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  • 1
    Abstract: The genetic basis of epidermolysis bullosa, a group of genetic disorders characterized by the mechanically induced formation of skin blisters, is largely known, but a number of cases still remain genetically unsolved. Here, we used whole-exome and targeted sequencing to identify monoallelic mutations, c.1A〉G and c.2T〉C, in the translation initiation codon of the gene encoding kelch-like protein 24 (KLHL24) in 14 individuals with a distinct skin-fragility phenotype and skin cleavage within basal keratinocytes. Remarkably, mutation c.1A〉G occurred de novo and was recurrent in families originating from different countries. The striking similarities of the clinical features of the affected individuals point to a unique and very specific pathomechanism. We showed that mutations in the translation initiation codon of KLHL24 lead to the usage of a downstream translation initiation site with the same reading frame and formation of a truncated polypeptide. The pathobiology was examined in keratinocytes and fibroblasts of the affected individuals and via expression of mutant KLHL24, and we found mutant KLHL24 to be associated with abnormalities of intermediate filaments in keratinocytes and fibroblasts. In particular, KLHL24 mutations were associated with irregular and fragmented keratin 14. Recombinant overexpression of normal KLHL24 promoted keratin 14 degradation, whereas mutant KLHL24 showed less activity than the normal molecule. These findings identify KLHL24 mutations as a cause of skin fragility and identify a role for KLHL24 in maintaining the balance between intermediate filament stability and degradation required for skin integrity.
    Type of Publication: Journal article published
    PubMed ID: 27889062
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  • 2
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  130. Kongress der Deutschen Gesellschaft für Chirurgie; 20130430-20130503; München; DOC13dgch088 /20130426/
    Publication Date: 2013-04-27
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 3
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Journal of pineal research 18 (1995), S. 0 
    ISSN: 1600-079X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: As for many hormones, melatonin levels in the blood suggest that it is discharged from the pineal gland in a pulsatile manner. Recently, the existence of short-term episodes, superimposed on the circadian pattern of circulating melatonin, has been questioned. Because plasma melatonin levels reflect not only the secretory process, but also the effects of distribution and degradation, secretory rates were estimated from peripheral levels, using a deconvolution procedure. Fourteen healthy volunteers were studied during the night, while sleeping in the dark (2300–0700), and seven of them subsequently were used in a replicate study. Plasma melatonin levels were measured at 10-min intervals by a direct, specific radioimmunoassay. Pulse analysis was performed using the computer program ULTRA. Approximately 30% more pulses were detected on the overall secretory profiles than on plasma profiles. The pulses occurred at random intervals and were often superimposed on tonic basal secretion. Their number, amplitude, and distribution over time were variable depending on subjects. Also the mean melatonin secretory rate varied more than threefold across individuals. Despite the large interindividual variability, the subjects, who were used in replicate experiment, displayed a rather similar secretory profile. We conclude that in normal adult men, melatonin secretion undergoes two distinct secretory modes, in which episodic secretion is superimposed on tonic secretion in subject-dependent variable proportions.
    Type of Medium: Electronic Resource
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