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ABSTRACT: Autosomal-dominant woolly hair (ADWH) is a rare disorder characterized by tightly curled hair. The molecular basis of ADWH has not previously been reported. In this study, we identified a Pakistani family with ADWH. The family showed linkage to chromosome 12q12-q14.1, containing the type II keratin gene cluster. We discovered a heterozygous mutation, p.Asn148Lys, within the helix initiation motif of the keratin 74 (KRT74) gene in all affected family members. KRT74 encodes the inner root sheath (IRS)-specific epithelial (soft) keratin 74. We demonstrate that the mutant K74 protein results in disruption of keratin intermediate filament formation in cultured cells, most likely in a dominant-negative manner. Furthermore, we sequenced the mouse Krt71-74 genes in the dominant Caracul-like 4 (Cal4) allele, which is characterized by a wavy-coat phenotype and maps to the same region of mouse chromosome 15 as the Caracul (Ca) and Reduced coat (Rco) alleles. We identified a heterozygous mutation, p.Glu440Lys, not in Krt74 but in the neighboring gene, Krt71. Krt71 was previously reported to harbor Ca and Rco mutations, as well as a coding SNP that is associated with curly-coated dogs. In this study, we define the ADWH phenotype resulting from a mutation in a hair-follicle-specific epithelial keratin in humans. Our findings not only further underscore the crucial roles of the IRS-specific epithelial keratin genes Krt71-74 in hair disorders but also open the possibility that these genes might function as genetic determinants of normal variation in hair texture across mammalian species.
The American Journal of Human Genetics 03/2010; 86(4):632-8. · 10.60 Impact Factor
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ABSTRACT: X-linked recessive hypohidrotic ectodermal dysplasia (XLHED; OMIM 305100) is a rare genodermatosis characterized clinically by developmental abnormalities affecting the teeth, hair and sweat glands. Mutations in the EDA-A1 gene have been associated with XLHED. Recently, mutations in the EDA-A1 gene have also been implicated in isolated X-linked recessive hypodontia (XLRH; OMIM 313500).
We analyzed the DNA from members of 3 unrelated Pakistani families with XLRH for mutations in the EDA-A1 gene through direct sequencing and performed haplotype analysis.
We identified a common missense mutation in both families designated c.1091T→C (p.M364T). Haplotype analysis revealed that this is a founder mutation in the 3 families.
XLHED is a syndrome with variable clinical presentations that contain a spectrum of findings, including hypodontia. We suggest that XLRH should be grouped under XLHED as both share several phenotypic and genotypic similarities.
Dermatology 01/2010; 221(3):243-7. · 2.05 Impact Factor
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ABSTRACT: Congenital insensitivity to pain (CIP) (OMIM 243000) is a rare autosomal-recessive disorder. Clinically, CIP is characterized by insensitivity to all modalities of pain except neuropathic pain, and recurrent injuries frequently go unnoticed. CIP is caused by mutations in the SCN9A gene encoding for the Na1.7 channel.
We analyzed the DNA from members of a consanguineous Pakistani family for mutations in the SCN9A gene through direct sequencing after performing linkage studies.
We identified a novel missense mutation designated R523X in all affected individuals. A screening assay ruled out the possibility of polymorphism.
We identified a novel mutation in the Na1.7 channel leading to CIP, extending the spectrum of mutations in the Na1.7 channel, and enhancing our understanding of the physiology of pain.
Dermatology 01/2010; 221(2):179-83. · 2.05 Impact Factor
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ABSTRACT: Autosomal recessive congenital ichthyosis (ARCI) can be divided into 3 types including lamellar ichthyosis (OMIM 242304), nonbullous congenital ichthyosiform erythroderma (OMIM 242100) and harlequin ichthyosis (OMIM 242500). The last type is uncommon since newborns with harlequin ichthyosis usually die shortly after birth. Several genes have been linked to ARCI, but these represent only 60% of the known genetic causes of this condition.
After having performed a linkage analysis, we analyzed the DNA of 2 consanguineous Pakistani families with ARCI for NIPAL4 mutations and performed in situ hybridization (ISH) for NIPAL4 mRNA in the epidermis.
The haplotype analysis revealed a linkage to chromosome 5, and we identified a recurrent missense mutation, p.A176D, in affected individuals from both families. We also determined by ISH that NIPAL4 mRNA is highly expressed in the granular cell layer of the epidermis, consistent with the ARCI phenotype.
Our results expand the spectrum of the clinical manifestations of the NIPAL4 gene and further extend our understanding of its molecular function.
