A new amyloidosis caused by fibrillar aggregates of mutated corneodesmosin.
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
Cécile
C
UMR5165 Centre National de la Recherche Scientifique - University of Toulouse III, Toulouse, France.
Bousset
Luc
L
Clemmensen
Ole
O
Sourigues
Yannick
Y
Bygum
Anette
A
Chavanas
Stéphane
S
Coudane
Fanny
F
Hsu
Chiung-Yueh
CY
Betz
Regina C
RC
Melki
Ronald
R
Simon
Michel
M
Serre
Guy
G
D000368:Aged; D000686:Amyloidosis / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002942:Circular Dichroism; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure*; D006801:Humans; D007039:Hypotrichosis / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D046529:Microscopy, Electron, Transmission; D016253:Microscopy, Immunoelectron; D009154:Mutation; D017510:Protein Folding; D012535:Scalp / Q000378:metabolism / Q000473:pathology; D017550:Spectroscopy, Fourier Transform Infrared; D014961:X-Ray Diffraction
C109656:CDSN protein, human; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins