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Dec 28, 2010 - Novel mutations in the keratin-74 (KRT74) gene underlie autosomal dominant woolly hair/hypotrichosis in Pakistani families. Naveed Wasif ...
Hum Genet (2011) 129:419–424 DOI 10.1007/s00439-010-0938-9

ORIGINAL INVESTIGATION

Novel mutations in the keratin-74 (KRT74) gene underlie autosomal dominant woolly hair/hypotrichosis in Pakistani families Naveed Wasif • Syed Kamran ul-Hassan Naqvi • Sulman Basit • Nadir Ali • Muhammad Ansar • Wasim Ahmad

Received: 25 September 2010 / Accepted: 19 December 2010 / Published online: 28 December 2010 Ó Springer-Verlag 2010

Abstract Autosomal dominant woolly hair (ADWH) is an inherited condition of tightly curled and twisted scalp hair. Recently, a mutation in human keratin-74 (KRT74) gene has been shown to cause this form of hereditary hair disorder. In the present study, we have described two families (A and B) having multiple individuals affected with autosomal dominant form of hair loss disorders. In family A, 10 individuals showed ADWH phenotype while in the family B, 14 individuals showed hypotrichosis of the scalp. Genotyping using polymorphic microsatellite markers showed linkage of both the families to type II keratin gene cluster on the chromosome 12q12-14.1. Mutation analysis of the KRT74 gene identified two novel mutations in the affected individuals of the families. The sequence analysis revealed a splice acceptor site mutation (c.IVS8-1G[A) in family A and a missense variant (c.1444G[A, p.Asp482Asn) in family B. Mutations identified in the present study extend the body of evidence implicating the KRT74 gene in the pathogenesis of autosomal dominant hair loss disorders.

Introduction Humans with hereditary hair disorders present sparse to complete absence of hair on scalp and other body parts.

N. Wasif, S. Kamran ul-Hassan Naqvi contributed equally to this work. N. Wasif  S. K. u.-H. Naqvi  S. Basit  N. Ali  M. Ansar  W. Ahmad (&) Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan e-mail: [email protected]

In a few cases such hair disorders result in the appearance of tightly curled twisted woolly hair on the scalp. Until now at least eight autosomal recessive and four autosomal dominant forms of isolated hair loss disorders have been mapped on different human chromosomes and the corresponding genes have been identified in the majority of such cases. The autosomal recessive forms of hair loss disorders have been shown to result from mutations in hairless (HR, MIM 225060) (Ahmad et al. 1998; Cichon et al. 1998), desmoglein 4 (DSG4, MIM 607892) (Kljuic et al. 2003), lipase-H (LIPH, MIM 607365) (Kazantseva et al. 2006; Ali et al. 2007), G-protein coupled receptor (P2RY5, MIM 609239) (Shimomura et al. 2008; Pasternack et al. 2008; Azeem et al. 2008; Tariq et al. 2009) and desmocollin-3 (DSC3, MIM 600271) (Ayub et al. 2009) genes. The genes for the three recently reported autosomal recessive forms of hair loss disorders (Naz et al. 2010; Basit et al. 2010a, b) have not been identified to date. The autosomal dominant forms of hair loss disorders have been shown to result from mutations in corneodesmosin (CDSN, MIM 602593) (Levy-Nissenbaum et al. 2003), in the inhibitory upstream open-reading-frame (U2HR) of the hairless (HR) (Wen et al. 2009; Du¨zenli et al. 2009), APC-downregulatedby-1 (APCDD1, MIM 607479) (Shimomura et al. 2010a), and Keratin-74 (KRT74, MIM 608248) (Shimomura et al. 2010b) genes. In the present study, we have investigated two Pakistani families with autosomal dominant form of hair loss disorders and established linkage to the type II keratin gene cluster containing KRT71–KRT74 genes on the chromosome 12q12-14.1. Sequence analysis of the KRT74 gene revealed a novel splice acceptor site mutation (c.IVS81G[A) in one family and a missense mutation (c.1444G[A, p.Asp482Asn) in the other family.

