Showing papers by "John A. McGrath published in 2019"

An essential role for the Zn2+ transporter ZIP7 in B cell development

Abstract: Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection.

Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02

Abstract: Frontal fibrosing alopecia (FFA) is a recently described inflammatory and scarring type of hair loss affecting almost exclusively women. Despite a dramatic recent increase in incidence the aetiopathogenesis of FFA remains unknown. We undertake genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and perform statistical meta-analysis. We observe genome-wide significant association with FFA at four genomic loci: 2p22.2, 6p21.1, 8q24.22 and 15q2.1. Within the 6p21.1 locus, fine-mapping indicates that the association is driven by the HLA-B*07:02 allele. At 2p22.1, we implicate a putative causal missense variant in CYP1B1, encoding the homonymous xenobiotic- and hormone-processing enzyme. Transcriptomic analysis of affected scalp tissue highlights overrepresentation of transcripts encoding components of innate and adaptive immune response pathways. These findings provide insight into disease pathogenesis and characterise FFA as a genetically predisposed immuno-inflammatory disorder driven by HLA-B*07:02.

Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa.

Abstract: BACKGROUNDRecessive dystrophic epidermolysis bullosa (RDEB) is a severe form of skin fragility disorder due to mutations in COL7A1 encoding basement membrane type VII collagen (C7), the main constituent of anchoring fibrils (AFs) in skin. We developed a self-inactivating lentiviral platform encoding a codon-optimized COL7A1 cDNA under the control of a human phosphoglycerate kinase promoter for phase I evaluation.METHODSIn this single-center, open-label phase I trial, 4 adults with RDEB each received 3 intradermal injections (~1 × 106 cells/cm2 of intact skin) of COL7A1-modified autologous fibroblasts and were followed up for 12 months. The primary outcome was safety, including autoimmune reactions against recombinant C7. Secondary outcomes included C7 expression, AF morphology, and presence of transgene in the injected skin.RESULTSGene-modified fibroblasts were well tolerated, without serious adverse reactions or autoimmune reactions against recombinant C7. Regarding efficacy, there was a significant (P < 0.05) 1.26-fold to 26.10-fold increase in C7 mean fluorescence intensity in the injected skin compared with noninjected skin in 3 of 4 subjects, with a sustained increase up to 12 months in 2 of 4 subjects. The presence of transgene (codon-optimized COL7A1 cDNA) was demonstrated in the injected skin at month 12 in 1 subject, but no new mature AFs were detected.CONCLUSIONTo our knowledge, this is the first human study demonstrating safety and potential efficacy of lentiviral fibroblast gene therapy with the presence of COL7A1 transgene and subsequent C7 restoration in vivo in treated skin at 1 year after gene therapy. These data provide a rationale for phase II studies for further clinical evaluation.TRIAL REGISTRATIONClincalTrials.gov NCT02493816.FUNDINGCure EB, Dystrophic Epidermolysis Bullosa Research Association (UK), UK NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London, and Fondation Rene Touraine Short-Exchange Award.

Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer

Abstract: Cancers often begin as cells that grow in connected sheets or clumps known as epithelial cells. To spread, the cancer cells need to change into cells that can break away from the group and move through the tissues. In prostate cancer, this process can happen years after successful treatment, but researchers are not sure why. Prostate cancer grows in response to testosterone. This hormone circulates around the body, and when it goes into a cell it helps select which genes are switched on or off. Testosterone-blocking drugs can help slow prostate cancer growth by changing this switching on and off of genes. But, over time, some cancers become resistant to the effects of these drugs and start to spread. This may be down to complexities in how testosterone controls gene activity. To produce a protein, a human cell first makes a copy of the corresponding gene. This copy is then modified, cutting and pasting different parts of the sequence (a process called ‘splicing’) before the protein is produced. The patterns of splicing a cell exhibits depend on splicing regulator proteins. Testosterone can change splicing patterns in prostate cancer cells, but researchers did not know how. To find out, Munkley et al. examined a set of genes that turn off in response to testosterone-blocking drugs in people with prostate cancer. This revealed that testosterone controls a master splicing regulator called ESRP2, which is normally present in epithelial cells. In prostate cancer cells in mice, extra ESRP2 slowed tumour growth. But, although ESRP2 levels are high in human prostate cancer cells to begin with, they drop in response to testosterone-blocking drugs. In the laboratory grown cells, the result was a switch away from 'epithelial-like' gene splicing patterns. Some of the new splicing patterns correlated with better patient prognosis, but other splicing patterns might help cancer cells to spread around the body. These results raise the possibility that blocking testosterone may impair prostate cancer growth, but also inadvertently prepare cancer cells to break away from tumours. A more complete understanding of how testosterone controls splicing could help explain why some tumours initially shrink when testosterone is blocked, but then later spread. Identifying the genes controlled by ESRP2 may reveal new drug targets to improve prostate cancer treatment.

