Publications by authors named "Leonard M Milstone"

55 Publications

Factor Xa: Thrombokinase from Paul Morawitz to J Haskell Milstone.

J Thromb Thrombolysis 2021 Jan 23. Epub 2021 Jan 23.

Department of Dermatology, Yale Medical School, 333 Cedar St, New Haven, CT, 06520-8059, USA.

In 1904 Paul Morawitz postulated that an enzyme, which he named thrombokinase, would be the primary activator of prothrombin. Fifty years passed before J Haskell Milstone isolated, purified and functionally characterized the enzyme we now call Factor Xa. This essay summarizes Milstone's work on thrombokinase, and finds context for why his efforts succeeded while others struggled.
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http://dx.doi.org/10.1007/s11239-021-02387-6DOI Listing
January 2021

Consensus recommendations for the use of retinoids in ichthyosis and other disorders of cornification in children and adolescents.

Pediatr Dermatol 2021 Jan 10;38(1):164-180. Epub 2020 Nov 10.

Departments of Dermatology and Pediatrics, University of California, San Francisco, San Francisco, CA, USA.

Topical and systemic retinoids have long been used in the treatment of ichthyoses and other disorders of cornification. Due to the need for long-term use of retinoids for these disorders, often beginning in childhood, numerous clinical concerns must be considered. Systemic retinoids have known side effects involving bone and eye. Additionally, potential psychiatric and cardiovascular effects need to be considered. Contraceptive concerns, as well as the additive cardiovascular and bone effects of systemic retinoid use with hormonal contraception must also be deliberated for patients of childbearing potential. The Pediatric Dermatology Research Alliance (PeDRA) Use of Retinoids in Ichthyosis Work Group was formed to address these issues and to establish best practices regarding the use of retinoids in ichthyoses based on available evidence and expert opinion.
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http://dx.doi.org/10.1111/pde.14408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984068PMC
January 2021

Alterations in connexin 26 protein structure from lethal keratitis-ichthyosis-deafness syndrome mutations A88V and G45E.

J Dermatol Sci 2019 09 10;95(3):119-122. Epub 2019 Jul 10.

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, 06520, USA; Department of Dermatology, Yale University, New Haven, CT, 06520, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jdermsci.2019.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263394PMC
September 2019

Mutations in PERP Cause Dominant and Recessive Keratoderma.

J Invest Dermatol 2019 02 12;139(2):380-390. Epub 2018 Oct 12.

Laboratory of Genetic Skin Diseases, INSERM Imagine Institute, Paris, France; University Paris Descartes, Paris, France; Department of Genetics, Necker-Enfants Malades Hospital, Paris, France. Electronic address:

Investigation of genetic determinants of Mendelian skin disorders has substantially advanced understanding of epidermal biology. Here we show that mutations in PERP, encoding a crucial component of desmosomes, cause both dominant and recessive human keratoderma. Heterozygosity for a C-terminal truncation, which produces a protein that appears to be unstably incorporated into desmosomes, causes Olmsted syndrome with severe periorificial and palmoplantar keratoderma in multiple unrelated kindreds. Homozygosity for an N-terminal truncation ablates expression and causes widespread erythrokeratoderma, with expansion of epidermal differentiation markers. Both exhibit epidermal hyperproliferation, immature desmosomes lacking a dense midline observed via electron microscopy, and impaired intercellular adhesion upon mechanical stress. Localization of other desmosomal components appears normal, which is in contrast to other conditions caused by mutations in genes encoding desmosomal proteins. These discoveries highlight the essential role of PERP in human desmosomes and epidermal homeostasis and further expand the heterogeneous spectrum of inherited keratinization disorders.
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http://dx.doi.org/10.1016/j.jid.2018.08.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586468PMC
February 2019

More than keratitis, ichthyosis, and deafness: Multisystem effects of lethal GJB2 mutations.

J Am Acad Dermatol 2019 Mar 2;80(3):617-625. Epub 2018 Oct 2.

Department of Dermatology, Yale School of Medicine, New Haven, Connecticut.

Background: Infant death in keratitis-ichthyosis-deafness (KID) syndrome is recognized; its association with specific genotypes and pathophysiology is inadequately understood.

