A Variable Monilethrix Phenotype Associated With a Novel Mutation, Glu402Lys, in the Helix Termination Motif of the Type II Hair Keratin hHb1
1998; Elsevier BV; Volume: 111; Issue: 1 Linguagem: Inglês
10.1046/j.1523-1747.1998.00234.x
ISSN1523-1747
AutoresHermelita Winter, Christine Labrèze, Valérie Chapalain, J.E. Surlève-Bazeille, Michel Mercier, Michael A. Rogers, Alain Taı̈eb, Jürgen Schweizer,
Tópico(s)melanin and skin pigmentation
ResumoMonilethrix 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. 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. helix initiation motif helix termination motif Monilethrix, a hereditary disorder of hair with autosomal dominant transmission, is characterized by the occurrence of thin and fragile hair, exhibiting a regular periodicity of nodes of normal thickness and abnormally narrow internodes at which the hair easily breaks. Affected individuals have normal hair at birth, but within the first few months of life develop a dystrophic alopecia. In mild cases, the disease is confined to the occiput and the nape of the neck and frequently improves with age or, temporarily, during pregnancy. In more severely affected individuals, exhibiting a moniliform phenotype also in the secondary sexual hair, eyebrows, and eyelashes, the disease has been found to persist throughout life. Follicular keratosis with perifollicular erythema and, occasionally, nail defects, have been observed as concomitant symptoms (McKee and Rosen, 1961McKee G.M. Rosen J. Monilethrix: a clinical and histological study, with a report of six cases and a review of the literature.J Cutan Dis Syph. 1961; 34: 444-462Google Scholar;Heydt, 1964Heydt G.E. Zur Kenntnis des Monilethrix-Syndroms.Arch Klin Exp Dermatol. 1964; 217: 15-29Crossref Scopus (17) Google Scholar;Gummer et al., 1981Gummer C.L. Dawber P.R.P. Swift J.A. Monilethrix: an electron microscopic and electron histochemical study.Br J Dermatol. 1981; 105: 529-541Crossref PubMed Scopus (46) Google Scholar;Zimmermann, 1983Zimmermann R. Monilethrix.Dermatol Monatsschr. 1983; 196: 638-645Google Scholar). A large number of genodermatoses has been shown to be due to mutations in keratin genes (Steinert, 1995Steinert P.M. IF pathology: molecular consequences of rod and end domain mutations.in: Parry D.A.D. Steinert P.M. Intermediate Filament Structure: Molecular Biology Intelligence Unit. Springer, Berlin1995: 145-175Google Scholar;Fuchs, 1997Fuchs E. Of mice and men: Genetic disorders of the cytoskeleton.Mol Biol Cell. 1997; 8: 189-203Crossref PubMed Scopus (76) Google Scholar). Keratins are divided into type I, acidic proteins and type II, basic to neutral proteins. They form the 10 nm intermediate filaments of epithelial cells by assembly of equimolar amounts of distinct pairs of type I and type II keratins. Keratins possess highly homologous central α-helical rod domains, flanked by non-α-helical and size-variable head and tail domains (Steinert, 1995Steinert P.M. IF pathology: molecular consequences of rod and end domain mutations.in: Parry D.A.D. Steinert P.M. Intermediate Filament Structure: Molecular Biology Intelligence Unit. Springer, Berlin1995: 145-175Google Scholar;Fuchs, 1997Fuchs E. Of mice and men: Genetic disorders of the cytoskeleton.Mol Biol Cell. 1997; 8: 189-203Crossref PubMed Scopus (76) Google Scholar). The short segments at the extremities of the rod domain, i.e., the helix initiation motif (HIM) and the helix termination motif (HTM), are particularly conserved among keratins and most disease-causing mutations are clustered in these regions (Steinert, 1995Steinert P.M. IF pathology: molecular consequences of rod and end domain mutations.in: Parry D.A.D. Steinert P.M. Intermediate Filament Structure: Molecular Biology Intelligence Unit. Springer, Berlin1995: 145-175Google Scholar;Fuchs, 1997Fuchs E. Of mice and men: Genetic disorders of the cytoskeleton.Mol Biol Cell. 1997; 8: 189-203Crossref PubMed Scopus (76) Google Scholar). 