Bone marrow transplant with post-transplant cyclophosphamide for recessive dystrophic epidermolysis bullosa expands the related donor pool and permits tolerance of nonhaematopoietic cellular grafts

Abstract: Background Recessive dystrophic epidermolysis bullosa (RDEB) is a severe systemic genodermatosis lacking therapies beyond supportive care for its extensive, life-limiting manifestations. Objectives To report the safety and preliminary responses of 10 patients with RDEB to bone marrow transplant (BMT) with post-transplant cyclophosphamide (PTCy BMT) after reduced-intensity conditioning with infusions of immunomodulatory donor-derived mesenchymal stromal cells (median follow-up 16 months). Methods BMT toxicities, donor blood and skin engraftment, skin biopsies, photographic and dynamic assessments of RDEB disease activity were obtained at intervals from pre-BMT to 1 year post-BMT. Results Related donors varied from haploidentical (n = 6) to human leucocyte antigen (HLA)-matched (n = 3), with one HLA-matched unrelated donor. Transplant complications included graft failure (n = 3; two pursued a second PTCy BMT), veno-occlusive disease (n = 2), posterior reversible encephalopathy (n = 1) and chronic graft-versus-host disease (n = 1; this patient died). In the nine ultimately engrafted patients, median donor chimerism at 180 days after transplant was 100% in peripheral blood and 27% in skin. Skin biopsies showed stable (n = 7) to improved (n = 2) type VII collagen protein expression by immunofluorescence and gain of anchoring fibril components (n = 3) by transmission electron microscopy. Early signs of clinical response include trends toward reduced body surface area of blisters/erosions from a median of 49·5% to 27·5% at 100 days after BMT (P = 0·05), with parental measures indicating stable quality of life. Conclusions PTCy BMT in RDEB provides a means of attaining immunotolerance for future donor-derived cellular grafts (ClinicalTrials.gov identifier NCT02582775). What's already known about this topic? Severe, generalized recessive dystrophic epidermolysis bullosa (RDEB) is marked by great morbidity and early death. No cure currently exists for RDEB. Bone marrow transplant (BMT) is the only described systemic therapy for RDEB. What does this study add? The first description of post-transplant cyclophosphamide (PTCy) BMT for RDEB. PTCy was well tolerated and provided excellent graft-versus-host disease prophylaxis, replacing long courses of calcineurin inhibitors in patients receiving human leucocyte antigen-matched sibling BMT. What is the translational message? The PTCy BMT platform permits identification of a suitable related donor for most patients and for subsequent adoptive transfer of donor nonhaematopoietic cells after establishment of immunological tolerance.

EMSY expression affects multiple components of the skin barrier with relevance to atopic dermatitis.

Abstract: Background Atopic dermatitis (AD) is a common, complex, and highly heritable inflammatory skin disease. Genome-wide association studies offer opportunities to identify molecular targets for drug development. A risk locus on chromosome 11q13.5 lies between 2 candidate genes, EMSY and LRRC32 (leucine-rich repeat-containing 32) but the functional mechanisms affecting risk of AD remain unclear. Objectives We sought to apply a combination of genomic and molecular analytic techniques to investigate which genes are responsible for genetic risk at this locus and to define mechanisms contributing to atopic skin disease. Methods We used interrogation of available genomic and chromosome conformation data in keratinocytes, small interfering RNA (siRNA)–mediated knockdown in skin organotypic culture and functional assessment of barrier parameters, mass spectrometric global proteomic analysis and quantitative lipid analysis, electron microscopy of organotypic skin, and immunohistochemistry of human skin samples. Results Genomic data indicate active promoters in the genome-wide association study locus and upstream of EMSY; EMSY, LRRC32, and intergenic variants all appear to be within a single topologically associating domain. siRNA-knockdown of EMSY in organotypic culture leads to enhanced development of barrier function, reflecting increased expression of structural and functional proteins, including filaggrin and filaggrin-2, as well as long-chain ceramides. Conversely, overexpression of EMSY in keratinocytes leads to a reduction in markers of barrier formation. Skin biopsy samples from patients with AD show greater EMSY staining in the nucleus, which is consistent with an increased functional effect of this transcriptional control protein. Conclusion Our findings demonstrate an important role for EMSY in transcriptional regulation and skin barrier formation, supporting EMSY inhibition as a therapeutic approach.

