Des modifications du gène PMP22 (Peripheral Myelin Protein 22) sont responsables de neuropathies du système nerveux périphérique : l’Hypersensibilité à la Pression (HNPP : Hereditary Neuropathy with liability to Pressure Palsy) lorsqu’il est délété, CMT1A (Charcot-Marie-Tooth type 1A) lorsqu’il est dupliqué et CMT1E ou HNPP lors de mutations ponctuelles. Cependant, le rôle de la protéine PMP22 dans ces neuropathies demeure obscur. Dans un premier temps, nous nous sommes intéressés aux partenaires d’interactions potentiels de PMP22 : l’intégrine α6β4 (un récepteur des laminines), pourrait être impliqué dans le CMT1A. Dans cette étude, nous avons utilisé un modèle de rat transgénique portant des copies supplémentaires de PMP22 de souris. Chez ce modèle, nous avons mis en évidence des variations d’expression génique des intégrines, ainsi qu’une mauvaise localisation cellulaire de celles-ci. Ces variations des niveaux d’expression des intégrines sont les témoins d’un retard de la maturation des cellules de Schwann myélinisantes, expliquant la diminution de l’épaisseur des gaines de myéline, observée chez les rats CMT1A. Dans un second temps, nous avons étudié le cas particulier d’un patient sans expression de PMP22, en raison de deux mutations composites sur les deux allèles de PMP22. Nous avons observé que l’absence de PMP22 chez l’homme entraine une absence complète de myéline due à un blocage de l’initialisation de la myélinisation lors de la formation du mésaxone. Dans un troisième temps, nous avons effectué une étude comparative de modèles animaux et de patients atteints de CMT1A / 1E et d’HNPP permettant de valider l’utilisation de tels modèles dans l’étude de ses neuropathies. Enfin, nous nous sommes intéressés d’un point de vue informatique à la structure tridimensionnelle de différentes protéines dont PMP22 grâce à la dynamique moléculaire. Ce modèle tridimensionnel de PMP22 est le point de départ de l’étude des mutations ponctuelles ainsi que des interactions de PMP22 avec son environnement. Grâce aux animaux modèles et à l’étude de patients, nous avons montré le rôle indispensable de PMP22 dans l’initialisation de la myélinisation ainsi que son effet sur les intégrines dans le CMT1A. L’utilisation de modèles informatiques tridimensionnels créés de PMP22 permettra de comprendre les effets des mutations ponctuelles sur sa structure, et ses interactions. / Interactions study of PMP22 protein with integrins in Charcot-Marie-Tooth disease type 1A pathogenesisChanges in the PMP22 gene (Peripheral Myelin Protein 22) are responsible for peripheral nervous system neuropathies: Hereditary Neuropathy with liability to Pressure Palsy (HNPP) when PMP22 is deleted, Charcot Marie Tooth disease subtype 1A (CMT1A) when PMP22 is duplicated and CMT1E or HNPP when point mutations are present on the PMP22 gene. However, the PMP22 role in these neuropathies remains unclear. Firstly, we studied one of the PMP22 interaction partner: the α6β4 integrin (a laminin receptor), which could be involved in the CMT1A. During this study, we used a transgenic rat model carrying supplementary copies of PMP22 gene from mouse. With this model, we showed variations of expression of integrins genes and a mislocalization of integrins proteins. These variations of integrins witnesses a delay in myelinating Schwann cells maturation, explaining the reduction of myelin sheath thickness observed on CMT1A rats. In a second time, we studied the case of a patient without PMP22 expression, carrying compound mutations one the two alleles of PMP22. We showed that the lack of PMP22 on human leads to a complete lack of myelin due to a blocking in mesaxon formation. In a third time, we conducted a comparative study of animal models and patients with CMT1A / 1E and HNPP. This study allows us to validate the use of such models in the study of neuropathies. Finally, thanks to computational tools we studied the three-dimensional structure of different protein, including PMP22 by using molecular dynamics. This three-dimensional model is the starting point of point mutations study as well as PMP22 interactions with its environments. With animal models and through the study of patients, we have demonstrated the indispensable role of PMP22 in myelin initiation as well as, its effect on integrins expression in CMT1A. The use of PMP22 three-dimensional computational model will help us to understand effects of point mutation on PMP22 structure and interactions.

