A Variable Monilethrix Phenotype Associated With a Novel Mutation, Glu402Lys, in the Helix Termination Motif of the Type II Hair Keratin hHb1

Abstract

Monilethrix is a rare human hair disorder with autosomal dominant transmission that can be caused by mutations in hair keratins. Up until now, pathogenic mutations in the type II hair cortex keratins hHb6 and hHb1 were restricted to a highly conserved glutamic acid residue Glu413 (Glu117 of the 2B subdomains) in the EIATYRRLLEGEE helix termination motif of the two keratins. The critical glutamic acid residue was substituted either by a lysine or, less frequently, by an aspartic acid residue. Here we report a novel mutation in a French monilethrix family, which again consists of a lysine substitution of another highly conserved glutamic acid residue, Glu402 (Glu106 of the 2B subdomain), in the EIATYRRLLEGEE motif of hHb1. Family members bearing the hHb1 Glu402Lys mutation exhibit a particularly variable disease phenotype. The pedigree comprises two infant members, one with pronounced dystrophic alopecia, follicular keratosis, and clear-cut moniliform hair, and one with no hair loss at all and moniliform hair detectable only by electron microscopy, as well as an adult individual without any clinically or electron microscopically detectable symptoms, but with clear historical proof of the disease.

The Catalog of Human Hair Keratins

“…8b). In this respect, it is highly astonishing that the impact of a disruptive mutation in a cortex keratin, hHb1 or hHb6, is obviously not attenuated by the high number of paralleling unaffected keratin pairings but entails such dramatic alterations as the beaded-hair phenotype in Monilethrix patients (33,34).…”

A locus for hereditary hypotrichosis localized to human chromosome 18q21.1

“…11 A form of alopecia, monilethrix (MIM 158000), was localized to chromosome 12q13 and is due to mutations in the hair cortex keratin gene HB1 or HB6. 12 The severity of alopecia is variable from patient to patient and is also variable over time in the same individual. Perifollicular hyperkeratosis is a consistent feature of monilethrix.…”

Characterization of a 190-Kilobase Pair Domain of Human Type I Hair Keratin Genes

“…Both can be divided into type I (acidic) and type II (basic-neutral) proteins that form the 10-nm intermediate filament network of epithelial cells by obligatory association of equimolar amounts of type I and type II keratins (1,2). Disturbances of intermediate filament formation through deleterious mutations in keratins can lead to a weakening of the structural integrity of the respective epithelial cells, resulting in hereditary disorders of skin, mucosa, nail, or hair (3)(4)(5)(6)(7). Although initial studies of hair keratin proteins of several species indicated the existence of eight major type hair keratins, four type I members, termed Ha1-Ha4, and four type II members, termed Hb1-Hb4, as well as of one minor hair keratin pair, Hax/Hbx (8 -11), it has recently been shown that the hair keratin family is distinctly more complex.…”