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Maladie de Steinert 

ou dystrophie myotonique de Steinert (type I)

Myopathie héréditaire: maladie autosomique dominante

Signes cliniques: dystrophie musculaire, myotonie et anomalies sur de nombreux autres organes (yeux, coeur atteinte respiratoire, gonades)

1 cas pour 7500 naissances

Aspects moléculaires: 

Anomalie génétique liée à des répétitions excessives du codon CTG sur le bras long du chromosome 19, and la partie 3' UTR de la DMPK (dystrophic myotonin protein kinase).

Cette anomalie provoque un épissage anormal des protéines tau. (Sergeant N, 2001)

Il est possible de reproduire cette anomalie dans une souris transgénique (Seznec H, 2001)

5' 3'


Myotonic dystrophy type 1 (DM1) is a dominantly inherited multisystemic disorder caused by unstable expansion of CTG trinucleotide repeats in a gene encoding a serine/threonine protein kinase, named DMPK . The normal allele is polymorphic, ranging from 5 to 35 CTG repeats whereas in DM1 the pathologic allele expands from 50 to multiple thousands of CTG repeats. Expansion of the CTG repeat is correlated with the disease severity and with the anticipation of the age of onset . The clinical expression of DM1 is extremely variable and includes myotonia and progressive muscle weakness, frontal baldness, cataract, cardiac conduction defects, hypogonadism, endocrine deficiency and mental retardation .

Neurofibrillary tangles (NFT) in the neocortex and in subcortical nuclei of DM1 patients have been described in several studies . NFT, as described in Alzheimer's disease, consists of intraneuronal accumulation of paired helical filaments (PHF) . They result from the aggregation of hyperphosphorylated microtubule-associated tau proteins , referred to as PHF-tau or pathological tau proteins .

Tau protein belongs to the family of microtubule-associated proteins . They are essentially expressed in neurons where their essential function is to regulate the microtubule network. In the adult human brain, alternative splicing of exons 2, 3 and 10 of the single tau gene transcript gives six tau isoforms (Fig. 1A). Mutations in the tau gene are responsible for Frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) . The mutations are distributed over exons 9 to 13 and in the introns flanking the exon 10. These mutations lead to alteration of tau protein binding to microtubule or affect the post-transcriptional maturation of tau pre-mRNA and thus changing the tau isoform stoichiometry of expression .

Yet, tau pathology is observed in 22 neurodegenerative disorders merged as tauopathies . Four tauopathy classes are distinguishable by the tau protein isoforms that constitute the specific pathological tau electrophoretic profile . Thus, in AD the six isoforms determine the pathological tau triplet at 60, 64 and 69 kDa and the minor 74 kDa component (Class 1) . Tau isoforms containing the exon 10 compose the pathological tau doublet at 64 and 69 kDa (Class 2) that is observed in PSP and corticobasal degeneration (CBD) . The tau isoforms lacking the exon 10 constitute the typical doublet at 60 and 64 kDa of Pick’s disease (PiD) (Class 3) . Depending on the tau gene mutation, FTDP-17 pathological tau patterns belong to classes 1 to 3 . In contrast, the pathological tau profile of class 4 is characterized by a major 60 kDa component, a 64 kDa and minor 69 kDa component. It is restricted to DM1 . These data suggest that specific sets of isoforms are expressed in particular subsets of neurons selectively affected according to the neurodegenerative disorder .

Upon multiple molecular mechanism hypotheses, recent data suggest that the expanded CUG repeat in the 3’ UTR of the DMPK mRNA act as a gain-of-function mutation by sequestering RNA binding proteins, leading to depletion of transcripts that require these protein for normal gene expression . The specific pathological tau pattern observed in DM1 suggests that a specific set of tau protein isoforms is implicated in this neurodegenerative disorder . Our results suggest that the (CTG)n expansion is altering the processing of tau pre-mRNA splicing, leading to a change in tau protein isoforms expression.

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