Dermatology 12/2009; 220(1):8-14. · 2.05 Impact Factor
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Journal of dermatological science 11/2009; 56(3):205-7. · 3.71 Impact Factor
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ABSTRACT: Papillon-Lefèvre syndrome (PLS; OMIM 245000) is a rare autosomal recessive disorder. Clinically, PLS is characterized by hyperkeratosis involving the palms, soles, elbows and knees which is followed later on by periodontitis, destruction of alveolar bone and loss of primary and permanent teeth. The condition is caused by mutations in the cathepsin C (CTSC) gene.
We analyzed the DNA of members from 3 consanguineous families for mutations in the CTSC gene by direct sequencing analysis. We then performed haplotype analysis.
We identified an identical recurrent missense mutation, R272P, in all 3 families. Microsatellite marker analysis around the CTSC gene revealed the same haplotype on the mutation-carrying allele in all 3 families.
The presence of this common mutation in families from 2 different geographical areas provides evidence for a founder effect for CTSC mutations in PLS.
Dermatology 10/2009; 219(4):289-94. · 2.05 Impact Factor
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Journal of Investigative Dermatology 10/2009; 130(3):892-5. · 6.31 Impact Factor
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ABSTRACT: Mal de Meleda (MDM) (MIM #248300) is an autosomal recessive palmoplantar keratoderma (PPK). It is characterized clinically by erythematous hyperkeratotic plaques over palms and soles that start early in life and progress later in life in a transgradiens form associated with pain, macerations, foul odor, pseudoainhum, brachydactyly, onychodystrophy and perioral erythema.
To look for SLURP-1 gene mutations in patients with MDM.
We collected peripheral blood samples from Pakistani family members affected with MDM and 100 population-matched unrelated healthy control individuals in EDTA-containing tubes. All exons of the SLURP-1 gene with adjacent sequences at exon-intron borders were amplified. The amplified PCR products were directly sequenced in an ABI Prism 310 Automated Sequencer. Screening assay, using the restriction enzyme HphI was performed.
We determined three mutations in the SLURP-1 gene: one novel mutation, c.Ivs1+1G>A, and two recurrent mutations, p.R96X and p.G86R. Screening assays for the novel mutation excluded the possibility of polymorphism. In vivo transcription assays showed that the mutation c.Ivs1+1G>A leads to aberrant splicing events.
Our results expand the spectrum of mutations in SLURP-1 gene.
Journal of dermatological science 08/2009; 56(1):27-32. · 3.71 Impact Factor
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ABSTRACT: Autozygosity mapping in consanguineous families has proven to be a powerful method for identifying recessive disease genes. Using this technique with whole genome SNP data generated from low density mapping arrays, we previously identified two genes that underlie autosomal recessive woolly hair (ARWH/hypotrichosis; OMIM278150), specifically P2RY5 and Lipase H (LIPH). In the current study, we sought to identify a novel disease locus for ARWH/hypotrichosis by analyzing two large consanguineous families from Pakistan who had initially been excluded for mutations at either of these disease loci by haplotype analysis with microsatellite markers. A genome-wide analysis of 10 members from each of the two families failed to identify significant regions of autozygosity or linkage. Upon genotyping an additional 10 family members in one of the families, parametric linkage analysis identified a region on chromosome 3q27 with evidence for linkage (Z = 2.5). Surprisingly, this region contains the LIPH gene. Microsatellite markers located within the LIPH gene were used for haplotype analysis and demonstrated that not one, but two haplotypes were segregating with the phenotype in each of these families. DNA sequencing identified two distinct LIPH mutations (280_369dup90 and 659_660delTA). Each affected individual (n = 38) was either homozygous for one mutation (n = 7 and 16 respectively), or compound heterozygous (n = 15). A review of the literature identified several reports of compound heterozygotes in consanguineous families. Prompted by this finding, we derived the probability that a patient affected with a recessive disease is carrying two mutations at the disease locus. We suggest that the validity of the IBD assumption may be challenged in large consanguineous families.