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., 1990Ito O.M. Hashimoto K. Sato Y. Pathogenesis of monilethrix: computer stereography and electron miroscopy.J Invest Dermatol. 1990; 95: 186-194Abstract Full Text PDF PubMed Google Scholar;De Berker et al., 1993De Berker D.A.R. Ferguson D.J.P. Dawber R.P.R. Monilethrix: a clinicopathological illustration of a cortical defect.Br J Dermatol. 1993; 128: 327-331Crossref PubMed Scopus (36) Google Scholar). 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., 1995Healy N.E. Holmes S. Belgaid C.E. Stephenson A.M. McLean W.H.I. Rees J.L. Munro C.S. A gene for monilethrix is closely linked to the type II keratin gene cluster at 12q13.Hum Mol Genet. 1995; 4: 2399-2402Crossref PubMed Scopus (53) Google Scholar;Stevens et al., 1996Stevens H.P. Kelsell D.P. Bryant S.P. Bishop D.T. Dawber R.P.R. Spurr N.K. Leigh I.M. Linkage of monilethrix to the trichocyte and epithelial keratin gene cluster on 12q11-q13.J Invest Dermatol. 1996; 106: 795-797Crossref PubMed Scopus (40) Google Scholar;Birch-machin et al., 1997Birch-machin M.A. Healy E. Turner R. et al.Mapping of monilethrix to the type II keratin gene cluster at chromosome 12q13 in three new families, including one with variable expression.Br J Dermatol. 1997; 137: 339-343Crossref PubMed Scopus (26) Google Scholar), 1Korge BP, Richards G, Puenter C et al. : Monilethrix links to the keratin type II cluster at 12q13 and cloning of a possible candidate gene J Invest Dermatol 106:843, 1996 (abstr.)1Korge BP, Richards G, Puenter C et al. : Monilethrix links to the keratin type II cluster at 12q13 and cloning of a possible candidate gene J Invest Dermatol 106:843, 1996 (abstr.)which also harbors the type II hair keratin genes (Rogers et al., 1995Rogers M.A. Nischt R. Korge B. et al.Sequence data and chromosomal location of human type I and type II hair keratin genes.Exp Cell Res. 1995; 220: 357-362Crossref PubMed Scopus (53) Google Scholar). At present, four human type II hair keratins have been characterized in our laboratory (Rogers et al., 1995Rogers M.A. Nischt R. Korge B. et al.Sequence data and chromosomal location of human type I and type II hair keratin genes.Exp Cell Res. 1995; 220: 357-362Crossref PubMed Scopus (53) Google Scholar,Rogers et al., 1997Rogers M.A. Langbein L. Praetzel S. Moll I. Krieg T. Winter H. Schweizer J. Sequences and differential expression of three novel human type II hair keratins.Differentiation. 1997; 61: 187-194Crossref PubMed Scopus (52) Google Scholar). Out of these, hHb5 is synthesized in matrix and lower cortex cells, whereas hHb1, hHb3, and hHb6 are sequentially expressed in the cortex of the hair shaft (Rogers et al., 1997Rogers M.A. Langbein L. Praetzel S. Moll I. Krieg T. Winter H. Schweizer J. Sequences and differential expression of three novel human type II hair keratins.Differentiation. 1997; 61: 187-194Crossref PubMed Scopus (52) Google Scholar). We have recently analyzed the HIM and HTM of these keratin genes for mutations in four unrelated British, French, German, and Canadian monilethrix families as well as in four unrelated single patients. We detected three types of mutations that could causally be related to the disease (Winter et al., 1997bWinter H. Rogers M.A. Gebhardt M. et al.A new mutation in the type II hair cortex keratin hHb1 involved in the inherited hair disorder monilethrix.Hum Genet. 1997 b; 101: 165-169Crossref PubMed Scopus (91) Google Scholar, Winter et al., 1997aWinter H. Rogers M.A. Langbein L. et al.Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix.Nature Genet. 1997 a; 16: 372-374Crossref PubMed Scopus (159) Google Scholar). The most frequent gene mutation that occurred in six cases, led to a lysine substitution of the highly conserved glutamic acid residue 413 in the HTM of hHb6 [Glu413Lys; originally, this mutation was designated Glu410Lys, because it was derived from a partial hHb6 cDNA clone, but based on the recently published complete hHb6 sequence (Bowden et al., 1998Bowden P.E. Hainey S.D. Parker G. Jones D.O. Zimonjic D. Popescu N. Hodgins M.B. Characterization and chromosamal localization of human hair-specific keratin genes and comparative expression during the hair growth cycle.J Invest Dermatol. 