CMT 1A: medaka fish functional and comparative analyses of pmp22

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BMC Neurosci. 2009 Jun 17;10(1):60.

Functional and comparative genomics analyses of pmp22 in medaka fish.

Itou J, Suyama M, Imamura Y, Deguchi T, Fujimori K, Yuba S, Kawarabayasi Y,

Kawasaki T.

ABSTRACT: BACKGROUND: Pmp22, a member of the junction protein family

Claudin/EMP/PMP22, plays an important role in myelin formation. Increase of

pmp22 transcription causes peripheral neuropathy, Charcot-Marie-Tooth disease

type1A (CMT1A).

The pathophysiological phenotype of CMT1A is aberrant axonal myelination which

induces a reduction in nerve conduction velocity (NCV).

Several CMT1A model rodents have been established by overexpressing pmp22. Thus,

it is thought that pmp22 expression must be tightly regulated for correct myelin

formation in mammals.

Interestingly, the myelin sheath is also present in other jawed vertebrates.

The purpose of this study is to analyze the evolutionary conservation of the

association between pmp22 transcription level and vertebrate myelin formation,

and to find the conserved non-coding sequences for pmp22 regulation by

comparative genomics analyses between jawed fishes and mammals.

RESULTS: A transgenic pmp22 over-expression medaka fish line was established.

The transgenic fish had approximately one fifth the peripheral NCV values of

controls, and aberrant myelination of transgenic fish in the peripheral nerve

system (PNS) was observed.

We successfully confirmed that medaka fish pmp22 has the same exon-intron

structure as mammals, and identified some known conserved regulatory motifs.

Furthermore, we found novel conserved sequences in the first intron and 3'UTR.

CONCLUSIONS: Medaka fish undergo abnormalities in the PNS when pmp22

transcription increases. This result indicates that an adequate pmp22

transcription level is necessary for correct myelination of jawed vertebrates.

Comparison of pmp22 orthologs between distantly related species identifies

evolutionary conserved sequences that contribute to precise regulation of pmp22

expression.