Generation and Clinical Application of Gene-Modified Autologous Epidermal Sheets in Netherton Syndrome: Lessons Learned from a Phase 1 Trial.

Abstract: Netherton syndrome (NS) is a rare autosomal recessive skin disorder caused by mutations in SPINK5. It is a debilitating condition with notable mortality in the early years of life. There is no cura...

Identification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa-Associated Squamous Cell Carcinoma.

Abstract: Purpose: Squamous cell carcinoma (SCC) of the skin is the leading cause of death in patients with the severe generalized form of the genetic disease recessive dystrophic epidermolysis bullosa (RDEB). Although emerging data are identifying why patients suffer this fatal complication, therapies for treatment of RDEB SCC are in urgent need. Experimental Design: We previously identified polo-like kinase 1 (PLK1) as a therapeutic target in skin SCC, including RDEB SCC. Here, we undertake a screen of 6 compounds originally designated as PLK1 inhibitors, and detail the efficacy of the lead compound, the multipathway allosteric inhibitor ON-01910, for targeting RDEB SCC in vitro and in vivo. Results: ON-01910 (or rigosertib) exhibited significant specificity for RDEB SCC: in culture rigosertib induced apoptosis in 10 of 10 RDEB SCC keratinocyte populations while only slowing the growth of normal primary skin cells at doses 2 orders of magnitude higher. Furthermore, rigosertib significantly inhibited the growth of two RDEB SCC in murine xenograft studies with no apparent toxicity. Mechanistically, rigosertib has been shown to inhibit multiple signaling pathways. Comparison of PLK1 siRNA with MEK inhibition, AKT inhibition, and the microtubule-disrupting agent vinblastine in RDEB SCC shows that only PLK1 reduction exhibits a similar sensitivity profile to rigosertib. Conclusions: These data support a "first in RDEB" phase II clinical trial of rigosertib to assess tumor targeting in patients with late stage, metastatic, and/or unresectable SCC.

Revertant mosaic fibroblasts in recessive dystrophic epidermolysis bullosa.

Abstract: Background Revertant mosaicism has been described previously in recessive dystrophic epidermolysis bullosa (RDEB), manifesting as regions of skin with normal mechanical and biological characteristics. Here we report the discovery of revertant dermal fibroblasts, unique in that all other documented cases of revertant mosaicism occur in epidermal keratinocytes. Objectives To determine the cause of revertant mosaicism found in a patient with RDEB from isolated epidermal keratinocytes and dermal fibroblasts in blister and mosaic skin regions. Methods Skin biopsies were taken from blister and mosaic skin regions of a patient with RDEB. Allele identification was confirmed and the type VII collagen (C7) content and COL7A1 expression profile of isolated keratinocytes and fibroblasts was determined. Results Keratinocytes isolated from the mosaic area had a slight increase in C7, although overall expression of COL7A1 was unchanged between blister and mosaic fibroblasts. Differential allele expression was identified in blister and mosaic fibroblasts using targeted RNA sequencing (TREx), where the allele harbouring a point mutation was preferentially expressed over that containing a frameshift mutation. A crossing over event was identified in mosaic fibroblasts that was not present in blister fibroblasts, yielding a functional COL7A1 allele in a subset of cells. Conclusions In documenting a novel case of revertant mosaicism in RDEB, we have identified dermal fibroblasts as having the capacity to correct blistering functionally. We have also pioneered the use of TREx in quantifying allele-specific expression. Using fibroblasts instead of keratinocytes for RDEB therapies offers advantages in the local and systemic therapy of RDEB. What's already known about this topic? Revertant mosaicism has been previously documented in patients with recessive dystrophic epidermolysis bullosa (RDEB), however, it has only been found in epidermal keratinocytes. What does this study add? We have demonstrated that COL7A1 gene reversion in dermal fibroblasts occurs and is able to form functional skin in a patient with RDEB. Additionally, we have pioneered a new application for targeted RNA sequencing in quantifying allele-specific expression in fibroblasts and keratinocytes. What is the translational message? This opens up possibilities for using fibroblasts as local and systemic therapy for patients with RDEB.