Human Heredity 05/2009; 68(2):117-30. · 1.79 Impact Factor
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ABSTRACT: Autosomal-recessive woolly hair (ARWH)/hypotrichosis is a hereditary hair disorder which is characterized by tightly curled hair and is associated with sparse hair. ARWH can be caused by mutations in the P2RY5 or lipase H (LIPH) gene. Disruption of either gene results in phenotypes with features of both wooly hair (WH) and hypotrichosis. In this study, we identified two Guyanese families with ARWH. Both families are of recent Indian descent. Mutation analysis resulted in the identification of mutations in the LIPH gene in both families. Affected individuals in the first family carry compound heterozygous mutations Ex7_8del and 1303_1309dupGAAAACG in the LIPH gene, while those in the second family have a homozygous mutation 659_660delTA in the LIPH gene. The mutations Ex7_8del and 659_660delTA were identified earlier in several Pakistani families with ARWH. Haplotype analysis using microsatellite markers close to the LIPH gene defined a founder haplotype shared in families from Pakistan and Guyana. Proteomic analysis of hair shaft samples from one of the families revealed no substantial changes among the proteins identified, indicating that the syndrome does not involve global alterations in protein expression. Our results further suggest a crucial role of LIPH gene in hair growth.
Journal of Investigative Dermatology 04/2009; 129(8):1927-34. · 6.31 Impact Factor
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ABSTRACT: Striate palmoplantar keratoderma (SPPK; OMIM #148700) is a rare autosomal dominant genodermatosis characterized by linear hyperkeratosis on the digits and hyperkeratosis on the palms and soles. SPPK is known to be caused by heterozygous mutations in either the desmoglein 1 (DSG1), desmoplakin (DSP), or keratin 1 (KRT1) genes.
To define the molecular basis of SPPK in five Pakistani families showing a clear autosomal dominant inheritance pattern of SPPK.
Based on previous reports of DSG1 mutations in SPPK, we performed direct sequencing of the DSG1 gene of all five families.
Mutation analysis resulted in the identification of one recurrent mutation (p.R26X) and four novel mutations (c.Ivs4-2A>G, c.515C>T, c.Ivs9-3C>G, and c.1399delA) in the DSG1 gene. Each mutation is predicted to cause haploinsufficiency of DSG1 protein.
The results of our study further underscore the significance of the desmoglein gene family in diseases of epidermal integrity.
Journal of Dermatological Science 01/2009; 53(3):192-7. · 3.72 Impact Factor
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ABSTRACT: Woolly hair (WH) is characterized by the presence of fine and tightly curled hair. WH can appear as a symptom of some systemic diseases, or without associated findings (nonsyndromic WH). Nonsyndromic WH is known to be inherited as either an autosomal-dominant (OMIM 194300) or recessive (ARWH; OMIM 278150) trait. In this study, we identified 11 consanguineous families of Pakistani origin with ARWH, as well as associated features including sparse and hypopigmented hair shafts. We first checked for mutations in the P2RY5 gene, which encodes an orphan G-protein-coupled receptor that we recently identified as a cause of ARWH. However, none of the 11 families had mutations in the P2RY5 gene. To identify the disease locus, we performed linkage studies in one of these families using the Affymetrix 10K array, and identified a region of suggestive linkage on chromosome 3q27. This region contains the lipase H (LIPH) gene which has been recently shown to underlie an autosomal-recessive form of hypotrichosis. Mutation analysis resulted in the identification of a total of 5 pathogenic mutations in the LIPH of all 11 families analyzed. These results show that LIPH is a second causative gene for ARWH/hypotrichosis, giving rise to a phenotype clinically indistinguishable from P2RY5 mutations.
Journal of Investigative Dermatology 11/2008; 129(3):622-8. · 6.31 Impact Factor
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ABSTRACT: During the last decade, several causative genes for hereditary hair diseases have been identified, which have disclosed the molecular mechanisms involved in hair follicle morphogenesis and cycling. We and others recently reported that mutations in the P2RY5 gene, encoding an orphan G protein-coupled receptor, underlie autosomal recessive woolly hair (WH)/hypotrichosis. Although these findings clearly reveal the involvement of P2RY5 mutations in hereditary hair diseases, the clinical manifestations of P2RY5 mutations have not completely been elucidated because of limited information to date. In this study, we ascertained a consanguineous family of Iranian origin with an affected girl showing sparse and hypopigmented scalp hair. She exhibited the WH phenotype with normal hair density at birth, but progressed with age to develop hypotrichosis. Direct sequencing analysis resulted in the identification of a novel homozygous mutation in the P2RY5 gene of the patient, which results in a non-conservative amino acid change, G146R, at the protein level. Our findings extend the mutation spectrum of P2RY5 mutations, and further support a crucial role of P2Y5 in hair growth in humans.