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Materials and methods Human subjects In the present study, we have investigated two large families (A and B) with autosomal dominant form of hair loss disorders from the remote areas of Pakistan. In family A, 10 individuals showed ADWH phenotype while in the family B, 14 individuals showed hypotrichosis (sparse hair) of the scalp. At least three affected individuals from each family underwent examination at the local government hospitals. Venous blood samples were collected from 16 individuals including 9 affected (II-1, III-2, III-3, III-4, III-5, V-1, V-5, V-6, V-7) in family A and 9 individuals including 5 affected (IV-4, IV-5, V-3, V-5, V-6) in family B (Fig. 1). Approval of the study was obtained from the Quaid-i-Azam University Institutional Review Board (IRB). Informed written consents were provided by all those subjects who participated in the study. Extraction of genomic DNA and genotyping Genomic DNA was extracted from the blood samples by TM GenElute blood genomic DNA kit (Sigma–Aldrich, USA). Based on the clinical features of the affected individuals and the mode of inheritance, the families were tested for linkage to recently reported keratin-74 (KRT74, MIM 608248) gene located on chromosome 12q12-14.1 (D12S1701, D12S339, D12S1629, D12S803, D12S1618, Fig. 1 Pedigrees and haplotypes of family A with ADWH and family B with hypotrichosis, linked to the KRT74 gene on chromosome 12q12-14.1. The diseased haplotype is indicated by solid filled bars. Circles and squares represent females and males, respectively. Clear symbols represent unaffected individuals while filled symbols represent affected individuals. Crossed symbols represent deceased individuals

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D12S1651, D12S1691, D12S1726), APC-downregulatedby-1 (APCDD1, MIM 607479) gene on the chromosome 18p11.32-p11.23 (D18S843, D18S464, D18S1153, D18S1150, D18S378, D18S1158, D18S1116, D18S482, D18S71), corneodesmosin (CDSN, MIM 602593) gene on chromosome 6p21.3 (D6S1281, D6S1621, D6S981, D6S2260, D6S105, D6S497) and inhibitory upstream open-reading-frame (U2HR) of the hairless (HR) on the chromosome 8p21.2 (D8S282, D8S298, D8S1861, D8S1786, D8S1733, D8S1752). The conditions used for amplification of the microsatellite markers were the same as described earlier (Azeem et al. 2008). Screening KRT71 and KRT74 DNA sequencing of the KRT74 gene was performed in all available affected and normal individuals of both the families. In addition, KRT71 gene was sequenced in the two affected and two normal individuals of family B. Primer sets flanking coding and splice junctions of the genes were designed using Primer3 software (http://frodo. wi.mit.edu/primer3/). Primer sequences are available upon request. Purification of PCR-amplified products was performed using commercially available kits (Marligen Biosciences, Ijamsville, MD USA). Sequencing of the gene was performed with Big Dye Terminator v3.1 Cycle Sequencing Kit together with an ABI Prism 310 Genetic Analyzer (Applera, Foster City, CA, USA). Bioedit sequence alignment tool (Bioedit editor version 6.0.7) was

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used to align the sequence of each amplicon with the reference sequence of KRT74 (Ensembl accession ID: Human ENST00000305620) and KRT71 (Ensembl accession ID: Human ENST00000267119) obtained from Ensembl Genome Browser (http://www.ensembl.org/Homo_sapiens/ Gene).

Results Clinical findings At least three affected individuals of each family underwent examination at local government hospitals. In family A, all the affected individuals showed features of tightly curled hair restricted to 2–3 in, twisted and entangled with each other (Fig. 2). In family B, affected individuals showed features of hair loss compatible with a condition of hypotrichosis. Detailed interviews with elders of this family revealed that affected individuals were born with sparse hair on the scalp. After ritual shaving which is usually performed a week after birth, hair regrew but started falling again at the age of 3–5 years in a patchy hair loss pattern leading to the present state of sparse hair on the scalp (Fig. 2). Eyebrows, eyelashes, sweating, teeth and nails were normal in the affected individuals of both the families. Affected male individuals of the families showed

Fig. 2 Clinical presentation of ADWH and hypotrichosis phenotype. Phenotypic appearance of an affected male III-5 (a) and an affected female V-6 (b) in family A showing tightly curled twisted scalp hair. In family B, affected males IV-5 (c) and V-3 (d) showing sparse hair on the scalp