Dermatological manifestations of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP): a case series of 28 patients.

Abstract: Dear Editor, Hereditary Fibrosing Poikiloderma with Tendon Contractures, Myopathy and Pulmonary Fibrosis (POIKTMP [MIM 615704]) is a recently described autosomal dominant disorder due to missense mutations in the FAM111B gene. Key features are early-onset poikiloderma, muscle contractures in particular of the triceps surae, diffuse progressive fatty myopathy, pulmonary fibrosis in adulthood and exocrine pancreatic insufficiency. Dermatological manifestations seem to be constant and early however, a precise description is lacking. This article is protected by copyright. All rights reserved.

Pterygium and thinning of nails as an unusual manifestation in Clouston syndrome

Abstract: Dear Editor, A 64-year-old Thai man presented with irregular, brittle and thin fingernails and toenails that had progressed from adolescence (Fig. 1). Other features included painful thickened palms and soles since childhood, as well as loss of scalp and body hair, and hypodontia. Sweating was normal, as was his eyesight and hearing and his physical and mental development. Examination showed 20-nail dystrophy with hypoplasia and pterygium formation but without nail fold abnormalities. He also had marked hyperkeratotic plaques on the palms and soles, diffuse thinning of scalp hair with extensive alopecia, and loss of eyebrows, axillary and pubic hair (Fig. 1a–g). Oral examination showed generalized severe dental attrition and tooth loss (Fig. 1h). Collectively, the clinical features were suggestive of Clouston syndrome (Online Mendelian Inheritance in Man 129500), despite the unusual nails. Within the family, five other individuals (Fig 1i) had similar clinical features of childhood onset of keratoderma, progressive hair loss and nail thinning/dystrophy, with the three affected adults also demonstrating later onset of hypodontia. None of the other unaffected family members had isolated hair, nail, tooth or other skin abnormalities. Following informed consent, ethics’ committee approval and in full accordance with the Declaration of Helsinki, Sanger sequencing of the proband’s DNA for GJB6, encoding connexin 30, revealed a heterozygous single nucleotide transition, c.263C>T, which results in the amino acid substitution, p.Ala88Val, within the transmembranous domain of this gap junction protein (Fig. 1j,k). This particular missense mutation has been reported previously as a pathogenic change in Clouston syndrome. Clinically, however, hypoplastic nail and teeth abnormalities are not regarded as classic features of Clouston syndrome and we therefore Sanger sequencedWNT10A, a gene frequently implicated in ectodermal anomalies; no potentially pathogenic mutations were found. Clouston syndrome is characterized by the triad of nail dystrophy, alopecia and palmoplantar hyperkeratosis. Of note, nail abnormalities usually consist of thickening or shortening (micronychia), onychorrhexis or triangular nail plates which can resemble pachyonychia congenita. Indeed, most cases of Clouston syndrome have thick and hyperconvex nails. Pincer nails, without thickening, also have been reported (connexin 30 mutation p.Gly11Arg). In contrast to these previous reports, our patient, and all other family members with Clouston syndrome, had thin nails. Thus far, four mutations in GJB6 have been reported in Clouston syndrome: Gly11Arg, Val37Glu, Asp50Asn and Ala88Val. Notably, in Asia the missense mutations p.Gly11Arg and p.Arg88Val have been found in large Chinese families and also de novo. To the best of our knowledge, our case is the first Thai individual with Clouston syndrome to undergo molecular studies, although the same mutation p.Ala88Val has been reported in subjects from India, Malaysia, Wales and Japan (https://databases.lovd.nl/shared/variants/GJB6/unique). Details of specific nail abnormalities in those reports are mostly lacking, apart from the Japanese case who had shedding of several fingernails, nail shortening and thickening with distal onycholysis, although that individual also had an additional heterozygous variant, p.Val27Ile, in a different gap junction protein, connexin 26. In summary, our data reinforce p.Ala88Val as a recurrent connexin 30 mutation in Clouston syndrome while demonstrating that there can be phenotypic variability, particularly for the nails.

Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer

Abstract: Prostate is the most frequent cancer in men. Prostate cancer progression is driven by androgen steroid hormones, and delayed by androgen deprivation therapy (ADT). Androgens control transcription by stimulating androgen receptor (AR) activity, yet also control pre-mRNA splicing through less clear mechanisms. Here we find androgens regulate splicing through AR-mediated transcriptional control of the epithelial-specific splicing regulator ESRP2. Both ESRP2 and its close paralog ESRP1 are highly expressed in primary prostate cancer. Androgen stimulation induces splicing switches in many endogenous ESRP2-controlled mRNA isoforms, including a key splicing switch in the metastatic regulator FLNB which is associated with disease relapse. ESRP2 expression in clinical prostate cancer is repressed by ADT, which may thus inadvertently dampen epithelial splice programmes. Supporting this, FLNB splicing was reciprocally switched by the AR antagonist bicalutamide (Casodex®). Our data reveal a new mechanism of splicing control in prostate cancer with important implications for metastatic disease progression. Key points Transcriptional regulation of ESRP2 by the androgen receptor controls splice isoform patterns in prostate cancer cells. Splicing switches regulated by the androgen-ESRP2 axis include a splice isoform in the FLNB gene that is a known metastatic driver. Both ESRP1 and ESRP2 are highly expressed in prostate cancer tissue. Ectopic expression of ESRP1 and 2 inhibits prostate cancer cell growth. By repressing ESRP2 expression androgen deprivation therapy (ADT) may dampen epithelial splicing programmes to inadvertently prime disease progression towards metastasis.

Genetic analysis in Egyptian patients with Chediak-Higashi syndrome reveals new LYST mutations.

Abstract: N. S. Gomaa, J. Y. W. Lee, A. El Sharkawy, Y. F. El Chazli, H. M. A. Hassab, N. N. Doghaim, J. A. McGrath and A. Onoufriadis St John’s Institute of Dermatology, School of Basic and Medical Biosciences, King’s College London, London, UK; Dermatology Department, Faculty of Medicine, Tanta University, Tanta, Egypt; and Pediatric Hematology-Oncology Unit, Faculty of Medicine, Alexandria University, Alexandria, Egypt

Detailed hair shaft analysis in a man with delayed-onset Chediak-Higashi syndrome.

Abstract: Chediak-Higashi syndrome (OMIM# 214500) is listed as a 'grey hair syndrome' and is a rare hair shaft disorder, which is inherited in an autosomal recessive fashion, with mutations of the CHS1/LYST gene that regulates vesicle trafficking and size of lysosomes and other organelles. Clinical features include silvery hair, partial albinism, recurrent infections, photosensitivity, gingivitis and neurological complications. Diagnosis can be challenging and is usually made in childhood on the basis of the clinical findings, presence of giant granules in the cytoplasm of white blood cells, and of the characteristic hair shaft light microscopy and polaroscopic findings. This article is protected by copyright. All rights reserved.

PADI3, hair disorders and genomic investigation.