1998; 110: 158-164Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar) the correct position of this mutation can now be given as Glu413Lys]. Recently, this mutation has also been described by Korge et al 2Korge BP, Healy E, Traupe H et al. : Monilethrix is caused by mutation in the helix termination peptide of human type II hair keratin hHb6 in three families. J Invest Dermatol 109:409, 1997 (abstr.) 2Korge BP, Healy E, Traupe H et al. : Monilethrix is caused by mutation in the helix termination peptide of human type II hair keratin hHb6 in three families. J Invest Dermatol 109:409, 1997 (abstr.) in three unrelated monilethrix pedigrees. In another family, the hHb6 glutamic acid residue 413 was found to be substituted by an aspartic acid residue, whereas in still another family, the equivalent of the hHb6 Glu413Lys mutation occurred in hair keratin hHb1 [Glu413Lys; due to a mistake in the amino acid numbering of hair keratin hHb1 between residues 305 and 325 (Exp Cell Res 220:357–362, 1995), the position of the glutamic acid residue found to be mutated in the monilethrix family described in Hum Gen 101:165–169, 1997, must read 413 instead of 403] (Winter et al., 1997bWinter H. Rogers M.A. Gebhardt M. et al.A new mutation in the type II hair cortex keratin hHb1 involved in the inherited hair disorder monilethrix.Hum Genet. 1997 b; 101: 165-169Crossref PubMed Scopus (91) Google Scholar, Winter et al., 1997aWinter H. Rogers M.A. Langbein L. et al.Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix.Nature Genet. 1997 a; 16: 372-374Crossref PubMed Scopus (159) Google Scholar). In this study, we describe a French three-generation monilethrix family in which the disease is caused by a novel mutation, Glu402Lys, also located in the HTM of hHb1. The pedigree of the three-generation French family is shown in Figure 1. The propositus was a 4 y old girl, III-1, who had normal looking hair at birth. After physiologic hair loss in the first months of life, she showed regrowth of short and brittle hairs together with keratosis pilaris from the lower neck to the vertex. Keratosis pilaris was also observed on elbows and knees. Light microscopic examination revealed regularly beaded hairs, typical for monilethrix. Eyebrows, eyelashes, and nails of the patient appeared normal. Hairs of the other members of the family were unremarkable to the naked eye, and, on questioning, none of the adult individuals of the family complained about alopecia at an early age. Similarly, the patient's mother denied signs of hair loss of her 1 y old son, III-2. Thus, individual III-1 appeared to be a sporadic case. Both the patient's mother, II-1, as well as her maternal grandfather, I-2, were afflicted with psoriasis. In the mother, the disease was confined to the scalp and was diagnosed at age 19; since then she received iterative treatment with topical steroid lotions. The grandfather suffered from psoriasis vulgaris, including the scalp. Clinical signs of psoriasis were absent in monilethrix patient III-1 and her brother III-2. After Ethic Committee Approval, blood was drawn from consenting members of the family as well as from 50 unrelated, healthy control individuals, to whom the aim and the nature of the study had been explained. Genomic DNA was isolated using a Blood and Tissue Culture DNA Extraction System (Qiagen, Hilden, Germany). For scanning electron microscopy, hairs were mounted on an aluminum specimen holder with a double sided adhesive tape and coated with a 10 nm thick layer of gold in a sputtering evaporator. Hairs were examined using a Philips SEM 315 electron microscope at a voltage of 10 kV. The gene segments encoding the α-helical 1A and 2B subdomains of the type II hair cortex keratins hHb1, hHb3, and hHb6 (Rogers et al., 1997Rogers M.A. Langbein L. Praetzel S. Moll I. Krieg T. Winter H. Schweizer J. Sequences and differential expression of three novel human type II hair keratins.Differentiation. 