Objective: We sought to discover characteristics that account for poor outcomes in lethal KID syndrome.

Methods: We collected 4 new cases and 9 previously reported, genotyped cases of lethal KID syndrome. We performed new molecular modeling of the lethal mutants GJB2 p.A88V and GJB2 p.G45E.

Results: Infant death occurred in all patients with GJB2 p.G45E and p.A88V; it is unusual with other GJB2 mutations. Early death with those 2 "lethal" mutations is likely multifactorial: during life all had ≥1 serious infection; most had poor weight gain and severe respiratory difficulties; many had additional anatomic abnormalities. Structural modeling of GJB2 p.G45E identified no impact on the salt bridge previously predicted to account for abnormal central carbon dioxide sensing of GJB2 p.A88V.

Limitations: This clinical review was retrospective.

Conclusion: GJB2 p.G45E and p.A88V are the only KID syndrome mutations associated with uniform early lethality. Those electrophysiologically severe mutations in GJB2 reveal abnormalities in many organs in lethal KID syndrome. All patients with KID syndrome may have subtle abnormalities beyond the eyes, ears, and skin. Early genotyping of KID syndrome births will inform prognostic discussion.
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http://dx.doi.org/10.1016/j.jaad.2018.09.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372339PMC
March 2019

CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris.

J Am Acad Dermatol 2018 Sep 1;79(3):487-494. Epub 2018 Mar 1.

Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut; Department of Genetics, Yale University School of Medicine, New Haven, Connecticut; Department of Pathology, Yale University School of Medicine, New Haven, Connecticut. Electronic address:

Background: Heterozygous mutations in caspase recruitment domain family member 14 gene (CARD14) have been shown to be associated with psoriasis and familial pityriasis rubra pilaris (PRP). Many subjects with CARD14 mutations display features of both disorders, which can result in diagnostic uncertainty. In addition, these eruptions are often recalcitrant to conventional psoriasis therapies such as methotrexate, oral retinoids, and tumor necrosis factor-α inhibitors.

Objective: We sought to describe the clinical characteristics, family history, and response to therapy in subjects with papulosquamous eruptions due to mutations in CARD14.

Methods: Subjects were referred for genetic testing as part of a registry of subjects with inherited disorders of keratinization. DNA was isolated from blood or saliva, and multiplex targeted sequencing or whole exome sequencing was performed. Clinical histories of subjects with CARD14 mutations were reviewed.

Results: We identified 15 kindreds with CARD14-associated papulosquamous eruption (CAPE). Characteristic features of CAPE include early age of onset; prominent involvement of the cheeks, chin, and ears; family history of psoriasis or PRP; minimal response to conventional topical and systemic psoriasis therapies; and improvement with ustekinumab.

Limitations: Relatively small sample size.

Conclusions: Many subjects with CARD14 mutations display characteristics of both psoriasis and PRP. We propose the term CARD14-associated papulosquamous eruption to describe this spectrum of disease. Subjects with clinical features suggestive of CAPE should undergo CARD14 sequencing and may benefit from treatment with ustekinumab.
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http://dx.doi.org/10.1016/j.jaad.2018.02.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098739PMC
September 2018

Establishing and Validating an Ichthyosis Severity Index.

J Invest Dermatol 2017 09 6;137(9):1834-1841. Epub 2017 Jun 6.

Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA. Electronic address:

We designed and validated a Visual Index for Ichthyosis Severity for scale and erythema that provides (1) written descriptions of the features characteristic of each level of severity, (2) visual standards for four body sites, and (3) two distinct standards to account for different types of scale. We tested the Visual Index for Ichthyosis Severity for reliability and reproducibility using two different settings: one that utilized scoring of 60 test photographs by 10 dermatologists, and one with in-person evaluations on 85 subjects by 12 dermatologists at the Foundation for Ichthyosis and Related Skin Types conference. The validation process revealed high reliability and reproducibility for both scale and erythema. The interrater and intrarater intraclass correlation coefficients for scale were consistently near or greater than 0.7 in both settings. By contrast, the interrater reliability for erythema was higher during in-person validation compared with validation on test photographs. Our analysis indicates that the Visual Index for Ichthyosis Severity performs better in person than with photographs, an important consideration in the design of clinical trials. Power analysis predicts that a 1-point difference on this 5-step scale would be detectable with 12 subjects in each of two defined groups. This index provides a tool for clinical phenotyping and assessment of therapeutic response for many disorders of keratinization.
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http://dx.doi.org/10.1016/j.jid.2017.04.037DOI Listing
September 2017

Nail removal in pachyonychia congenita: Patient-reported survey outcomes.

