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Novel keratin 16 mutations and protein expression studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma

Novel keratin 16 mutations and protein expression studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma
Novel keratin 16 mutations and protein expression studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma
Pachyonychia congenita type 1 (PC-1) is an autosomal dominant ectodermal dysplasia characterized by nail dystrophy, focal non-epidermolytic palmoplantar keratoderma (FNEPPK) and oral lesions. We have previously shown that mutations in keratin 16 (K16) cause fragility of specific epithelia resulting in phenotypes of PC-1 or FNEPPK alone. Here, we report 2 novel mutations in K16 causing distinct phenotypes. A heterozygous missense mutation (L124R) was detected in a kindred with PC-1. In a family where mild FNEPPK was the only phenotype, a 23 bp deletion and a separate 1 bp deletion downstream were found in exon 6: [1244–1266del; 1270delG]. At the protein level, these mutations remove 8 residues and substitute 2 residues in the helix termination motif (HTM) of the K16 polypeptide. The HTM sequence is conserved in all known intermediate filament proteins and for convenience, this complex mutation was designated ?HTM. Transient expression of K16 cDNAs carrying either the L124R or the ?HTM mutation in epithelial cell line PtK2 produced aggregation of the keratin cytoskeleton. However, the aggregates observed with the ?HTM mutation were morphologically different and appeared to be less disruptive to the endogenous cytoskeleton. Therefore, loss of the HTM sequence may render this mutant K16 less capable of contributing to filament assembly and decrease its dominant-negative effect, resulting in the milder FNEPPK phenotype.
0906-6705
170-177
Smith, F. J. D.
ed6ac972-0a2d-472b-9ea1-017e931b6b89
Fisher, M. P.
dc80462b-49e4-41d5-a147-28660168a2d2
Healy, E.
400fc04d-f81a-474a-ae25-7ff894be0ebd
Rees, J. L.
52f4998d-90a8-417f-ac5b-775534c9c2a3
Bonifas, J. M.
732b7834-ba3b-4930-ba30-d7fb27027c5c
Epstein, E. H.
752adb78-d681-4c19-bb1d-700168213bf7
Tan, E. M. L.
ed8198d6-708f-43ce-a9c7-021a0d2ce256
Uitto, J.
bfb4af2e-fac9-42e8-8cf0-f0a255381684
McLean, W. H. I.
b6952c02-4f4c-4eed-bca1-38c4a317deb1
Smith, F. J. D.
ed6ac972-0a2d-472b-9ea1-017e931b6b89
Fisher, M. P.
dc80462b-49e4-41d5-a147-28660168a2d2
Healy, E.
400fc04d-f81a-474a-ae25-7ff894be0ebd
Rees, J. L.
52f4998d-90a8-417f-ac5b-775534c9c2a3
Bonifas, J. M.
732b7834-ba3b-4930-ba30-d7fb27027c5c
Epstein, E. H.
752adb78-d681-4c19-bb1d-700168213bf7
Tan, E. M. L.
ed8198d6-708f-43ce-a9c7-021a0d2ce256
Uitto, J.
bfb4af2e-fac9-42e8-8cf0-f0a255381684
McLean, W. H. I.
b6952c02-4f4c-4eed-bca1-38c4a317deb1

Smith, F. J. D., Fisher, M. P., Healy, E., Rees, J. L., Bonifas, J. M., Epstein, E. H., Tan, E. M. L., Uitto, J. and McLean, W. H. I. (2000) Novel keratin 16 mutations and protein expression studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma. Experimental Dermatology, 9 (3), 170-177. (doi:10.1034/j.1600-0625.2000.009003170.x). (PMID:10839714)

Record type: Article

Abstract

Pachyonychia congenita type 1 (PC-1) is an autosomal dominant ectodermal dysplasia characterized by nail dystrophy, focal non-epidermolytic palmoplantar keratoderma (FNEPPK) and oral lesions. We have previously shown that mutations in keratin 16 (K16) cause fragility of specific epithelia resulting in phenotypes of PC-1 or FNEPPK alone. Here, we report 2 novel mutations in K16 causing distinct phenotypes. A heterozygous missense mutation (L124R) was detected in a kindred with PC-1. In a family where mild FNEPPK was the only phenotype, a 23 bp deletion and a separate 1 bp deletion downstream were found in exon 6: [1244–1266del; 1270delG]. At the protein level, these mutations remove 8 residues and substitute 2 residues in the helix termination motif (HTM) of the K16 polypeptide. The HTM sequence is conserved in all known intermediate filament proteins and for convenience, this complex mutation was designated ?HTM. Transient expression of K16 cDNAs carrying either the L124R or the ?HTM mutation in epithelial cell line PtK2 produced aggregation of the keratin cytoskeleton. However, the aggregates observed with the ?HTM mutation were morphologically different and appeared to be less disruptive to the endogenous cytoskeleton. Therefore, loss of the HTM sequence may render this mutant K16 less capable of contributing to filament assembly and decrease its dominant-negative effect, resulting in the milder FNEPPK phenotype.

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Published date: June 2000
Organisations: Clinical & Experimental Sciences

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Local EPrints ID: 334310
URI: https://eprints.soton.ac.uk/id/eprint/334310
ISSN: 0906-6705
PURE UUID: 67f418ba-45b6-46f3-bddb-121cf3ab47c7

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Date deposited: 07 Mar 2012 12:16
Last modified: 16 Jul 2019 22:10

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