1997; 61: 187-194Crossref PubMed Scopus (52) Google Scholar) were amplified by the polymerase chain reaction (PCR), using recently published gene-specific primer pairs (Winter et al., 1997aWinter H. Rogers M.A. Langbein L. et al.Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix.Nature Genet. 1997 a; 16: 372-374Crossref PubMed Scopus (159) Google Scholar). PCR was performed by means of the Expand Long Template PCR System (Boehringer, Mannheim, Germany) under conditions described previously (Winter et al., 1997aWinter H. Rogers M.A. Langbein L. et al.Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix.Nature Genet. 1997 a; 16: 372-374Crossref PubMed Scopus (159) Google Scholar). PCR products were separated by agarose gel electrophoresis, purified using silica gel beads (Boehringer, Mannheim, Germany) and sequenced directly according to the Thermo Sequenase radiolabeled chain terminator cycle sequencing protocol (Amersham, Braunschweig, Germany) using the corresponding gene-specific PCR primers as sequencing primers. The heterozygous G-A mutation detected in the hHb1 gene of the clinically affected member of the family destroys a Taq I recognition site. Therefore, in addition to direct DNA sequence analysis, restriction fragment length polymorphism analysis was used to follow the mutation within the family and to exclude it from several normal unrelated individuals. To this end, PCR products were generated using the hHb1 gene-specific forward primer from exon 7 (Winter et al., 1997aWinter H. Rogers M.A. Langbein L. et al.Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix.Nature Genet. 1997 a; 16: 372-374Crossref PubMed Scopus (159) Google Scholar) in combination with the reverse primer, 5′-AGGGATGGGGAAGGGTGGTTCTGG-3′, derived from the initial intron 7 sequences of the hHb1 gene (Winter et al., 1997bWinter H. Rogers M.A. Gebhardt M. et al.A new mutation in the type II hair cortex keratin hHb1 involved in the inherited hair disorder monilethrix.Hum Genet. 1997 b; 101: 165-169Crossref PubMed Scopus (91) Google Scholar). The purified DNA fragments were digested for 3 h at 65°C with 10 U of Taq I and analyzed on 3% NuSieve-agarose gel. Based on the apparently predominant involvement of mutated type II cortex keratins in the etiology of monilethrix (Winter et al., 1997bWinter H. Rogers M.A. Gebhardt M. et al.A new mutation in the type II hair cortex keratin hHb1 involved in the inherited hair disorder monilethrix.Hum Genet. 1997 b; 101: 165-169Crossref PubMed Scopus (91) Google Scholar, Winter et al., 1997aWinter H. Rogers M.A. Langbein L. et al.Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix.Nature Genet. 1997 a; 16: 372-374Crossref PubMed Scopus (159) Google Scholar),2 our mutation analyses of the family focused on the gene sequences coding for the initial 1A and the terminal 2B α-helical regions of the three type II hair keratins hHb1, hHb3, and hHb6 (Rogers et al., 1995Rogers M.A. Nischt R. Korge B. et al.Sequence data and chromosomal location of human type I and type II hair keratin genes.Exp Cell Res. 1995; 220: 357-362Crossref PubMed Scopus (53) Google Scholar,Rogers et al., 1997Rogers M.A. Langbein L. Praetzel S. Moll I. Krieg T. Winter H. Schweizer J. Sequences and differential expression of three novel human type II hair keratins.Differentiation. 