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normal mustache and beard hair. No other skin problem was observed in any affected individual of the families. Genotyping and mutational analysis The families were tested for linkage by genotyping highly polymorphic microsatellite markers linked to recently reported genes involved in dominant forms of hereditary hair loss disorders. This included KRT74 gene located on the chromosome 12q12-14.1 (D12S1701, D12S339, D12S1629, D12S803, D12S1618, D12S1651, D12S1691, D12S1726), APCDD1 gene on the chromosome 18p11.32p11.23 (D18S843, D18S464, D18S1153, D18S1150, D18S378, D18S1158, D18S1116, D18S482, D18S71), CDSN gene on the chromosome 6p21.3 (D6S1281, D6S1621, D6S981, D6S2260, D6S105, D6S497) and U2HR on the chromosome 8p21.2 (D8S282, D8S298, D8S1861, D8S1786, D8S1733, D8S1752). The markers typed in both the affected and unaffected individuals of the families were fully informative and established linkage to KRT74 gene on the chromosome 12q12-14.1. In family A, sequence analysis of the KRT74 gene identified a novel mutation affecting the splice acceptor site sequence AG of intron 8 (c.IVS8-1G[A) in all the nine affected individuals of the family (Fig. 3). All the seven normal individuals of the family showed wild-type splice acceptor site sequence. The sequence alteration in the affected individuals abolished a site for restriction enzyme PvuII in the mutant allele (Fig. 4). In control unaffected individuals, PvuII restriction analysis of PCR-amplified 471 bp fragment generated two fragments of 340 and 131 bp. In case of affected individuals, PvuII restriction analysis showed an undigested 471 bp fragment, representing a mutant allele, and digested 340 and 131 bp fragments representing a normal allele (Fig. 4). In family B, two genes KRT71 and KRT74 were sequenced in the affected and normal individuals of the families. DNA sequence analysis of KRT71 failed to detect any functional sequence variant, however, sequencing of KRT74 revealed a novel heterozygous missense mutation involving G to A transition at cDNA position 1444 (c.1444G[A) in exon 9 of the gene in all the five affected individuals (Fig. 3). This heterozygous mutation resulted in substitution of an aspartate to asparagine amino acid residue at position 482 (p.Asp482Asn). All the four unaffected individuals of the family showed wildtype sequence. To ensure that the splice site mutation identified in family A does not represent a neutral polymorphism in the Pakistani population, a panel of 100 ethnically matched, unrelated, unaffected control individuals were screened by PvuII restriction analysis and the mutation was not identified outside the family. Non-polymorphic nature of the missense mutation detected in the family B was verified by screening 300 unrelated, unaffected control individuals.

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Fig. 3 Sequence analysis of KRT74 gene mutations. Partial DNA sequence of exon 9 of KRT74 gene from an unaffected individual showing the homozygous wild type splice acceptor site (AG) (a) and from an affected individual showing the heterozygous status of splice acceptor site (c.IVS8-1G[A) (b) in family A. Partial DNA sequence

Fig. 4 PvuII restriction enzyme analysis of the splice site mutation (c.IVS8-1G[A) detected in the family A. Lane 1: 100 bp DNA ladder (MBI Fermentas UK). Lane 2 and 3: A PvuII undigested 471 bp fragment representing a mutant allele, and 340 and 131 bp fragments representing PvuII digested normal allele in affected individuals. Lane 4 and 5: 340 and 131 bp fragments representing PvuII digested normal alleles in unaffected individuals

Discussion The human keratin gene family contains 54 distinct functional genes, which are grouped into three categories including epithelial keratins, hair keratins and keratin pseudogenes (Schweizer et al. 2006). Based on the biochemical nature of keratins, they are divided into acidic type I and basic to neutral type II keratins. Keratin type I gene cluster on the chromosome 17q21.2 contains 28 keratins, while type II keratin gene cluster on the chromosome 12q13.13 contains 26 keratins (Arin 2009). In humans, mutations in 21 hair keratins and hair follicle specific epithelial keratins are associated with hereditary disorders including generalized epidermolysis bullosa simplex (EBS, MIM 131900) (Bonifas et al. 1991; Dong et al. 1993), bullous congenital ichthyosiform erythroderma (BCIE, MIM 113800) (Cheng et al. 1992; Chipev et al. 1992; Rothnagel et al. 1992), epidermolytic plamoplantar keratoderma (EPPK, MIM 144200) (Coleman et al. 1999; Kon et al. 2006), pachyonychia congenita type I (PC1, MIM 167200) (Bowden et al. 1995; McLean et al.

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of exon 9 of KRT74 gene from an unaffected member showing homozygous wild type sequence (c) and from an affected member showing heterozygous status of the missense mutation (c.1444G[A, p.Asp482Asn) (d) in family B. Arrows represent position of the mutations in each panel