A neuropatia hansênica e a neuropatia hereditária com suscetibilidade à pressão (Hereditary Neuropathy with liability to Pressure Palsies - HNPP) são mononeuropatias múltiplas em que os estudos da condução nervosa (ECN) mostram geralmente alentecimento focal em topografias muito semelhantes. Na ausência de uma história familiar de HNPP e das manifestações na pele típicas da hanseníase, o diagnóstico diferencial entre elas pode ser muito difícil. Procurando identificar características que ajudassem a distinguir essas doenças, revisamos e catalogamos os dados da história clínica e dos ECN de 39 pacientes com HNPP e 78 pacientes com neuropatia hansênica. A manifestação inicial mais frequente na hanseníase foi o déficit sensitivo (43 pacientes-55.1%) e na HNPP foi a fraqueza muscular localizada indolor (24 pacientes-61%). Fraqueza muscular foi significativamente superior na HNPP e déficit sensitivo foi significativamente superior na hanseníase (p<0.001). A evolução clínica foi estável ou progressiva até o tratamento em todos os pacientes com hanseníase e na HNPP dez pacientes (25.6%) tiveram um curso progressivo e 29 (74.4%) uma evolução com flutuações. O padrão predominante ao exame neurológico foi a mononeuropatia múltipla: 66 pacientes (84.6%) na hanseníase e 26 pacientes (66.7%) na HNPP. Espessamento neural foi mais frequente na hanseníase (p=0,001) e déficit sensitivo intradérmico foi observado somente na hanseníase (p<0,001). Episódio prévio ou atual de paralisia aguda de nervo foi referido somente na HNPP (p<0,001). O padrão dos ECN prevalente foi a neuropatia sensitivo-motora assimétrica com alentecimento focal da condução (NSMAAF): 44 pacientes (56.4%) na hanseníase e 31 pacientes (94.0%) na HNPP. Os parâmetros clínicos mais úteis em distinguir as duas doenças foram: a perda sensitiva intradérmica com comprometimento precoce das fibras finas e ocorrência de reação hansênica na hanseníase; o envolvimento motor inicial predominante, episódios de paralisia aguda de nervo e a evolução com flutuações na HNPP. Se o paciente a ser avaliado apresentar mononeuropatia múltipla com alentecimentos focais da velocidade de condução, os seguintes achados neurofisiológicos sugerem hanseníase: a não detecção de potenciais sensitivos ou motores, a redução da amplitude dos potenciais de ação sensitivos dos nervos sural, fibular superficial e radial superficial (< 8,8 ?V), a redução da amplitude do potencial de ação muscular composto dos nervos ulnar e tibial posterior, a redução da velocidade de condução do potencial de ação muscular composto do nervo ulnar motor no segmento do antebraço (< 43 m/s) e a presença de dispersão temporal frequente; enquanto os seguintes achados sugerem HNPP: aumento desproporcional da latência distal do nervo mediano motor e a presença de bloqueio de condução. / The Hansen\'s disease neuropathy (HDN) and the Hereditary Neuropathy with liability to Pressure Palsies (HNPP) are multiple mononeuropathies whose nerve conduction studies (NCS) usually show focal slowing at very similar topographies. In the absence of a family history of HNPP and the typical skin manifestations of HD, the differential diagnosis between them may be very difficult. In order to identify characteristics that may distinguish these diseases, we reviewed the data of 39 patients with HNPP and of 78 patients with HDN. The most frequent presenting sign was a sensory deficit in 43 patients (55.1%) in the HDN and a localized painless muscular weakness in 24 patients (61%) in the HNPP. Muscle weakness was significantly higher in HNPP and sensory deficit was significantly higher in leprosy (p<0.001). The disease was stable or progressive until treatment in all patients with HDN and among HNPP ten patients (25.6%) had a progressive course and 29 (74.4%) an intermittent evolution. Neural thickening was more frequent in leprosy (p=0.001) and intradermal sensory deficit was observed only in leprosy (p<0.001). Previous or current episode of acute nerve palsy was reported only in HNPP (p<0.001). The predominant pattern on neurological examination was the multiple mononeuropathy: 66 patients (84.6%) in the HDN and 26 patients (66.7%) in the HNPP. The most prevalent pattern of NCS was an asymmetric sensorimotor neuropathy with focal slowing (ASMNFS): 44 patients (56.4%) in HDN and 31 patients (94.0%) in HNPP. The most helpful clinical parameters in distinguishing these diseases were the presence of leprosy reaction and the intradermal sensory loss with predominant early involvement of small nerve fibers in HDN; the initial predominant motor involvement, episodes of acute nerve palsies and the intermittent evolution in HNPP. If the patient evaluation show a pattern of multiple mononeuropathy with focal slowing, the following neurophysiological findings suggest HDN: no detection of sensory or motor potentials, amplitude reduction of the sural, superficial fibular and superficial radial (<8.8 ?V) nerves, amplitude reduction of the motor ulnar and posterior tibial nerves, reduction of the conduction velocity of the motor ulnar nerve at the forearm segment (<43 m/s) and the presence of frequent temporal dispersion; while the following findings suggest HNPP: a disproportionate increase in the motor distal latency of the median nerve and the presence of conduction block.