Mapping of monilethrix to the type II keratin gene cluster at chromosome 12q13 in three new families, including one with variable expressivity

Abstract

Monilethrix is an autosomal dominant disorder chiefly affecting hair. The degree of hair dystrophy is highly variable, as is the presence of additional features, such as follicular keratoscs. In three British families of monilethrix. linkage has recently been reported to the type II keratin gene cluster at chromosome 12ql 3. and it has been suggested that the disease is due to a defect in the hard keratins of hair and nail. If monilethrix is a keratin disorder, we would predict that some pedigrees might map to the type I keratin gene cluster on 17q where hard keratin genes are also found. We have now studied clinically and by linkage analysis three new and unrelated pedigrees from England. Scotland and Spain, the lirst of which showed a variant phcnotype. In this family the disease was expressed in four of 12 cases only as a follicular keralosis of the neck, elbows and knees, and without clinical or historical evidence of hair anomalies: non-penetrance in an obligate carrier was also observed. In all three families, we have established linkage to a series of microsatellite markers at the type II locus at 12ql3 (2^,,^ =6-34 at e = {)-0() for D12S368) and have excluded linkage from the type I keratin gene cluster on 17q. It remains probable that monilethrix is a disorder of hard keratins, but at present there is no evidence that it is due to defects in type I keratins.

The genetics of hair shaft disorders

“…130,131 The gene for monilethrix is linked to the type II keratin gene cluster on chromosome 12q13. [132][133][134] Studies have isolated mutations in type II hair cortex keratins hHB6 and hHB1. The gene is divided structurally into a-helical rod domains, helix initiation motifs (HIM), and helix termination motifs (HTM).…”

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

“…Previous ultrastructural hair studies of monilethrix patients suggested disturbances in keratin expression and ordered intermediate filament formation in trichocytes of both the hair matrix and the cortex of the hair shaft (Ito et al, 1990;De Berker et al, 1993). Further evidence for monilethrix as a possible keratin disease was provided by genetic linkage of several unrelated pedigrees to the type II keratin gene cluster on chromosome 12q13 (Healy et al, 1995;Stevens et al, 1996;Birch-Machin et al, 1997), 1 which also harbors the type II hair keratin genes (Rogers et al, 1995). At present, four human type II hair keratins have been characterized in our laboratory (Rogers et al, 1995(Rogers et al, , 1997.…”

Recurrent missense mutations in the hair keratin gene hHb6 in monilethrix

“…1 Because the hairs are very thin and fragile, they tend to fracture close to the scalp, producing dystrophic alopecia. 3 In the milder form, the disease involves only the occipital regions and the nape of the neck, but in the more severe form, the entire scalp, secondary sexual hair, eyebrows, eyelashes, and occasionally the nails may be affected. The variability of the monilethrix phenotype suggests that other factors also affect gene or disease expression.…”