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2386 East Heritage Way, Suite B, Salt Lake City, Utah 84109 USA Phone +1-877-628-7300 • Email—[email protected] www.PC-Project.org Hum Genet (1997) 101:165Ð169 © Springer-Verlag 1997

ORIGINAL INVESTIGATION

Hermelita Winter á Michael A. Rogers á Mathias Gebhardt á Uwe Wollina á Lionell Boxall á David Chitayat á Riyana Babul-Hirji á Howard P. Stevens á Abreham Zlotogorski á Jürgen Schweizer A new in the type II hair cortex hHb1 involved in the inherited hair disorder

Received: 24 June 1997 / Accepted: 30 July 1997

Abstract Monilethrix is a rare dominant hHb1 and hHb6 are largely coexpressed in cortical tri- characterized by beaded or moniliform hair which results chocytes of the hair shaft. This indicates that monilethrix from the periodic thinning of the hair shaft and shows a is a disease of the hair cortex. high propensity to excess weathering and fracturing. Sev- eral cases of monilethrix have been linked to the type II keratin gene cluster on chromosome 12q13 and causative Introduction heterozygous of a highly conserved glutamic acid residue (Glu 410 Lys and Glu 410 Asp) in the helix Monilethrix is a rare congenital hair disease that is inher- termination motif of the type II hair keratin hHb6 have re- ited as an autosomal dominant condition with variable ex- cently been identified in monilethrix patients of two unre- pression. The disease has been named for the regular lated families. In the present study, we have investigated beaded appearence of affected hairs, which exhibit ellipti- two further unrelated monilethrix families as well as a sin- cal nodes of normal thickness alternating with narrow, dy- gle case. Affected members of one family and the single strophic constrictions. These internodes possess a high patient exhibited the prevalent hHb6 Glu 410 Lys muta- tendency to weathering and fracture, leading to the char- tion. In the second family, we identified in affected indi- acteristic clinical appearance of dystrophic alopecia, i.e., viduals a lysine substitution of the corresponding glu- short, stubbly hair associated with follicular hyperkerato- tamic acid residue, Glu 403, in the type II hair keratin sis and perifollicular erythema. In the mildest forms, the hHb1, suggesting that this site represents a mutational disease involves only the occipital regions and the nape of hotspot in these highly related type II hair . Both the neck, but in its more severe form, the entire scalp, secondary sexual hair, eyebrows, and eyelashes may also be involved. In addition, monilethrix is occasionally asso- ciated with fragility and splitting of nails (McKee and H. Winter (౧) á M. A. Rogers á J. Schweizer Rosen 1961; Gummer et al. 1981; Zimmermann 1983). German Cancer Research Center, Research Program 2, Previous ultrastructural hair studies of monilethrix pa- Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany tients suggested local edematous degeneration in matrix Tel.: +496221-423248; Fax: +496221-422995 cells of the hair bulb, together with cytolysis and dis- M. Gebhardt á U. Wollina rupted keratin filament packing in cortex cells of the hair Department of Dermatology, University of Jena, Erfurter Strafle 35, Germany shaft (Ito et al. 1990; De Berker et al. 1993). More impor- tantly, several pedigrees of monilethrix have recently been L. Boxall linked to the type II keratin gene cluster on chromosome Department of Dermatology, The Hospital of Sick Children, Toronto, Ontario, Canada M5G 1X8 12q13 (Healy et al. 1995; Korge et al. 1996; Stevens et al. 1996), which also harbors the genes for type II hair ker- D. Chitayat á R. Babul-Hirji atins (Rogers et al. 1995a). Although there is evidence for Department of Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8 genetic heterogeneity in monilethrix (Richard et al. 1996), the disease has therefore been suggested to be caused by a H. P. Stevens hair keratin defect (Healy et al. 1995; Korge et al. 1996; Academic Department of Dermatology, St. Bartholomew’s and the Royal London School of Medicine Stevens et al. 1996). and Dentistry, 2 Newark Street, London E1 2AT, UK A large number of hereditary diseases of skin, skin ap- pendages, and oral mucosa have been shown as being due A. Zlotogorski Department of Dermatology, Hadassah University Hospital, to mutations in keratin genes (for review, see Steinert 1995; Ein Karem, Jerusalem 91120, Israel Fuchs 1996). Keratins are grouped into type I, acidic pro- 166 teins, and type II, basic to neutral , which form the 10-nm intermediate filament network in cells of epithelial Results origin by obligatory association of equimolar amounts of distinct pairs of type I and type II keratins (Steinert 1995; The pedigree of the four-generation German monilethrix Fuchs 1996). Keratins possess highly homologous central family 1, is indicated in Fig. 1. The affected individuals α-helical rod domains, flanked by non α-helical head and presented were two girls (patient IV-1, 13 years and pa- tail domains of variable size. The short regions at the ex- tient IV-2, 12 years) and their brother (patient IV-3, 8 tremities of the rod domain, designated helix initiation mo- years). At birth, all patients had normal hair growth, but tif (HIM) and helix termination motif (HTM), are particu- showed diffuse alopecia in the first year of age, which was larly conserved in keratins, and disease-causing mutations particularly pronounced in patient IV-1. At present, hair are prevalent in these regions (Steinert 1995; Fuchs 1996). growth has improved in patients IV-2 and IV-3, whereas We have recently characterized four human type II hair their sister IV-1 still exhibits areas of sparse and short, 2- keratins. One of them, hHb5, is synthesized in matrix cells, to 3-mm-long hair, particularly over the nape of the neck. whereas the other three, hHb1, hHb3, and hHb6, are se- The patients were afflicted with follicular quentially expressed in the cortex of the hair shaft (Rogers of the knees, which was also seen in the neck of individ- et al. 1995a, 1997). In our laboratory, genetic analyses of ual IV-1. In all three cases, light microscopic inspection of these four hair keratin genes in two unrelated British and hair revealed typical features of monilethrix. The chil- French monilethrix families revealed two different het- dren’s father III-2, their uncle III-4, grandmother II-2, erozygous point mutations in the hHb6 hair keratin gene grand-aunts II-3 and II-4, as well as descendents III-6 and (Winter et al. 1997). The mutation in the British family led IV-4 of the latter, all suffered from early diffuse alopecia. to a non-conservative lysine substitution of a highly con- Hair with monilethrix phenotype could clearly be con- served glutamic acid residue (Glu410Lys) in the HTM of firmed in individuals III-2, III-4, III-6, and IV-4 using hHb6, whereas in the French family, a different point mu- light microscopy. The case presented in the Canadian tation in the same glutamic acid codon resulted in a con- three-generation family (Fig. 1) was a 5-year-old girl, III-2, servative substitution by aspartic acid (Glu-410Asp). These who was born with complete alopecia and later was noted mutations provided the first evidence for hair keratins be- to have poor scalp hair growth associated with follicular ing involved in a hereditary hair disease (Winter et al. 1997). In this study we have investigated two more unrelated monilethrix families as well as a single case. We confirm the Glu410Lys mutation in the HTM of hHb6 in one fam- ily and in the single patient, and describe a positionally identical Glu to Lys mutation in the type II hair keratin hHb1 in affected individuals of the second family.