Experimental Dermatology 10/2008; 18(3):218-21. · 3.54 Impact Factor
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ABSTRACT: While there have been significant advances in understanding the genetic etiology of human hair loss over the previous decade, there remain a number of hereditary disorders for which a causative gene has yet to be identified. We studied a large, consanguineous Brazilian family that presented with woolly hair at birth that progressed to severe hypotrichosis by the age of 5, in which 6 of the 14 offspring were affected. After exclusion of known candidate genes, a genome-wide scan was performed to identify the disease locus. Autozygosity mapping revealed a highly significant region of extended homozygosity (lod score of 10.41) that contained a haplotype with a linkage lod score of 3.28. Results of these two methods defined a 9-Mb region on chromosome 13q14.11-q14.2. The interval contains the P2RY5 gene, in which we recently identified pathogenic mutations in several families of Pakistani origin affected with autosomal recessive woolly and sparse hair. After the exclusion of several other candidate genes, we sequenced the P2RY5 gene and identified a homozygous mutation (C278Y) in all affected individuals in this family. Our findings show that mutations in P2RY5 display variable expressivity, underlying both hypotrichosis and woolly hair, and underscore the essential role of P2RY5 in the tissue integrity and maintenance of the hair follicle.
Genomics 09/2008; 92(5):273-8. · 3.02 Impact Factor
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ABSTRACT: Atrichia with papular lesions (APL) (OMIM#209500) is a rare autosomal recessively inherited form of irreversible alopecia characterized by papular lesions of keratin-filled cysts on various regions of the body. Males and females are equally affected and present with a distinct pattern of total hair loss on scalp, axilla and body. It begins shortly after birth with the development of hair loss, and patients are normally devoid of eyelashes and eyebrows. Mutations in the hairless (HR) gene have been previously shown to be responsible for APL.
In this study, we studied the molecular basis of APL in three unrelated families of Pakistani origin.
Molecular analysis of the HR genes was performed on genomic DNA from probands and family members.
DNA sequencing of the HR gene in family A revealed a novel homozygous 2bp deletion in exon 6 leading to a frameshift and a downstream premature termination codon in exon 8 (1782-83delAG). In family B, we identified a novel homozygous deletion of a G nucleotide at the exon 15-intron 15 boundary, termed 3097delG. Family C carries a previously reported missense mutation consisting of an A-to-G transition at nucleotide 276 resulting in the mutation N970S in exon 14.
Two mutations identified in this study are novel mutations in the HR gene and extend the body of evidence implicating the hairless gene family in the pathogenesis of human skin disorders. The one previously reported mutation suggests it may represent a recurrent mutation, or alternatively, an allele that is widely dispersed around the world.
Journal of Dermatological Science 05/2008; 50(1):25-30. · 3.72 Impact Factor
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ABSTRACT: The genetic determinants of hair texture in humans are largely unknown. Several human syndromes exist in which woolly hair comprises a part of the phenotype; however, simple autosomal recessive inheritance of isolated woolly hair has only rarely been reported. To identify a gene involved in controlling hair texture, we performed genetic linkage analysis in six families of Pakistani origin with autosomal recessive woolly hair (ARWH; OMIM 278150). All six families showed linkage to chromosome 13q14.2-14.3 (Z = 17.97). In all cases, we discovered pathogenic mutations in P2RY5, which encodes a G protein-coupled receptor and is a nested gene residing within intron 17 of the retinoblastoma 1 (RB1) gene. P2RY5 is expressed in both Henle's and Huxley's layers of the inner root sheath of the hair follicle. Our findings indicate that disruption of P2RY5 underlies ARWH and, more broadly, uncover a new gene involved in determining hair texture in humans.
Nature Genetics 04/2008; 40(3):335-9. · 35.53 Impact Factor
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ABSTRACT: P-cadherin is a member of the classical cadherin family that forms the transmembrane core of adherens junctions. Recently, mutations in the P-cadherin gene (CDH3) have been shown to cause two inherited diseases in humans: hypotrichosis with juvenile macular dystrophy (HJMD) and ectodermal dysplasia, ectrodactyly, macular dystrophy (EEM syndrome). The common features of both diseases are sparse hair and macular dystrophy of the retina, while only EEM syndrome shows the additional finding of split hand/foot malformation (SHFM). We identified five consanguineous Pakistani families with either HJMD or EEM syndrome, and detected pathogenic mutations in the CDH3 gene of all five families. In order to define the role of P-cadherin in hair follicle and limb development, we performed expression studies on P-cadherin in the mouse embryo, and demonstrated the predominant expression of P-cadherin not only in the hair follicle placode, but also at the apical ectodermal ridge (AER) of the limb bud. Based on the evidence that mutations in the p63 gene also result in hypotrichosis and SHFM, and that the expression patterns of p63 and P-cadherin overlap in the hair follicle placode and AER, we postulated that CDH3 could be a direct transcriptional target gene of p63. We performed promoter assays and ChIP, which revealed that p63 directly interacts with two distinct regions of the CDH3 promoter. We conclude that P-cadherin is a newly defined transcriptional target gene of p63, with a crucial role in hair follicle morphogenesis as well as the AER during limb bud outgrowth in humans, whereas it is not required for either in mice.