Abstract: Back in 1973, Dupr e et al. described a new hair shaft abnormality resulting in hair of an unusual texture and appearance. This disorder became known as uncombable hair syndrome (UHS), also known as ‘spun glass hair syndrome’, ‘pili trianguli et canaliculi’ or ‘cheveux incoiffables’. Clinically, the hair often appeared fair, dry, frizzy and resistant to being combed flat, although the phenotype typically improved later in childhood. Some cases occurred sporadically but in others there were autosomal dominant or autosomal recessive inheritance patterns. In 2016, Basmanav et al. used whole exome sequencing to identify the molecular basis of UHS. Looking for rare loss-offunction variants they identified biallelic mutations in three genes: PADI3, TGM3 and TCHH in a total of 11 children. The two enzymes peptidyl arginine deiminase 3 (PADI3) and transglutaminase 3 (TGM3) are responsible for post-translational protein modifications and, along with their target structural protein trichohyalin (TCHH), are involved in hair shaft formation. Of note, PADI3 represents a member of the peptidyl arginine deiminase family of enzymes that catalyse the post-translational deimination of proteins by converting L-arginine residues into citrulline. Supportive cell culture experiments, tri-dimensional protein models and scanning electron microscopy collectively demonstrated clear differences in the structural organization and activity of mutant and wild-type proteins and helped elucidate the molecular genetic causes of UHS and shed light on its pathophysiology and hair physiology. Regarding the process of identifying the three candidate genes in UHS, whole exome sequencing was the ideal investigative method. Whole exome sequencing is a genomic technique for sequencing the protein-coding region of genes in the genome; there are about 180 000 exons which make up ~1% of the human genome. Whole exome sequencing is therefore an efficient way to identify very rare genetic variants that are present in a small number of individuals and that underlie rare Mendelian diseases. Roll on to 2019 and PADI3 mutations have now been implicated in another hair disorder, central centrifugal cicatricial alopecia (CCCA). CCCA represents the most common cause of scarring alopecia, predominantly affecting the central scalp, in women of African descent. In terms of its aetiology, mechanical hair straightening, use of chemical relaxers and heat have all been implicated as possible causative factors in CCCA and the condition is often referred to as ‘hot comb alopecia’. Such trigger factors, however, may be absent in some cases, adding to the complexity of the aetiology of CCCA. Despite the absence of accurate population studies, the incidence of CCCA has been reported to be 2 7–5 6% with an average age of 36 years at presentation. Familial CCCA is very rare and even the reported pedigrees have been mostly limited to two generations, which could simply represent segregation of common variation in a common disease rather than strong supportive evidence for Mendelian inheritance. To investigate a possible genetic basis to CCCA, Malki et al. have used whole exome sequencing in a study of 16 African women with CCCA and identified four heterozygous alleles (one splice site, three missense) in PADI3 in five individuals. Extending the cohort, the authors reported a total of six PADI3 predicted missense and splice disrupting alleles in 14 of 58 patients (24%). Evaluation of whether this observation represents an elevation in protein disrupting alleles, however, was limited to a comparison with observations of PADI3 alleles in 58 control participants of African origin – and herein lies a challenge with the interpretation of these data. Over the past 20 years of genetics research, investigators have developed and applied a rigorous framework for the evaluation of genetic associations. This framework, including control for population stratification and rigorous multiple testing thresholds, has dramatically reduced the reporting of spurious associations in the literature. While the reported PADI3 findings in CCCA are intriguing, further experimentation is required to ensure that this association is robust and not confounded by population stratification. Aside from the genetics, the Malki et al. study also included supportive data showing reduced expression of PADI3 protein in CCCA scalp skin, along with in vitro studies of mutant PADI3 protein aggregation and decreased enzyme activity. These observations cannot be directly connected to the characteristic clinicopathological features of CCCA, including the premature desquamation of the inner root sheath, the dislocation and eventual loss of hair shafts, and perifollicular inflammation and fibrosis leading to the scarring phenotype, but the data do provide fresh insight into the pathobiology of CCCA. Indeed, despite the reservations about the genetic association methodology, the authors may well be correct in highlighting PADI3 as an important protein in CCCA. For most common diseases where there is evidence of heritability, but the majority of affected individuals lack any clear evidence for Mendelian inheritance, association studies provide a framework to identify variants with effect sizes that do not result in clear familial segregation. Such studies require the ascertainment of large numbers of cases and controls to ensure they are sufficiently powered to detect variants robustly with expected moderate effect sizes. A genome-wide association

Genetics of Scars and Keloids

Abstract: Clinical, epidemiological, and experimental data suggest that genetics plays a role in the pathogenesis of keloids. In this chapter, we review the contribution of genetics to the pathobiology of keloids, including assessment of keloid-related syndromes, genetic linkage analyses, genome-wide association studies, individual fibrosis-related genes, and ongoing insights from genomic medicine. Collectively, the evidence improves understanding of the molecular basis of keloid formation, and indicates possible new strategies for prevention, diagnosis, and treatment.