1997; 61: 187-194Crossref PubMed Scopus (52) Google Scholar). Sequence analyses of the PCR amplified 1A gene regions of the various cortex keratins did not reveal aberrations from the reported sequences (Rogers et al., 1995Rogers M.A. Nischt R. Korge B. et al.Sequence data and chromosomal location of human type I and type II hair keratin genes.Exp Cell Res. 1995; 220: 357-362Crossref PubMed Scopus (53) Google Scholar,Rogers et al., 1997Rogers M.A. Langbein L. Praetzel S. Moll I. Krieg T. Winter H. Schweizer J. Sequences and differential expression of three novel human type II hair keratins.Differentiation. 1997; 61: 187-194Crossref PubMed Scopus (52) Google Scholar) in any of the family members investigated. The same held true for the HTM coding 2B regions of hHb3 and hHb6 (results not shown). In contrast, analysis of the corresponding region of the hHb1 gene led to the detection of a heterozygous G-A point mutation in the clinically affected individual III-1 (Figure 2). The mutation site concerned the first position of the GAG triplet that encodes glutamic acid residue 402 of hHb1 (residue 106 of the 2B subdomain) and led to its substitution by lysine (Figure 2). This hHb1 gene mutation was absent in the patient's father II-2 (Figure 2), as well as in 50 unrelated healthy control individuals (results not shown; see, however, Figure 3). Surprisingly, the G-A mutation was, however, also present in both the clinically unremarkable mother, II-1, and brother, III-2, of patient III-1. Because the mutation destroys a Taq I recognition site, TCGA, in the affected hHb1 allele (see Figure 2), restriction fragment length polymorphism analysis was used to document this finding by means of a diagnostic, Taq I resistant 208 bp fragment in individuals II-1 and III-2, and to exclude the mutation from several control individuals (Figure 3).Figure 3Screening for the G-A point mutation in the hHb1 gene by restriction fragment length polymorphism analysis. Genomic DNA from members of the family and seven unrelated control individuals was amplified to produce a 208 bp fragment containing the critical mutation site. The Taq I digested PCR fragments were resolved on a 3.5% agarose gel and stained with ethidium bromide. The mutation destroys a Taq I restriction site in one hHb1 allele of family members II-1, III-1, and III-2. Therefore, an undigested 208 bp band is diagnostic for the mutation. Cleaved products of 119 bp and 89 bp indicate normal, unrelated control individuals as well as the unaffected member II-2 of the pedigree.View Large Image Figure ViewerDownload (PPT) In view of the discrepancy between the apparently normal appearance of the scalp hair of individuals II-1 and III-2 and the presence of the novel hHb1 gene mutation, hairs of these individuals as well as those of individual III-1 were examined by both light and scanning electron microscopy. In keeping with the light microscopic findings, electron microscopic analysis of hairs of patient III-1 confirmed a typically beaded pattern with a high frequency of internodal trichoschisis (Figure 4a). Light microscopic inspection of hairs collected from individual III-2 revealed few fractured hairs especially in the nuchal area, but subsequent electron microscopic examination unambiguously showed that about 80% of the hairs had a characteristic, although mild moniliform appearance. We did not observe internodal trichoschisis but, instead, noticed occasional cuticular ruffling (Figure 4b). In contrast, neither light nor electron microscopic analysis of hairs of the mutation-positive adult individual II-1 revealed any structural abnormalities (Figure 4c). We had access, however, to a hair sample that was removed from individual II-1 at an age of 12 mo and since then was kept by her mother in a locket. Analysis of this sample clearly showed that about 20% of the hairs had a thinner diameter than the majority of hairs and clearly displayed a mild moniliform pattern (Figure 4d,e). In contrast to individual III-2, archival moniliform hairs of individual II-1 frequently exhibited signs of internodal cuticular damage (Figure 4e). Thus, contrary to the original assumption of a seemingly sporadic case, these data demonstrate that the disease is a hereditary trait in this family. In order to emphasize the particular circumstances that led to this recognition, members II-1 and III-2 of the pedigree are marked differently than the clinically unequivocal case (see Figure 1). Recent investigations have identified the inherited human hair disorder monilethrix as the first hair disease, which can be caused by mutations in hair keratins (Winter et al., 1997aWinter H. Rogers M.A. Langbein L. et al.Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix.Nature Genet. 1997 a; 16: 372-374Crossref PubMed Scopus (159) Google Scholar, Winter et al., 1997bWinter H. Rogers M.A. Gebhardt M. et al.A new mutation in the type II hair cortex keratin hHb1 involved in the inherited hair disorder monilethrix.Hum Genet. 1997 b; 101: 165-169Crossref PubMed Scopus (91) Google Scholar).2 The two hair keratins involved, hHb6 and hHb1, belong to the type II keratin subfamily and are sequentially expressed in the cortex of the hair shaft (Rogers et al., 1997Rogers M.A. Langbein L. Praetzel S. Moll I. Krieg T. Winter H. Schweizer J. Sequences and differential expression of three novel human type II hair keratins.Differentiation. 1997; 61: 187-194Crossref PubMed Scopus (52) Google Scholar). The critical mutations were invariably located in the HTM of the hair keratins and confined to a highly conserved glutamic acid residue, Glu413, which, in most cases, was substituted by a lysine residue or, less frequently in hHb6, by an aspartic acid residue (Winter et al., 1997aWinter H. Rogers M.A. Langbein L. et al.Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix.Nature Genet. 1997 a; 16: 372-374Crossref PubMed Scopus (159) Google Scholar, Winter et al., 1997bWinter H. Rogers M.A. Gebhardt M. et al.A new mutation in the type II hair cortex keratin hHb1 involved in the inherited hair disorder monilethrix.Hum Genet. 1997 b; 101: 165-169Crossref PubMed Scopus (91) Google Scholar). In the monilethrix family investigated in this study, we detected a novel Glu-Lys mutation, Glu402Lys, again located in the HTM of hHb1. This striking accumulation of monilethrix-causing mutations in the HTM of type II hair keratins is unusual, because in most type II epithelial keratins, the rate of pathogenic mutations is about equal in the HIM and HTM (Steinert, 1995Steinert P.M. IF pathology: molecular consequences of rod and end domain mutations.in: Parry D.A.D. Steinert P.M. Intermediate Filament Structure: Molecular Biology Intelligence Unit. Springer, Berlin1995: 145-175Google Scholar;Fuchs, 1997Fuchs E. Of mice and men: Genetic disorders of the cytoskeleton.Mol Biol Cell. 1997; 8: 189-203Crossref PubMed Scopus (76) Google Scholar). The situation found in hair keratins hHb1 and hHb6 has, however, its counterpart in the epithelial type II keratin K2e, in which mutations causing ichthyosis bullosa of Siemens are also more frequent in the HTM (Kremer et al., 1994Kremer H. Zeeuven P. McLean W.H.I. Mariman E.C.M. Lane E.B. Kerkhof P.C.M. van de Ropers H.I.H. Steijlen P.M. Ichthyosis bullosa of Siemens is caused by mutations in the keratin 2e gene.J Invest Dermatol. 1994; 103: 286-289Abstract Full Text PDF PubMed Scopus (91) Google Scholar;McLean et al., 1994McLean W.H.I. Morley S.M. Lane E.B. et al.Ichthyosis bullosa of Siemens – a disease involving keratin 2e.J Invest Dermatol. 1994; 103: 277-:281Abstract Full Text PDF PubMed Scopus (95) Google Scholar;Rothnagel et al., 1994Rothnagel J.A. Traupe H. Wojcik S. et al.Mutations in the rod domain of keratin 2e in patients with ichthyosis bullosa of Siemens.Nature Genet. 1994; 7: 485-490Crossref PubMed Scopus (130) Google Scholar;Jones et al., 1996Jones D.O. Watts C. Mills C. Sharpe G. Marks R. Bowden P.E. A new keratin 2e mutation in ichthyosis bullosa of Siemens.J Invest Dermatol. 