J Am Acad Dermatol 2017 05;76(5):990-992

Yale Medical School, New Haven, Connecticut.

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http://dx.doi.org/10.1016/j.jaad.2016.08.060DOI Listing
May 2017

Expanding the Genotypic Spectrum of Bathing Suit Ichthyosis.

JAMA Dermatol 2017 06;153(6):537-543

Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut10Department of Genetics, Yale University School of Medicine, New Haven, Connecticut11Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.

Importance: Bathing suit ichthyosis (BSI) is a rare congenital disorder of keratinization characterized by restriction of scale to sites of relatively higher temperature such as the trunk, with cooler areas remaining unaffected. Fewer than 40 cases have been reported in the literature. Bathing suit ichthyosis is caused by recessive, temperature-sensitive mutations in the transglutaminase-1 gene (TGM1). Clear genotype-phenotype correlations have been difficult to establish because several of the same TGM1 mutations have been reported in BSI and other forms of congenital ichthyosis. We identify novel and recurrent mutations in 16 participants with BSI.

Objective: To expand the genotypic spectrum of BSI, identifying novel TGM1 mutations in patients with BSI, and to use BSI genotypes to draw inferences about the temperature sensitivity of TGM1 mutations.

Design, Setting, And Participants: A total of 16 participants with BSI from 13 kindreds were identified from 6 academic medical centers. A detailed clinical history was obtained from each participant, including phenotypic presentation at birth and disease course. Each participant underwent targeted sequencing of TGM1.

Main Outcomes And Measures: Phenotypic and genotypic characteristics in these patients from birth onward.

Results: Of the 16 participants, 7 were male, and 9 were female (mean age, 12.6 years; range, 1-39 years). We found 1 novel TGM1 indel mutation (Ile469_Cys471delinsMetLeu) and 8 TGM1 missense mutations that to our knowledge have not been previously reported in BSI: 5 have been previously described in non-temperature-sensitive forms of congenital ichthyosis (Arg143Cys, Gly218Ser, Gly278Arg, Arg286Gln, and Ser358Arg), and 3 (Tyr374Cys, Phe495Leu, and Ser772Arg) are novel mutations. Three probands were homozygous for Arg264Trp, Arg286Gln, or Arg315Leu, indicating that these mutations are temperature sensitive. Seven of 10 probands with a compound heterozygous TGM1 genotype had a mutation at either arginine 307 or 315, providing evidence that mutations at these sites are temperature sensitive and highlighting the importance of these residues in the pathogenesis of BSI.

Conclusions And Relevance: Our findings expand the genotypic spectrum of BSI and the understanding of temperature sensitivity of TGM1 mutations. Increased awareness of temperature-sensitive TGM1 genotypes should aid in genetic counseling and provide insights into the pathophysiology of TGM1 ichthyoses, transglutaminase-1 enzymatic activity, and potential therapeutic approaches.
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http://dx.doi.org/10.1001/jamadermatol.2017.0202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817618PMC
June 2017

Palmoplantar Keratoderma in Costello Syndrome Responsive to Acitretin.

Pediatr Dermatol 2017 Mar 23;34(2):160-162. Epub 2016 Dec 23.

Department of Dermatology, School of Medicine, Yale University, New Haven, Connecticut.

Costello syndrome (CS) is a multisystem congenital disorder characterized by coarse facial features, cardiac defects, intellectual disability, and predisposition to malignancies. Dermatologic findings can include cutaneous papillomas, skin redundancy, acanthosis nigricans, and keratosis pilaris. Palmoplantar keratoderma (PPK) is present in approximately 76% of patients with CS, with disabling functional consequences in severe cases. We report a case of CS with severe PPK that improved dramatically with systemic administration of acitretin 0.3 mg/kg/day.
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http://dx.doi.org/10.1111/pde.13057DOI Listing
March 2017

The X-Ray Crystal Structure of the Keratin 1-Keratin 10 Helix 2B Heterodimer Reveals Molecular Surface Properties and Biochemical Insights into Human Skin Disease.

