerand D, Brito I, Dubois T, De Koning L, Bouvard D, Louvard D, Gautreau A, Lallemand D. AMOTL1 Promotes Breast Cancer Progression and Is Antagonized by Merlin. Neoplasia 2016;18(1):10-24 (

    Boin A, Couvelard A, Couderc C, Brito I, Filipescu D, Kalamarides M, Bedossa P, De Koning L, Danelsky C, Dubois T, Hupé P, Louvard D, Lallemand D. Proteomic screening identifies a YAP-driven signaling network linked to tumor cell proliferation in human schwannomas. Neuro Oncol. 2014;16(9):1196-209 (