Materials and methods

Genomic DNA isolation

After Ethic Committee approval, venous blood was drawn from af- fected and unaffected members of two unrelated German and Canadian monilethrix families, from a single patient of an Israeli monilethrix family, as well as from 40 healthy, unrelated individu- als. Informed consent was obtained from all subjects after the rea- son and nature of the study had been explained. Genomic DNA was isolated using a blood and tissue culture DNA extraction sys- tem (Qiagen, Hilden, Germany).

PCR amplification and direct sequencing

The gene segments encoding the α-helical 1A and 2B subdomains of the type II hair keratins hHb1, hHb3, hHb5, and hHb6 were am- plified by PCR using the previously described gene-specific primer pairs for these regions (Winter et al. 1997). PCR was car- ried out with the Expand Long Template PCR system (Boehringer, Mannheim, Germany) using standard conditions (Winter et al. Fig. 1 Pedigrees of the German monilethrix family 1 and the 1997).The PCR products were separated by agarose gel elec- Canadian monilethrix family 2. Clinically affected individuals are trophoresis, purified using silica gel beads (Boehringer) and se- indicated by solid symbols, unaffected members by open symbols. quenced directly according to the Thermo Sequenase radiolabeled Clinically, individual I-1 of pedigree 2 (solid triangle) appeared chain terminator cycle sequencing protocol (Amersham, Braun- unaffected, but carried a mutation in the hHb1 gene. Individuals schweig, Germany) using the corresponding gene-specific forward whose DNA was analyzed in this study are marked by an asterisk. primers as sequencing primers. ? in pedigree 1 denotes unknown disease status 167