J Invest Dermatol 2017 01 3;137(1):142-150. Epub 2016 Sep 3.

Department of Dermatology, Yale University, New Haven, Connecticut, USA.

Keratins 1 (K1) and 10 (K10) are the primary keratins expressed in differentiated epidermis. Mutations in K1/K10 are associated with human skin diseases. We determined the crystal structure of the complex between the distal (2B) helices of K1 and K10 to better understand how human keratin structure correlates with function. The 3.3 Å resolution structure confirms many features inferred by previous biochemical analyses, but adds unexpected insights. It demonstrates a parallel, coiled-coil heterodimer with a predominantly hydrophobic intermolecular interface; this heterodimer formed a higher order complex with a second K1-K10-2B heterodimer via a Cys401 disulfide link, although the bond angle is unanticipated. The molecular surface analysis of K1-K10-2B identified several pockets, one adjacent to the disulfide linkage and conserved in K5-K14. The solvent accessible surface area of the K1-K10 structure is 20-25% hydrophobic. The 2B region contains mixed acidic and basic patches proximally (N-terminal), whereas it is largely acidic distally (C-terminal). Mapping of conserved and nonconserved residues between K1-K10 and K5-K14 onto the structure demonstrated the majority of unique residues align along the outer helical ridge. Finally, the structure permitted a fresh analysis of the deleterious effects caused by K1/K10 missense mutations found in patients with phenotypic skin disease.
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http://dx.doi.org/10.1016/j.jid.2016.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514376PMC
January 2017

Recurrent Coxsackievirus Infection in a Patient with Lamellar Ichthyosis.

Pediatr Dermatol 2016 Mar-Apr;33(2):e140-2. Epub 2016 Jan 29.

Department of Dermatology, School of Medicine, Yale University, New Haven, Connecticut.

We describe a case of coxsackievirus (CV) A6 infection in a patient with lamellar ichthyosis followed by subsequent CV A8 infection within the same year. Atypical cutaneous features characterized the infection. This observation, combined with the rapidity with which reinfection occurred, suggests that the natural history of CV infection may be altered in patients with underlying ichthyoses.
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http://dx.doi.org/10.1111/pde.12769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226923PMC
January 2017

Well-Differentiated Syringofibrocarcinoma in a Patient With Clouston Syndrome.

JAMA Dermatol 2016 Apr;152(4):484-6

Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut.

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http://dx.doi.org/10.1001/jamadermatol.2015.4496DOI Listing
April 2016

Connexin channels in congenital skin disorders.

Semin Cell Dev Biol 2016 Feb 13;50:4-12. Epub 2016 Jan 13.

Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794, USA. Electronic address:

Gap junctions and hemichannels comprised of connexins influence epidermal proliferation and differentiation. Significant advances in our understanding of the functional role of connexins in the skin have been made by studying the diseases caused by connexin mutations. Eleven clinically defined cutaneous disorders with an overlapping spectrum of phenotypes are caused by mutations in five different connexin genes, highlighting that disease presentation must be deciphered with an understanding of how connexin functions are affected. Increasing evidence suggests that the skin diseases produced by connexin mutations result from dominant gains of function. In palmoplantar keratoderma with deafness, the connexin 26 mutations transdominantly alter the function of wild-type connexin 43 and create leaky heteromeric hemichannels. In keratitis-ichthyosis-deafness syndrome, different connexin 26 mutations can either form dominant hemichannels with altered calcium regulation or increased calcium permeability, leading to clinical subtypes of this syndrome. It is only with detailed understanding of these subtle functional differences that we can hope to create successful pathophysiology driven therapies for the connexin skin disorders.
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http://dx.doi.org/10.1016/j.semcdb.2015.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779425PMC
February 2016

The Protein Acyl Transferase ZDHHC21 Modulates α1 Adrenergic Receptor Function and Regulates Hemodynamics.

