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Abstract

Epidermolytic palmoplantar keratosis (EPPK) cosegregates with breast and ovarian cancers in a large French pedigree, raising the possibility that a single genetic mutation might cause these conditions and offering a potential lead to the identification of a hereditary breast/ovarian cancer gene. We have performed linkage analysis and show that the EPPK locus lies on the long arm of chromosome 17 near the type I keratin gene cluster and the proposed breast cancer gene (BRCA1). The type I keratin 9 gene has been partially sequenced in four affected individuals. A single base mutation within the rod domain of the protein cosegregates with EPPK in all affected individuals tested. Although inheritance of this mutation is likely responsible for EPPK, it is unlikely to be the cause of the breast and ovarian cancer.

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Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and functional analyses.

Heidi E. Hutton, A Letai, Amy Paller … (1991)

Previously we demonstrated that transgenic mice expressing mutant basal epidermal keratin genes exhibited a phenotype resembling a group of autosomal dominant human skin disorders known as epidermolysis bullosa simplex (EBS). EBS diseases affect approximately 1: 50,000 and are of unknown etiology, although all subtypes exhibit blistering arising from basal cell cytolysis. We now demonstrate that two patients with spontaneous cases of Dowling-Meara EBS have point mutations in a critical region in one (K14) of two basal keratin genes. To demonstrate function, we engineered one of these point mutations in a cloned human K14 cDNA, and showed that a K14 with an Arg-125----Cys mutation disrupted keratin network formation in transfected keratinocytes and perturbed filament assembly in vitro. Since we had previously shown that keratin network perturbation is an essential component of EBS diseases, these data suggest that the basis for the phenotype in this patient resides in this point mutation.

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Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families.

M. King, H. B. Newman, John Austin … (1988)

Segregation analysis of breast cancer in families can provide the logical basis and the specific genetic models for mapping and identifying genes responsible for human breast cancer. Patterns of breast cancer occurrence in families were investigated by complex segregation analysis. In a sample of 1579 nuclear families ascertained through a population-based series of probands, an autosomal dominant model with a highly penetrant susceptibility allele fully explained disease clustering. From the maximum-likelihood Mendelian model, the frequency of the susceptibility allele was 0.0006 in the general population, and lifetime risk of breast cancer was 0.82 among susceptible women and 0.08 among women without the susceptibility allele. Inherited susceptibility affected only 4% of families in the sample: multiple cases of this relatively common disease occurred in other families by chance. The same genetic models, with higher gene frequency, explained disease clustering in an extended kindred at high risk of breast cancer. Evidence for a highly penetrant, autosomal dominant susceptibility allele for breast cancer in a high-risk family and the general population suggests that high-risk families can serve as models for understanding breast cancer in the population as a whole.

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Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkeratosis.

M Longley, D Roop, Joseph A Rothnagel … (1992)

Epidermolytic hyperkeratosis is a hereditary skin disorder characterized by blistering and a marked thickening of the stratum corneum. In one family, affected individuals exhibited a mutation in the highly conserved carboxyl terminal of the rod domain of keratin 1. In two other families, affected individuals had mutations in the highly conserved amino terminal of the rod domain of keratin 10. Structural analysis of these mutations predicts that heterodimer formation would be unaffected, although filament assembly and elongation would be severely compromised. These data imply that an intact keratin intermediate filament network is required for the maintenance of both cellular and tissue integrity.

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PubMed ID:: 7511021

DOI:: 10.1038/ng0194-106

ScienceOpen disciplines: Chemistry

Keywords: Adolescent,Adult,Amino Acid Sequence,Base Sequence,Breast Neoplasms,complications,genetics,Chromosomes, Human, Pair 17,DNA Mutational Analysis,DNA Primers,Female,France,Genetic Linkage,Humans,Keratins,Keratoderma, Palmoplantar,Male,Middle Aged,Molecular Sequence Data,Ovarian Neoplasms,Pedigree,Point Mutation

Epidermolytic palmoplantar keratoderma cosegregates with a keratin 9 mutation in a pedigree with breast and ovarian cancer.

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Photoluminescent Nanomaterials

Most cited references 17

Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and functional analyses.

Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families.

Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkeratosis.

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