Fig. 2 Mutation analysis of the genes of the type II hair keratins The same held true for the HTM-encoding 2B gene re- hHb6 in family 1 and hHb1 in family 2. Representative excerpts gions of hHb3 and hHb5 (results not shown). In contrast, from DNA sequencing gels show the sequence ladders in the mu- tated regions of an unaffected and an affected member of each analyses of the HTM-encoding regions of the hHb6 and family whose designation refers to the pedigrees in Fig. 1. Arrow- hHb1 gene led to the detection of a heterozygous G to A heads denote the mutation sites in the two genes and the heterozy- point mutation either of the hHb6 gene in family 1 and the gosity of the mutation in affected individuals. Exon 6/intron 7 single patient or of the hHb1 gene in family 2 (Fig. 2). In boundaries are indicated by small arrows. The nucleotide se- quences of the selected segments of normal and mutant hHb6 and all cases, the mutation site concerned the first position of hHb1 alleles are given in the schematic diagram; their numbering, the same glutamic acid codon, GAG, within the HTM as well as that of the deduced amino acid translations, refers to the coding region of the two genes and led to the substitution published hHb6 and hHb1 cDNA clones (Rogers et al. 1995a, of glutamic acid by a lysine residue (hHb6, Glu410Lys; 1997). For the discrimination of the two highly related genes, the hHb1, Glu403Lys; Fig. 2). The hHb6 gene mutation was initial intron 7 sequences are indicated in lower case letters. Mu- tated codons are boxed and the nucleotide and amino acid substitu- found in all clinically affected family 1 members from tions are highlighted by bold letters whom blood samples could be obtained (seven individu- als; Fig. 1). This was also true for the hHb1 gene mutation in individuals II-4 and III-2 of family 2. Surprisingly, hyperkeratosis. Light microscopy revealed short hairs however, the G to A mutation was also present in the clin- with prominent fusiform, regularly alternating segments ically unremarkable paternal grandmother I-1 of individ- of shaft thickening and thinning, typical of monilethrix. ual III-2, but not in the remaining family members. Both Clinically, all other members of the family seemed unaf- the hHb6 and hHb1 gene mutations were absent in 40 un- fected and none had noticable alopecia or early related, healthy control individuals. in life. However, systematic scanning electron micros- copy hair analyses clearly revealed moniliform hairs in the father, II-4, of patient III-2, whereas hairs of the rest of Discussion the family were interpreted as normal. The single Israeli patient (26 years) investigated presented typical monile- We were recently able to show that the hereditary hair dis- thrix hair in the posterior lower scalp with only minor ten- ease monilethrix is due to mutations in a hair keratin gene dency to fracture. The patient also exhibited keratotic pa- (Winter et al. 1997). We identified two types of causative pules on the neck. His mother was not afflicted by the dis- mutations in the same GAG codon in the HTM coding re- ease but both his sister (33 years) and his father (died at gion of the type II hair keratin hHb6 in two unrelated age 44 years) exhibited a distinctly more severe phenotype monilethrix families. The triplet encodes a glutamic acid with short, stubbly hair and keratotic papules covering the residue which is positionally conserved in virtually all entire scalp. In all monilethrix patients investigated in this type II and most type I keratins. One mutation, a G to A study, the secondary sexual hair, eyelashes, and eyebrows transition in the first position of the GAG codon, changed as well as the nails appeared normal. Glu to Lys, the other, a G to T transversion in the third po- The keratin mutation analyses in the two pedigrees sition of the GAG codon, led to the substitution of Glu by concerned the gene sequences coding for the HIMs and Asp. The Glu to Lys mutation was also found in three sin- HTMs of the four type II hair keratins, hHb1, hHb3, gle monilethrix patients. Thus, in five unrelated cases, we hHb5, and hHb6 (Rogers et al. 1995a, 1997). Direct se- not only noticed an apparent restriction of the causative quencing of the PCR-amplified 1A gene regions encoding mutations to a distinct hair keratin but also to a distinct the HIMs of the various keratins did not reveal deviations glutamic acid codon in its HTM coding region, with one from the reported sequences in both affected and unaf- type of mutation (Glu to Lys) being obviously prevalent fected members of the two families and the single patient. (Winter et al. 1997). In the present study, this tendency 168 seemed to be confirmed in the large German monilethrix filament assembly with K10 (Collin et al. 1992). Since family (family 1), in which affected members showed the K10 is already expressed in early spinous cells of the epi- Glu410Lys mutation in hHb6 which was also seen in the dermis, pathogenic mutations in its gene invariably lead single Israeli monilethrix patient. In the Canadian family to epidermolytic hyperkeratosis (Steinert (family 2), a mutation in a new hair keratin was found. 