Arterioscler Thromb Vasc Biol 2016 Feb 29;36(2):370-9. Epub 2015 Dec 29.

From the Section of Nephrology (E.P.M., L.J., J.M., H.V.) and Department of Dermatology (L.M.M.), Yale School of Medicine, New Haven, CT; and Vascular Biology and Therapeutics Program, Department of Pharmacology, Yale University School of Medicine, New Haven, CT (A.D.L., K.F.H., A.K.L., W.C.S.).

Objective: Palmitoylation, the reversible addition of the lipid palmitate to a cysteine, can alter protein localization, stability, and function. The ZDHHC family of protein acyl transferases catalyzes palmitoylation of numerous proteins. The role of ZDHHC enzymes in intact tissue and in vivo is largely unknown. Herein, we characterize vascular functions in a mouse that expresses a nonfunctional ZDHHC21 (F233Δ).

Approach And Results: Physiological studies of isolated aortae and mesenteric arteries from F233Δ mice revealed an unexpected defect in responsiveness to phenylephrine, an α1 adrenergic receptor agonist. In vivo, F233Δ mice displayed a blunted response to infusion of phenylephrine, and they were found to have elevated catecholamine levels and elevated vascular α1 adrenergic receptor gene expression. Telemetry studies showed that the F233Δ mice were tachycardic and hypotensive at baseline, consistent with diminished vascular tone. In biochemical studies, ZDHHC21 was shown to palmitoylate the α1D adrenoceptor and to interact with it in a molecular complex, thus suggesting a possible molecular mechanism by which the receptor can be regulated by ZDHHC21.

Conclusions: Together, the data support a model in which ZDHHC21 F233Δ diminishes the function of vascular α1 adrenergic receptors, leading to reduced vascular tone, which manifests in vivo as hypotension and tachycardia. This is to our knowledge the first demonstration of a ZDHHC isoform affecting vascular function in vivo and identifies a novel molecular mode of regulation of vascular tone and blood pressure.
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http://dx.doi.org/10.1161/ATVBAHA.115.306942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4984414PMC
February 2016

Imaging Functional Nucleic Acid Delivery to Skin.

Methods Mol Biol 2016 ;1372:1-24

Molecular Imaging Program at Stanford (MIPS), E150 Clark Center, Stanford University School of Medicine, 318 Campus Drive, Stanford, CA, 94305, USA.

Monogenic skin diseases arise from well-defined single gene mutations, and in some cases a single point mutation. As the target cells are superficial, these diseases are ideally suited for treatment by nucleic acid-based therapies as well as monitoring through a variety of noninvasive imaging technologies. Despite the accessibility of the skin, there remain formidable barriers for functional delivery of nucleic acids to the target cells within the dermis and epidermis. These barriers include the stratum corneum and the layered structure of the skin, as well as more locally, the cellular, endosomal and nuclear membranes. A wide range of technologies for traversing these barriers has been described and moderate success has been reported for several approaches. The lessons learned from these studies include the need for combinations of approaches to facilitate nucleic acid delivery across these skin barriers and then functional delivery across the cellular and nuclear membranes for expression (e.g., reporter genes, DNA oligonucleotides or shRNA) or into the cytoplasm for regulation (e.g., siRNA, miRNA, antisense oligos). The tools for topical delivery that have been evaluated include chemical, physical and electrical methods, and the development and testing of each of these approaches has been greatly enabled by imaging tools. These techniques allow delivery and real time monitoring of reporter genes, therapeutic nucleic acids and also triplex nucleic acids for gene editing. Optical imaging is comprised of a number of modalities based on properties of light-tissue interaction (e.g., scattering, autofluorescence, and reflectance), the interaction of light with specific molecules (e.g., absorbtion, fluorescence), or enzymatic reactions that produce light (bioluminescence). Optical imaging technologies operate over a range of scales from macroscopic to microscopic and if necessary, nanoscopic, and thus can be used to assess nucleic acid delivery to organs, regions, cells and even subcellular structures. Here we describe the animal models, reporter genes, imaging approaches and general strategies for delivery of nucleic acids to cells in the skin for local expression (e.g., plasmid DNA) or gene silencing (e.g., siRNA) with the intent of developing nucleic acid-based therapies to treat diseases of the skin.
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http://dx.doi.org/10.1007/978-1-4939-3148-4_1DOI Listing
August 2016

Expanding the Phenotypic Spectrum of Olmsted Syndrome.

