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Identification of novel mutations in basic hair keratins hHb1 and hHb6 in monilethrix: Implications for protein structure and clinical phenotype

Lookup NU author(s): Dr Eugene Healy, Professor Mark Birch-Machin, Professor Jonathan Rees

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Abstract

Monilethrix is an hereditary hair dystrophy recently shown to be due to mutations in the helix termination motif of two type II (basic) human hair keratin genes, hHb1 and hHb6. It has been suggested that mutation in hHb1 produces a less severe phenotype. We have studied hair keratin genes and clinical features in 18 unrelated pedigrees of monilethrix from Germany, Scotland, Northern Ireland, and Portugal, in 13 of which mutations have not previously been identified. By examining the rod domains of hHb1, hHb3 and hHb6, we have identified mutations in nine of the new pedigrees. We again found the glutamine-lysine substitution (E413K) in the helix termination motif of hHb6 in two families, and in another, the corresponding E413K substitution in the hHb1 gene. In four families a similar substitution E402K was present in a nearby residue. In addition two novel mutations within the helix initiation motif of hHb6 were found in Scottish and Portuguese cases, in whom the same highly conserved asparagine residue N114 was mutated to histidine (N114H) or aspartic acid (N114D) residues, respectively. In four other monilethrix pedigrees mutations in these domains of hHb1, hHb3, and hHb6 were not found. The mutations identified predict a variety of possible structural consequences for the keratin molecule. A comparison of clinical features and severity between cases with hHb1 and hHb6 mutations does not suggest distinct effects on phenotype, with the possible exception of nail dystrophy, commoner with hHb1 defects. Other factors are required to explain the marked variation in clinical severity within and between cases.


Publication metadata

Author(s): Korge BP, Hamm H, Jury CS, Traupe H, Irvine AD, Healy E, Birch-Machin M, Rees JL, Messenger AG, Holmes SC, Parry DAD, Munro CS

Publication type: Article

Publication status: Published

Journal: Journal of Investigative Dermatology

Year: 1999

Volume: 113

Issue: 4

Pages: 607-612

Print publication date: 01/01/1999

ISSN (print): 0022-202X

ISSN (electronic): 1523-1747

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1046/j.1523-1747.1999.00722.x

DOI: 10.1046/j.1523-1747.1999.00722.x

PubMed id: 10504448


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