1995; Fuchs 1996). In contrast, our studies have revealed While we still observed a Glu to Lys substitution, this mu- at least four type I human hair keratins that are sequen- tation, however, occurred in the type II hair keratin hHb1 tially synthesized in the hair cortex (Fink et al. 1995; at Glu403, which is the position equivalent to that of Rogers et al. 1995b; unpublished results). Of these, hHa1 Glu410 in hHb6. and hHa4 show expression patterns deceptively similar to Disease-causing lysine substitutions in the equivalent those of hHb1 and hHb6 (unpublished results), suggesting position of hHb6 Glu410 and hHb1 Glu403, have already that they might be type I partners of the latter. In view of been described in other keratins. This is, for example, the the general involvement of both type I and type II epithe- case for Glu493 of the late epidermal type II keratin K2e in lial keratins in the etiology of skin fragility syndromes the majority of families with bullosa of Siemens (Steinert 1995; Fuchs 1996), it is therefore intriguing that, (Kremer et al. 1994; McLean et al. 1994; Rothnagel et al. up to now, neither mutations in type I cortex keratins nor 1994; Jones et al. 1996), for Glu475 of the basal epider- linkage to the type I keratin gene cluster (Richard et al. mal type II keratin K5 in an sim- 1996) have been found associated with monilethrix. A plex family (Stephens et al. 1997), and for Glu509 of the possible clue for this may be that the critical mutations in type II corneal keratin K3 in families with Meesmann’s type II cortex keratins seem to be limited to their HTMs. corneal dystrophy (Irvine et al. 1997). There is evidence that single-residue substitutions in cer- The two type II hair keratins, in which mutations for tain positions in the HTM of the type I keratin K14 do not monilethrix have now been found, are constituents of the visibly compromise filament assembly, while those in the hair cortex, with hHb1 being the earliest and hHb6 the lat- type II keratin K5 heavily disturb this process (Letai et al. est and predominantly expressed differentiation-specific 1992, 1993; Wilson et al. 1992). This may indicate that cortex keratin (Rogers et al. 1997). There is, however, a HTMs of type II keratins are more susceptible to patho- third type II cortex keratin, hHb3, that is synthesized in genic mutations than those of type I keratins (Rothnagel et the region between these two keratins, so that three type II al. 1994). Provided type I cortex keratin mutations exhibit hair keratins are coexpressed in cortical trichocytes (Rogers a similar HTM restriction, they may, therefore, not show et al. 1997). The expression of one mutated allele of either up phenotypically and carriers of those mutations may re- hHb1 or hHb6 appears apparently sufficient, however, to main undetected. fatally weaken the particularly dense intermediate fila- It should be emphasized that the extensive variation in ment network that results from the association of the three the disease phenotype associated with the keratin hHb1 type II keratins with their corresponding type I partners. mutation in the Canadian family is reminiscent of a previ- The high incidence of Glu410Lys mutations in hHb6 ously described French monilethrix family carrying a con- and the demonstration that the corresponding site in hHb1 servative Glu410Asp mutation instead of the non-conser- can also be subject to lysine substitution, suggests that the vative Glu410Lys mutation in hHb6 (Winter et al. 1997). corresponding GAG codon represents a mutational hot Both families possess hair keratin-mutated members who spot of the two type II cortex keratin genes. The base lacked early alopecia and demonstrable moniliform hair at change observed might be promoted by a methylated CpG a later age, a feature that, up until now, has not been ob- deamination mutation of a 5-methyl cytosine on the anti- served in families and single patients exhibiting the hHb6 sense strand in both genes, which leads to a CG to CA Glu410Lys mutation. Whether these discrepancies depend transition in the sense strand. Methylated CpG sequences on which of the type II cortex keratins is mutated or on the are known to have a higher mutation rate than other dinu- type of mutation in a distinct type II cortex keratin re- cleotides (Cooper and Krawczak 1989). Considering that mains to be seen from further investigations. the HTM coding region in all three