J Invest Dermatol 2015 Nov 12;135(11):2879-2883. Epub 2015 Jun 12.

Centre for Dermatology and Genetic Medicine, College of Life Sciences and College of Medicine, Dentistry and Nursing, University of Dundee, Dundee, UK. Electronic address:

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http://dx.doi.org/10.1038/jid.2015.217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4652067PMC
November 2015

Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti.

J Clin Invest 2015 Apr 16;125(4):1703-7. Epub 2015 Mar 16.

Widespread reversion of genetic disease is rare; however, such events are particularly evident in some skin disorders in which normal clones develop on a background of affected skin. We previously demonstrated that mutations in keratin 10 (KRT10) cause ichthyosis with confetti (IWC), a severe dominant disorder that is characterized by progressive development of hundreds of normal skin spots via revertant mosaicism. Here, we report on a clinical and histological IWC subtype in which affected subjects have red, scaly skin at birth, experience worsening palmoplantar keratoderma in childhood, and develop hundreds of normal skin spots, beginning at around 20 years of age, that increase in size and number over time. We identified a causal de novo mutation in keratin 1 (KRT1). Similar to IWC-causing KRT10 mutations, this mutation in KRT1 resulted in a C-terminal frameshift, replacing 22 C-terminal amino acids with an alternate 30-residue peptide. Mutant KRT1 caused partial collapse of the cytoplasmic intermediate filament network and mislocalized to the nucleus. As with KRT10 mutations causing IWC, reversion of KRT1 mutations occurred via mitotic recombination. Because reversion is not observed with other disease-causing keratin mutations, the results of this study implicate KRT1 and KRT10 C-terminal frameshift mutations in the high frequency of revertant mosaicism in IWC.
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http://dx.doi.org/10.1172/JCI64415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396494PMC
April 2015

Crystal Structure of Human Profilaggrin S100 Domain and Identification of Target Proteins Annexin II, Stratifin, and HSP27.

J Invest Dermatol 2015 Jul 11;135(7):1801-1809. Epub 2015 Mar 11.

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA.

The fused-type S100 protein profilaggrin and its proteolytic products including filaggrin are important in the formation of a normal epidermal barrier; however, the specific function of the S100 calcium-binding domain in profilaggrin biology is poorly understood. To explore its molecular function, we determined a 2.2 Å-resolution crystal structure of the N-terminal fused-type S100 domain of human profilaggrin with bound calcium ions. The profilaggrin S100 domain formed a stable dimer, which contained two hydrophobic pockets that provide a molecular interface for protein interactions. Biochemical and molecular approaches demonstrated that three proteins, annexin II/p36, stratifin/14-3-3 sigma, and heat shock protein 27, bind to the N-terminal domain of human profilaggrin; one protein (stratifin) co-localized with profilaggrin in the differentiating granular cell layer of human skin. Together, these findings suggest a model where the profilaggrin N-terminus uses calcium-dependent and calcium-independent protein-protein interactions to regulate its involvement in keratinocyte terminal differentiation and incorporation into the cornified cell envelope.
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http://dx.doi.org/10.1038/jid.2015.102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466033PMC
July 2015

Gene expression profiling in pachyonychia congenita skin.

J Dermatol Sci 2015 Mar 14;77(3):156-65. Epub 2015 Jan 14.

TransDerm Inc., Santa Cruz, CA 95060, USA. Electronic address:

Background: Pachyonychia congenita (PC) is a skin disorder resulting from mutations in keratin (K) proteins including K6a, K6b, K16, and K17. One of the major symptoms is painful plantar keratoderma. The pathogenic sequelae resulting from the keratin mutations remain unclear.

Objective: To better understand PC pathogenesis.

Methods: RNA profiling was performed on biopsies taken from PC-involved and uninvolved plantar skin of seven genotyped PC patients (two K6a, one K6b, three K16, and one K17) as well as from control volunteers. Protein profiling was generated from tape-stripping samples.

