Two novel missense mutations in the myelin protein zero gene causes Charcot-Marie-Tooth type 2 and Déjérine-Sottas syndrome

Abstract

BackgroundThe Charcot-Marie-Tooth (CMT) phenotype caused by mutation in the myelin protein zero (MPZ) gene varies considerably, from early onset and severe forms to late onset and milder forms. The mechanism is not well understood. The myelin protein zero (P0) mediates adhesion in the spiral wraps of the Schwann cell's myelin sheath. The crystalline structure of the extracellular domain of the myelin protein zero (P0ex) is known, while the transmembrane and intracellular structure is unknown.FindingsOne novel missense mutation caused a milder late onset CMT type 2, while the second missense mutation caused a severe early onset phenotype compatible with Déjérine-Sottas syndrome.ConclusionsThe phenotypic variation caused by different missense mutations in the MPZ gene is likely caused by different conformational changes of the MPZ protein which affects the functional tetramers. Severe changes of the MPZ protein cause dysfunctional tetramers and predominantly uncompacted myelin, i.e. the severe phenotypes congenital hypomyelinating neuropathy and Déjérine-Sottas syndrome, while milder changes cause the phenotypes CMT type 1 and 2.

Glycans of myelin proteins

“…Is there any other evidence that mutation at position x 94 is linked to disease and is affecting glycosylation? There are three new mutations associated with a peripheral neuropathy occurring in position x 94 : G 94 →C (Boerkoel et al, ) and the recently discovered mutations G 94 →S and G 94 →D (Braathen et al, ); neither of these recently discovered mutations has yet been deposited (June, 2014) in the database http://www.uniprot.org/uniprot/P25189. Glycosylation has not been investigated in functional studies, the NetNGlyc 1.0 Server predicts that glycosylation is not prohibited for G 94 →C and may not occur in mutations G 94 →S and G 94 →D (Braathen et al, ).…”

Early-onset CMT1B due to the MPZ mutation c.320A>T associated with collateral inclusion body myopathy and Deafness

“…Mutations in the myelin protein zero (MPZ) gene cause hereditary, autosomal dominant demyelinating sensorimotor polyneuropathy Charcot-Marie-Tooth (CMT) 1B [1], late-onset, mixed demyelinating and axonal polyneuropathy [2,3]. late-onset autosomal dominant, axonal sensorimotor polyneuropathy CMT 2I/J [3,4], early-onset Dejerine-Sottas syndrome [5], or congenital hypomyelinating polyneuropathy [6,7,8,9]. Though MPZ-mutations have been reported to cause deafness [10,11,12] and may go along with elevated creatine-kinase (CK) [13], the association of an MPZ-mutation with early-onset demyelinating neuropathy, hypoacusis and neuropathological features of inclusion-body-myopathy (IBM), as in the following case, has not been reported.…”