Cloning of multiple keratin 16 genes facilitates prenatal diagnosis of pachyonychia congenita type 1

Smith, Frances J.D.; McKusick, Victor A.; Nielsen, Karl; Pfendner, Ellen G; Uitto, Jouni; McLean, Whi

doi:10.1002/(sici)1097-0223(199910)19:10<941::aid-pd663>3.3.co;2-n

Cited by 3 publications

(12 citation statements)

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“…Among these cases, four presented with the PC-1 phenotype, and had mutations L132P, DS130, Q122P and R127P. 16,26 The other two reported K16 mutations produced FNEPPK either with minimal nail changes, such as widening of the onychocorneal band and/or splinter haemorrhages, or no nail changes at all. These FNEPPK families had mutations N125S and R127C.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, using a recently developed long-range PCR strategy to amplify the entire K16 rod domain from genomic DNA without pseudogene contamination, 26 we have identified two new PC-1 mutations, R127P and Q122P in the 1A domain of K16. Both mutations were excluded from a population of 100 normal chromosomes by restriction enzyme analysis.…”

Section: Discussionmentioning

confidence: 99%

“…12 Small in-frame deletion mutations in the 1A domain of K16 and its expression partner, K6a, have also been found in PC-1 cases. 17,26 Such mutations would be predicted to disrupt the heptad repeat pattern necessary for the coiled-coil a-helical conformation of this domain, 33 and therefore might be predicted to lead to severe phenotypes. However, when one considers the FNEPPK mutations previously reported in the 1A domain, N125S and R127C, 31 it is less easy to explain the milder phenotype purely in molecular terms.…”

Section: Discussionmentioning

confidence: 99%

“…The functional K16 gene, KRT16A, was amplified from genomic DNA derived from affected members of both families using the specific long-range PCR conditions recently described. 26 In family A, heterozygous missense mutation 380G3C was identified in the proband (Fig. 4), predicting the amino acid substitution R127P, which affects the 10th residue of the helix 1A domain of the K16 polypeptide.…”

Section: K16 Mutation Analysis and Confirmationmentioning

confidence: 99%

“…23±25 Recently, we have cloned and fully sequenced two K16-like pseudogenes and developed a long-range polymerase chain reaction (PCR) system to amplify the functional K16 gene specifically. 26 Here, we have used this strategy to detect two novel K16 mutations in families with PC-1, including a family where some affected persons have cataract.…”

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confidence: 99%

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Novel proline substitution mutations in keratin 16 in two cases of pachyonychia congenita type 1

et al. 1999

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Pachyonychia congenita (PC) is a group of inherited ectodermal dysplasias, the characteristic phenotype being hypertrophic nail dystrophy. Two main clinical subtypes, PC-1 and PC-2, are inherited as autosomal dominant disorders, but other less well characterized clinical forms also exist. The PC-1 phenotype may be distinguished by the absence of the epidermal cysts found in PC-2, and it has been shown to be caused by mutations in either keratin K16 or its expression partner, the K6a isoform of K6. Mutations in K16 have also been shown to cause a milder related phenotype, focal non-epidermolytic palmoplantar keratoderma. Recently, we have developed a long-range polymerase chain reaction (PCR) strategy which allows specific amplification of the entire functional K16 gene (KRT16A), without amplification of the two K16 pseudogenes (psiKRT16B and psiKRT16C), enabling mutation analysis based on genomic DNA. Here, using this methodology, we describe novel mutations R127P and Q122P in the helix 1A domain of K16 in two families presenting with PC-1. Both mutations were excluded from 50 normal unrelated individuals by restriction enzyme analysis of K16 PCR fragments. In one family, ultrastructural analysis was performed, revealing distinctive tonofilament abnormalities. Specifically, keratin filament bundles were greatly condensed, but did not form the dense amorphous aggregates seen in a number of other keratin disorders. In the second kindred, autosomal dominant cataract was present in some but not all members affected by PC. As the cataract phenotype did not fully cosegregate with the K16 mutation, and given that K16 is not expressed in the lens, these two phenotypes may be coincidental.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: K16 Mutation Analysis and Confirmationmentioning

confidence: 99%

mentioning

confidence: 99%

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Novel proline substitution mutations in keratin 16 in two cases of pachyonychia congenita type 1

et al. 1999

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

Smith

Fisher

Healy

et al. 2000

Experimental Dermatology

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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 deltaHTM. Transient expression of K16 cDNAs carrying either the L124R or the deltaHTM mutation in epithelial cell line PtK2 produced aggregation of the keratin cytoskeleton. However, the aggregates observed with the deltaHTM 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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Delayed-onset pachyonychia congenita associated with a novel mutation in the central 2B domain of keratin 16

et al. 2001

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A young girl with clinical features of pachyonychia congenita type 1 was unusual in that the typical skin and nail changes were not noted until the age of 6 years. Direct sequencing of the KRT16A gene, encoding keratin K16, revealed a novel mutation K354N in the central 2B domain of the K16 polypeptide. The mutation created a new BsmI restriction site and therefore, the mutation was confirmed in the patient and excluded from both parents and 50 normal, unrelated individuals by BsmI digestion of KRT16A polymerase chain reaction products. This is the first time a mutation has been described in this location in a keratin other than K14, where similar mutations cause the milder Weber-Cockayne and/or Köbner types of epidermolysis bullosa simplex.

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Cloning of multiple keratin 16 genes facilitates prenatal diagnosis of pachyonychia congenita type 1

Cited by 3 publications

References 0 publications

Novel proline substitution mutations in keratin 16 in two cases of pachyonychia congenita type 1

Novel proline substitution mutations in keratin 16 in two cases of pachyonychia congenita type 1

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

Delayed-onset pachyonychia congenita associated with a novel mutation in the central 2B domain of keratin 16

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