Results: A comparison of PC-involved skin biopsies to adjacent uninvolved plantar skin identified 112 differentially-expressed mRNAs common to patient groups harboring K6 (i.e., both K6a and K6b) and K16 mutations. Among these mRNAs, 25 encode structural proteins including keratins, small proline-rich and late cornified envelope proteins, 20 are related to metabolism and 16 encode proteases, peptidases, and their inhibitors including kallikrein-related peptidases (KLKs), and serine protease inhibitors (SERPINs). mRNAs were also identified to be differentially expressed only in K6 (81) or K16 (141) patient samples. Furthermore, 13 mRNAs were identified that may be involved in pain including nociception and neuropathy. Protein profiling, comparing three K6a plantar tape-stripping samples to non-PC controls, showed changes in the PC corneocytes similar, but not identical, to the mRNA analysis.

Conclusion: Many differentially-expressed genes identified in PC-involved skin encode components critical for skin barrier homeostasis including keratinocyte proliferation, differentiation, cornification, and desquamation. The profiling data provide a foundation for unraveling the pathogenesis of PC and identifying targets for developing effective PC therapeutics.
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http://dx.doi.org/10.1016/j.jdermsci.2015.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374015PMC
March 2015

Phenotypic expansion in ichthyosis with confetti.

JAMA Dermatol 2015 Jan;151(1):15-6

Department of Dermatology, Yale School of Medicine, New Haven, Connecticut.

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http://dx.doi.org/10.1001/jamadermatol.2014.2525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319358PMC
January 2015

Harlequin ichthyosis: neonatal management and identification of a new ABCA12 mutation.

Pediatr Dermatol 2014 Mar-Apr;31(2):e63-4. Epub 2013 Nov 26.

Department of Dermatology, School of Medicine, Yale University, New Haven, Connecticut.

A case of harlequin ichthyosis with compound heterozygous mutations in ABCA12 was successfully managed with intensive neonatal care and endotracheal intubation and without oral retinoids. The individual's appearance improved dramatically during hospitalization and at discharge resembled congenital ichthyosiform erythroderma.
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http://dx.doi.org/10.1111/pde.12263DOI Listing
January 2015

Mutations in TGM1 in Ecuadorians with autosomal recessive congenital ichthyosis.

Int J Dermatol 2014 Apr 21;53(4):e312-3. Epub 2013 Nov 21.

National Secretary of Sience and Technology (SENESCYT) National Institute for Research in Public Health (INSPI), Guayaquil, Guayas, Ecuador.

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http://dx.doi.org/10.1111/ijd.12227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861992PMC
April 2014

Improving outcomes for harlequin ichthyosis.

J Am Acad Dermatol 2013 Nov;69(5):808-809

Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut.

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http://dx.doi.org/10.1016/j.jaad.2013.06.017DOI Listing
November 2013

Topical tazarotene for the treatment of ectropion in ichthyosis.

JAMA Dermatol 2013 May;149(5):598-600

Department of Dermatology, Yale University School of Medicine, PO Box 208059, New Haven, CT 06520, USA.

Importance: Ectropion is a complication of certain subtypes of ichthyosis and is often associated with substantial medical and cosmetic consequences. At present there is no standard of care for the treatment of ectropion in this population. Retinoids cause dyshesion and thinning of stratum corneum, thereby reducing hyperkeratosis that likely underlies ectropion in patients with ichthyosis. As such, retinoids provide a potential effective treatment for ectropion in this group of patients.

Observation: We describe a patient with recessive ichthyosis for whom daily application of topical tazarotene produced rapid and persistent improvement of bilateral lower eyelid ectropion without adverse effects.

Conclusions And Relevance: Additional studies will be necessary to more fully and systematically address the safety and efficacy of topical retinoids for the treatment of ectropion in patients with ichthyosis; however, this case illustrates that topical tazarotene and other retinoids provide a potential treatment option for ectropion in this population. We encourage clinicians to explore medical therapies as alternatives to surgical intervention for the treatment of ectropion in patients with ichthyosis.
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http://dx.doi.org/10.1001/jamadermatol.2013.239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3809825PMC
May 2013

Systemic retinoids in the management of ichthyoses and related skin types.

