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- Title
A new amyloidosis caused by fibrillar aggregates of mutated corneodesmosin.
- Abstract
Heterozygous nonsense mutations in the CDSN gene encoding corneodesmosin (CDSN), an adhesive protein expressed in cornified epithelia and hai follicles, cause hypotrichosis simplex of the scal (HSS), a nonsyndromic form of alopecia. Truncate mutants of CDSN (mutCDSN), which bear the N-terminal adhesive Gly/Ser-rich domain (GS domain) of the protein, abnormally accumulate as amorphous deposit at the periphery of hair follicles and in the papillar dermis of the patient skin. Here, we present evidence that the mutCDSN deposits display an affinity for amyloidophilic dyes, namely Congo red and thiofiavin T We also detected the serum amyloid protein component in the dermis of HSS patients. We demonstrate that recombinant forms of mutCDSN and of the GS domain assemble in vitro into ring-shaped oligomeri structures and fibrils. The amyloid-like nature of the fibrils was demonstrated by dye binding and Fourie transform infrared spectrometry measurements. We showed that the ring-shaped oligomers of mutCDSN, but not the fibrillar forms, are toxic to cultured keratino cytes. Finally, online algorithms predicted the GS do main to be a particularly disordered region of CDSN is agreement with circular dichroism measurements. This identifies HSS as a human amyloidosis related to the mutaggregation of natively unfolded mutCDSN polypep tides into amyloid fibrils.
- Subjects
AMYLOIDOSIS; KERATINOCYTES; HAIR follicles; BALDNESS; SKIN diseases
- Publication
FASEB Journal, 2010, Vol 24, Issue 9, p3416
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.10-155622