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A new amyloidosis caused by fibrillar aggregates of mutated corneodesmosin
Author(s) -
Caubet Cécile,
Bousset Luc,
Clemmensen Ole,
Sourigues Yannick,
Bygum Anette,
Chavanas Stéphane,
Coudane Fanny,
Hsu ChiungYueh,
Betz Regina C.,
Melki Ronald,
Simon Michel,
Serre Guy
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-155622
Subject(s) - amyloidosis , amyloid fibril , chemistry , biophysics , pathology , biology , medicine , amyloid β , disease
ABSTRACT Heterozygous nonsense mutations in the CDSN gene encoding corneodesmosin (CDSN), an adhesive protein expressed in cornified epithelia and hair follicles, cause hypotrichosis simplex of the scalp (HSS), a nonsyndromic form of alopecia. Truncated mutants of CDSN ( mut CDSN), which bear the N‐terminal adhesive Gly/Ser‐rich domain (GS domain) of the protein, abnormally accumulate as amorphous deposits at the periphery of hair follicles and in the papillary dermis of the patient skin. Here, we present evidence that the mut CDSN deposits display an affinity for amyloidophilic dyes, namely Congo red and thioflavin T. We also detected the serum amyloid protein component in the dermis of HSS patients. We demonstrated that recombinant forms of mut CDSN and of the GS domain assemble in vitro into ring‐shaped oligomeric structures and fibrils. The amyloid‐like nature of the fibrils was demonstrated by dye binding and Fourier transform infrared spectrometry measurements. We showed that the ring‐shaped oligomers of mut CDSN, but not the fibrillar forms, are toxic to cultured keratinocytes. Finally, online algorithms predicted the GS domain to be a particularly disordered region of CDSN in agreement with circular dichroism measurements. This identifies HSS as a human amyloidosis related to the aggregation of natively unfolded mut CDSN polypeptides into amyloid fibrils.—Caubet, C., Bousset, L., Clemmensen, O., Sourigues, Y., Bygum, A., Chavanas, S., Coudane, F., Hsu, C.‐Y., Betz, R. C., Melki, R., Simon, M., Serre, G. A new amyloidosis caused by fibrillar aggregates of mutated corneodesmosin. FASEB J . 24, 3416–3426 (2010). www.fasebj.org