Dermatol Ther 2013 Jan-Feb;26(1):26-38

DNA Repair Section, Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

The term retinoid includes both natural and synthetic derivatives of vitamin A. Retinoid-containing treatments have been used since ~1550BC by the early Egyptians. Treatment of ichthyosiform disorders with retinoids dates back at least to the 1930s. Early use of high-dose vitamin A demonstrated efficacy, but because vitamin A is stored in the liver, toxicity limited usefulness. Interest turned to synthetic retinoids in an effort to enhance efficacy and limit toxicity. Acetretin, isotretinoin and, in the past etretinate, have provided the most effective therapy for ichthyosiform conditions. They have been used for a variety of ages, including in newborns with severe ichthyosis and for decades in some patients. Careful surveillance and management of mucous membrane, laboratory, skeletal, and teratogenic side effects has made systemic retinoids the mainstay of therapy for ichthyosis and related skin types.
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http://dx.doi.org/10.1111/j.1529-8019.2012.01527.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3884695PMC
August 2013

Local delivery of gene-modifying triplex-forming molecules to the epidermis.

J Invest Dermatol 2013 Mar 27;133(3):685-691. Epub 2012 Sep 27.

Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA. Electronic address:

Epidermal keratinocytes are particularly suitable candidates for in situ gene correction. Intraperitoneal administration of a triplex-forming oligonucleotide (TFO) was previously shown to introduce DNA base changes in a reporter gene in skin, without identifying which cells had been targeted. We extend those previous experiments using two triplex-forming molecules, a peptide nucleic acid-antennapedia (PNA-Antp), and a TFO (AG30), as well as two lines of transgenic mice that have the chromosomally integrated λsupFG1 shuttle-reporter transgene. Successful in vivo genomic modification occurs in the epidermis and dermis in CD1 transgenic mice following either intraperitoneal or intradermal delivery of the PNA-Antp conjugate. FITC-PNA-Antp accumulates in nuclei of keratinocytes, and, after intradermal delivery of the PNA-Antp, chromosomally modified, keratin 5-positive basal keratinocytes persist for at least 10 days. In hairless (SKH1) mice with the λsupFG1 transgene, intradermal delivery of the TFO, AG30, introduces gene modifications in both tail and back skin, and these chromosomal modifications persist in basal keratinocytes for 10 days. Hairless mice should facilitate comparison of various targeting agents and methods of delivery. Gene targeting by repeated local administration of oligonucleotides may prove clinically useful for judiciously selected disease-causing genes in the epidermis.
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http://dx.doi.org/10.1038/jid.2012.351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532560PMC
March 2013

Impact of epidermal desquamation on tissue stores of iron.

J Dermatol Sci 2012 Jul 13;67(1):9-14. Epub 2012 Apr 13.

Department of Dermatology, Yale University School of Medicine, New Haven, CT 06510, USA.

Background: Although several billion corneocytes are shed from human skin daily, metabolic studies from 50 years ago led to the conclusion that corneocyte desquamation had no measurable impact on systemic protein or iron status in humans.

Objective: To measure iron content of internal organs after introducing local genetic changes in epidermis that alter iron metabolism in skin.

Methods: Iron was measured in tissues and blood from groups of animals 7 weeks after weaning in three different mouse models expressing a transgene in epidermis: a hyperproliferation model in which the HPV16 E7 gene causes a 3-fold increase in epidermal turnover; an epidermal iron sink model in which overexpression of the transferrin receptor causes a 3-4 fold increase of iron in epidermis; a systemic hemochromatosis knockout model that has been crossed with the epidermal iron sink model.

Results: In the hemochromatosis model with the iron sink transgene in epidermis, there was a statistically significant reduction in non-heme iron in serum and in the liver and kidney. In all models there was a statistically significant reduction in non-heme iron in the kidney.

Conclusion: Local changes in iron metabolism in epidermis can have a measurable impact on systemic iron metabolism. By implication, disruptions in epidermal homeostasis might affect systemic levels of trace nutrients, and circulating toxins might be remediated by sequestering them in epidermis.
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http://dx.doi.org/10.1016/j.jdermsci.2012.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3374011PMC
July 2012