1996; 108: 354-356Abstract Full Text PDF Scopus (30) Google Scholar). Similar to the hHb6/hHb1 Glu413Lys substitutions, the new hHb1 Glu402Lys substitution is caused by a G-A point mutation in the first position of the corresponding GAG codon. Throughout, these base changes are most probably due to a methylated CpG deamination mutation of a 5-methyl cytosine on the anti-sense strand of the keratin genes, leading to a G to A transition in the sense strands (Cooper and Krawczak, 1989Cooper D.N. Krawczak M. Cytosine methylation and the fate of CpG dinucleotides in vertebrate genomes.Hum Genet. 1989; 83: 181-188Crossref PubMed Scopus (251) Google Scholar). A pathogenic Glu-Lys substitution corresponding to Glu402 of the hHb1 hair keratin, has also been described in the type II epidermal keratin K2e (Glu482), in a family with ichthyosis bullosa of Siemens.3 Remarkably, this keratin mutation was also associated with a highly variable phenotype of the disease. 3Pitera R, Pitera JE, Eady RAJ et al. : Novel keratin mutations causing ichthyosis bullosa of Siemens: Phenotypic variations and K2e expression. J Invest Dermatol 104:632, 1995 (abstr.)The critical glutamic acid position represents a strictly conserved amino acid residue in the HTM of all known type II hair and epithelial keratin (Hatzfeld and Weber, 1991Hatzfeld M. Weber K. Modulation of keratin intermediate filament assembly by single amino acid exchanges in the consensus sequence at the C-terminal end of the rod domain.J Cell Sci. 1991; 99: 351-362PubMed Google Scholar;Powell et al., 1992Powell B. Crocker L. Rogers G. Hair follicle differentiation: expression, structure and evolutionary conservation of the hair type II keratin intermediate filament gene family.Development. 1992; 114: 417-433PubMed Google Scholar;Steinert, 1995Steinert P.M. IF pathology: molecular consequences of rod and end domain mutations.in: Parry D.A.D. Steinert P.M. Intermediate Filament Structure: Molecular Biology Intelligence Unit. Springer, Berlin1995: 145-175Google Scholar;Rogers et al., 1997Rogers M.A. Langbein L. Praetzel S. Moll I. Krieg T. Winter H. Schweizer J. Sequences and differential expression of three novel human type II hair keratins.Differentiation. 1997; 61: 187-194Crossref PubMed Scopus (52) Google Scholar), so that its nonconservative substitution by lysine does not tolerate ordered filament formation. A survey of the five monilethrix families and the four single patients investigated so far in our laboratory reveals that patients bearing the most prevalent hHb6 Glu413Lys mutation, invariably develop dystrophic alopecia and follicular hyperkeratosis in the occipital region and the nape of the neck within the first year after birth. As a rule, these conditions persisted into adulthood and an essential improvement of hair growth represented a rather sporadic event. In all cases, moniliform hair could easily be diagnozed by light microscopic examination (Winter et al., 1997aWinter H. Rogers M.A. Langbein L. et al.Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix.Nature Genet. 1997 a; 16: 372-374Crossref PubMed Scopus (159) Google Scholar, Winter et al., 1997bWinter H. Rogers M.A. Gebhardt M. et al.A new mutation in the type II hair cortex keratin hHb1 involved in the inherited hair disorder monilethrix.Hum Genet. 1997 b; 101: 165-169Crossref PubMed Scopus (91) Google Scholar). In contrast, pronounced interfamilial phenotypic variations of the disease were observed for those pedigrees in which affected members exhibited either the hHb6 Glu413Asp mutation or the hHb1 Glu413Lys mutation. In general, early alopecia and clearly visible monilethrix hair was an exceptional event and was restricted to the clinically presented case. In most instances, affected members showed apparently normal hair growth and, occasionally, unambiguous demonstration of moniliform hair patterns in both adolescents and adults required electron microscopic examination (Winter et al., 1997aWinter H. Rogers M.A. Langbein L. et al.Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix.Nature Genet. 