Development 03/2008; 135(4):743-53. · 6.60 Impact Factor
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ABSTRACT: Atrichia with papular lesions (APL) is a rare autosomal recessive form of inherited alopecia. Affected individuals present with a distinct pattern of total hair loss on the scalp, axilla and body shortly after birth and are essentially devoid of eyelashes and eyebrows. This form of hair loss is irreversible and the histology is consistent with an absence of mature hair follicles. In addition to total atrichia, APL patients also present with papules and follicular cysts filled with cornified material. Mutations in the Hairless (HR) gene have been shown to underlie APL.
Here, we studied five unrelated large Pakistani families with clinical manifestations of APL.
Based on previous reports of HR mutations in APL, we performed direct DNA sequencing analysis.
DNA sequencing of the HR gene in APL patients revealed three novel nonsense mutations in five unrelated families. All affected individuals were homozygous for a nonsense mutation due to C-to-T transitions at different positions in the amino acid sequence. Two families carry the mutation Q323X (CAG-TAG) in exon 3, two families harbor the mutation Q502X (CAG-TAG) in exon 6, and one family had a mutation at R940X (CGA-TGA) in exon 14. Haplotype analysis revealed that all affected individuals of both APL1 and APL16 families were homozygous for the same haplotype, and likewise, the mutation in families APL2 and APL19 was on the same haplotype.
We report three novel nonsense mutations in the HR gene in APL. Two of the newly identified mutations, Q323X and Q502X, were found to be shared between unrelated families and marker analysis confirmed an identical homozygous haplotype for APL1 and APL16, and for APL2 and APL19. These findings suggest that Q323X and Q502X did not arise independently, but instead appear to have been propagated in the population. Collectively, these findings contribute further evidence for the involvement of hairless mutations in papular atrichia.
Journal of Dermatological Science 01/2008; 48(3):207-11. · 3.72 Impact Factor
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ABSTRACT: The gene encoding human desmoglein 4 (DSG4) was recently cloned, and a mutation in this gene has been reported in several consanguineous Pakistani families affected with localized autosomal recessive hypotrichosis (LAH). In addition, various mutations in the Dsg4 gene have been identified in animal models of hypotrichosis that share a characteristic phenotype called "lanceolate hair". To date, the features of the hair-shaft anomaly in patients with LAH have not been well described. We report a Japanese patient affected with congenital hypotrichosis that was originally diagnosed as monilethrix because she had a hair-shaft abnormality that resembled moniliform hair. However, no mutations were found in the type II hair keratin genes, hHb1, hHb3, and hHb6, whose mutations cause monilethrix. Instead, we identified novel compound heterozygous mutations in the DSG4 gene of our patient. On the maternal allele is a novel S192P transition within the extracellular cadherin II domain of DSG4; on the paternal allele is a novel 2039insT mutation leading to the generation of unstable transcripts. Here we present the observation that mutations in the DSG4 gene can cause monilethrix-like congenital hypotrichosis. Based on our findings, we propose that LAH and monilethrix could overlap.
Journal of Investigative Dermatology 07/2006; 126(6):1281-5. · 6.31 Impact Factor
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ABSTRACT: Hair keratin-associated proteins (KAP) are a major component of the hair fiber, and play crucial roles in forming a strong hair shaft through a cross-linked network with keratin intermediate filaments (KIF), which are produced from hair keratins. Recently, the study of human KAP has advanced significantly. So far, five clusters of human KAP genes have been characterized, leading to the identification of more than 80 individual human KAP genes. In situ hybridization studies have demonstrated sequential and spatial expression patterns of these KAP members in differential portions of the hair fiber cortex and cuticle. Furthermore, several human KAP genes have size polymorphisms that are mainly because of variable numbers of cysteine-rich repeat segments, and the patterns of some of these size variants are distinct between different human populations.
Journal of Investigative Dermatology Symposium Proceedings 01/2006; 10(3):230-3. · 3.73 Impact Factor