cortex keratin genes is absolutely conserved (Rogers et al. 1997), we do not ex- Acknowledgements We thank all families for their cooperation and Christian Wolf, German Cancer Research Center, for excellent clude the possibility that further investigations could re- technical assistance. Howard P. Stevens is funded from a grant of veal monilethrix families with a lysine mutation in the the Wellcome Trust. This work was supported by the Deutsche corresponding glutamic acid residue of hHb3. Forschungsgemeinschaft (grant Schw 539/1Ð2). Up until now, pathogenic mutations in monilethrix seem to be restricted to type II cortex keratins. At first glance, this is reminiscent of a similar observation in References ichthyosis bullosa of Siemens, which only seems to be as- Collin C, Moll R, Kubicka S, Ouhayoun JP, Franke WW (1992) sociated with mutations in the late epidermal type II ker- Characterization of human cytokeratin K2e, an epidermal cy- atin K2e (Kremer at al. 1994; McLean et al. 1994; Roth- toskeletal synthesized late during differentiation. Exp nagel et al. 1994; Jones et al. 1996; Yang et al. 1997). The Cell Res 202: 132Ð141 latter is plausible in so far as, apparently, K2e does not Cooper DN, Krawczak M (1989) Cytosine methylation and the fate of CpG dinucleotides in vertebrate genomes. Hum Genet possess a defined, similarly late expressed type I partner 83: 181Ð188 in the epidermis, but is thought to compete with K1 for 169 De Berker DAR, Ferguson DJP, Dawber RPR (1993) Monilethrix: Richard G, Itin P, Lin JP, Bon A, Bale SJ (1996) Evidence for ge- a clinicopathological illustration of a cortical defect. Br J Der- netic heterogeneity in monilethrix. J Invest Dermatol 107: 812Ð matol 128: 327Ð331 814 Fink P, Rogers MA, Korge B, Winter H, Schweizer J (1995) A Rogers MA, Nischt R, Korge B, Krieg T, Fink TM, Lichter P, cDNA encoding the human type I hair keratin hHa1. Biochim Winter H, Schweizer J (1995a) Sequence data and chromoso- Biophys Acta 1264: 12Ð14 mal location of human type I and type II hair keratin genes. Fuchs E (1996) The cytoskeleton and disease: genetic disorders of Exp Cell Res 220: 357Ð362 intermediate filaments. Annu Rev Genet 30: 197Ð231 Rogers MA, Schweizer J, Krieg T, Winter H (1995b) A novel hu- Gummer CL, Dawber PRP, Swift JA (1981) Monilethrix: an elec- man type I hair keratin gene: evidence for two keratin hHa3 tron microscopic and electron histochemical study. Br J Der- isoforms. Mol Biol Rep 20: 155Ð161 matol 105: 529Ð541 Rogers MA, Langbein L, Praetzel S, Moll I, Krieg T, Winter H, Healy NE, Holmes S, Belgaid CE, Stephenson AM, McLean WHI, Schweizer J (1997) Sequences and differential expression of Rees JL, Munro CS (1995) A gene for monilethrix is closely three novel human type II hair keratins. Differentiation 61: 187Ð linked to the type II keratin gene cluster at 12q13. Hum Mol 194 Genet 4: 2399Ð2402 Rothnagel JA, Traupe H, Wojcik S, Huber M, Hohl D, Pittelkow Irvine AD, Cordon LD, Swensson O, Swensson B, Moore JE, MR, Saeki H, Ishibashi Y, Roop DR (1994) Mutations in the Frazer DG, Smith FJD, Knowlton RG, Christophers E, Rochels rod domain of keratin 2e in patients with ichthyosis bullosa of R, Uitto J, McLean WHI (1997) Mutations in cornea-specific Siemens. Nat Genet 7: 485Ð490 keratin K3 or K12 genes cause Meesmann’s corneal dystrophy. Steinert PM (1995) IF pathology: molecular consequences of rod Nat Genet 16: 184Ð187 and end domain mutations. 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J Invest Dermatol 103: 286Ð289 Winter H, Rogers MA, Langbein L, Stevens HP, Leigh IM, Letai A, Coulombe PA, Fuchs E (1992) Do the ends justify the Labreze C, Roul S, Taieb A, Krieg T, Schweizer J (1997) Mu- mean? Proline mutations at the ends of the keratin coiled-coil tations in the hair cortex keratin hHb6 cause the inherited hair rod segments are more disruptive than internal mutations. J disease monilethrix. Nat Genet 16:372Ð374 Cell Biol 116: 1181Ð1195 Yang JM, Lee S, Bang HD, Kim WS, Lee EL, Steinert PM (1997) Letai A, Coulombe PA, McCormick MB, Yu QC, Hutton E, Fuchs A novel threonineÐproline mutation at the end of 2B rod do- E (1993) Disease severity correlates with position of keratin main in the keratin 2e chain in ichthyosis bullosa of Siemens. point mutations in patients with epidermolysis bullosa simplex. J Invest Dermatol 109:116Ð118 Proc Natl Acad Sci USA 90: 3197Ð3201 Zimmermann R (1983) Monilethrix. Dermatol Monatsschr 196: McKee GM, Rosen J (1961) Monilethrix: a clinical and histologi- 638Ð645 cal study, with a report of six cases and a review of the litera- ture. J Cutan Dis Syph 34: 444Ð462 McLean WHI, Morley SM, Lane EB, Eady RAJ, Griffiths WAD, Paige DG, Harper JI, Higgins C, Leigh IM (1994) Ichthyosis bullosa of Siemens Ð a disease involving keratin 2e. J Invest Dermatol 103: 277Ð281