1995), pachyonychia congenita type II (PC2, MIM 167210) (Smith 2004; Xiao et al. 2004), monilethrix (MIM 158000) (Winter et al. 1997a, b; van Steensel et al. 2005), ectodermal dysplasia of hair and nail type (MIM 602032) (Naeem et al. 2006). Disorders of other body tissues/organs such as Meesmann corneal dystrophy, White sponge nevus of Cannon, and liver disease are also caused by mutations in keratins (Richard et al. 1995; Rugg et al. 1995; Irvine et al. 1997; Porter and Lane 2003; Nielsen et al. 2008). Recently, Shimomura et al. (2010b) have reported a first mutation (p.Glu440Lys) in keratin-74 (KRT74) gene causing autosomal dominant woolly hair in a large family. In the present investigation, we have identified a splice site (c.IVS8-1G[A) and a missense mutation (p.Asp482Asn) in the same KRT74 gene in two large Pakistani families. Clinical features of tightly curled and twisted scalp hairs observed in affected individuals of the family with splice site mutation were very similar to those reported by Shimomura et al. (2010b). However, affected individuals of the family carrying a missense mutation showed clinical features representing hypotrichosis with sparse hair on the scalp. The Keratin-74 (KRT74) gene is composed of nine exons encoding 529 amino acids K74 protein. Like other keratins, K74 protein is composed of N-terminal head domain (1–139 amino acids), the central a helical rod domain (140–149 amino acids) and C-terminal tail domain (450–529 amino acids). Approximately sixty-six (66) amino acids encoded by exon-9 are involved in the formation of functional tail domain (www.uniprot.org/uniprot/ Q7RTS7). Use of Alternative Splice Site Predictor (ASSP) (Wang and Marı´n 2006) software predicts that splice site mutation (c.IVS8-1G[A), identified in the present study, can create three alternative cryptic splice sites. This includes a cryptic splice site (accaccccagCTCTGCGGGT) at 38 nucleotides downstream within the coding sequence

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of exon 9, which can cause a deletion of 13 amino acids of the tail domain of K74 protein. Two other cryptic splice sites acccccaaagGTGTCTGCCA and aagttcccagGCCCTGAGTT can be created at 257 and 282 nucleotides downstream, respectively, in the 30 -untranslated region (30 -UTR) of KRT74 gene. Both of these cryptic sites can cause deletion of all of exon 9 coding sequence,as well as abolish the tail domain of K74 protein. Use of any of the three sites leads to synthesis of a truncated protein or absence of functional protein, possibly due to nonsensemediated mRNA decay (NMRD) (Weischenfeldt et al. 2005). More likely, haploinsufficiency of KRT74 is the predominant mechanism underlying woolly hair in the family. Mutations in desmoglein-1 (Dua-Awereh et al. 2009) and keratin-5 (Betz et al. 2006) causing palmoplantar keratoderma and Dowling-Degos disease, respectively, have been predicted to result from haploinsufficiency of the two genes. The missense mutation (p.Asp482Asn) identified in the present family B resides in the tail domain of K74 protein. Substitution of aspartic acid with asparagines can create an additional site for N-linked glycosylation resulting in modification of the protein chains. Considering the effect of missense mutations p.Glu440Lys in KRT74 and p.Gly464Val in KRT71 (Shimomura et al. 2010b), it is more likely that the missense mutation (p.Asp482Asn) also potentially affect the keratin intermediate filament formation. As reviewed by Schweizer et al. (2007) expression of human hair keratins and hair follicle specific epithelial keratins is restricted to different layers of hair follicle. At least nine type I (KRT39, KRT34, KRT36, KRT33a, KRT33b, KRT37, KRT38, KRT31, KRT35) and four type II keratins (KRT86, KRT83, KRT81, KRT85) express in various parts of hair follicle cortex. The expression of few type I (KRT39, KRT40, KRT32, KRT35) and type II keratins (KRT82, KRT85) is restricted to cuticle layer. The inner root sheath (IRS) specific keratins are expressed in different layers of IRS. Three type I keratins (KRT25, KRT27, KRT28) express in Henle and Huxley layers and cuticle of IRS while expression of another type I keratin (KRT26) is restricted to IRS cuticle. A type II keratin KRT71 shows expression in all three layers of IRS, while KRT74 expression is restricted to Huxley layer and KRT73, KRT72 express in IRS cuticle. A type II keratin KRT75 expresses in companion layer of hair follicle. The IRS is a critical structure supporting the hair shaft (Langbein et al. 2003). Recently, Shimomura et al. (2010b) have reported that K74 specifically expresses in Huxley layer, which plays an important role in maintaining the structure of hair follicle. These authors further predicted that disruption of K74 results in a collapse of keratin intermediate filament complex which affects the growth and elongation of hair shaft.

423 Acknowledgments We are grateful to all members of the family for their invaluable participation and cooperation in this study. The work presented here was funded by Higher Education Commission (HEC), Islamabad, Pakistan. Naveed Wasif and Syed Kamran ul-Hassan Naqvi were supported by indigenous PhD fellowships from HEC, Islamabad, Pakistan.

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