1997 a; 16: 372-374Crossref PubMed Scopus (159) Google Scholar, Winter et al., 1997bWinter H. Rogers M.A. Gebhardt M. et al.A new mutation in the type II hair cortex keratin hHb1 involved in the inherited hair disorder monilethrix.Hum Genet. 1997 b; 101: 165-169Crossref PubMed Scopus (91) Google Scholar). These conditions were especially pronounced in the present family in which, at first glance, the clinical data spoke for a rather severe, but sporadic case of the disease. Only subsequent to the detection of the novel hHb1 Glu402Lys mutation in further members of the family, could the typical signs of monilethrix be diagnosed by electron microscopic examination of the hairs of these individuals. Moreover, the confirmation of an autosomal dominant transmission of the disease was only possible by analysis of archival hairs, removed during childhood, which unlike the present hairs of the individual, clearly contained the beaded hair type. To our knowledge, this is the first demonstration that a moniliform hair phenotype in childhood can improve, becoming nonidentifiable at a later age. It is tempting to speculate that the severe and consistent clinical phenotype associated with the hHb6 Glu413Lys mutation is due to the theoretically high disruptive strength of this nonconservative substitution of the glutamic acid residue, which, in addition, occupies a critical d-position within the α-helical heptad repeats, and is therefore crucial for the stabilization of the coiled-coils formed initially during filament assembly (Steinert, 1995Steinert P.M. IF pathology: molecular consequences of rod and end domain mutations.in: Parry D.A.D. Steinert P.M. Intermediate Filament Structure: Molecular Biology Intelligence Unit. Springer, Berlin1995: 145-175Google Scholar;Fuchs, 1997Fuchs E. Of mice and men: Genetic disorders of the cytoskeleton.Mol Biol Cell. 1997; 8: 189-203Crossref PubMed Scopus (76) Google Scholar). The distinctly milder and highly variable phenotype resulting from the hHb6 Glu413Asp mutation would then be compatible with the expectedly weaker disruptive consequences, caused by the exchange of two negatively charged, structurally related amino acid residues. By the same reasoning, however, it seems difficult to explain why the equivalent of the hHb6 Glu413Lys mutation in hHb1 leads to a similarly mild and variable phenotype than the hHb6 Glu413Asp mutation. Recent studies in our laboratory, however, have shown that the expression of hHb1 in the cortex of the hair shaft occurs distinctly earlier than that of hHb6, which in turn represents the latest expressed cortical keratin (Rogers et al., 1997Rogers M.A. Langbein L. Praetzel S. Moll I. Krieg T. Winter H. Schweizer J. Sequences and differential expression of three novel human type II hair keratins.Differentiation. 1997; 61: 187-194Crossref PubMed Scopus (52) Google Scholar). Therefore, the possibility exists that identically mutated but differently expressed cortex keratins produce monilethrix phenotypes of different severity. The earlier cortical expression of hHb1 may then also explain why the newly discovered nonconservative Glu402Lys mutation in this keratin is also associated with a mild and variable monilethrix phenotype. Moreover, it cannot generally be excluded that the action of presently unknown genetic factors that modify the expression of affected genes through genetic and/or epigenetic events, may also lead to the manifestation of individually varying phenotypes within monilethrix families. Taken together, however, it is clear that further mutation studies in more monilethrix families are needed in order to establish a reliable genotype-phenotype correlation for this hair keratin disease. We thank the members of the family for their cooperation and Christian Wolf, German Cancer Research Center, for excellent technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft (grant Schw 539/1–2).
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