Abraham Zlotogorski

Mutant Adenosine Deaminase 2 in a Polyarteritis Nodosa Vasculopathy

BACKGROUND Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood. METHODS We carried out exome sequencing in persons from multiply affected families of Georgian Jewish or German ancestry. We performed targeted sequencing in additional family members and in unrelated affected persons, 3 of Georgian Jewish ancestry and 14 of Turkish ancestry. Mutations were assessed by testing their effect on enzymatic activity in serum specimens from patients, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein. RESULTS In all the families, vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2). All the Georgian Jewish patients were homozygous for a mutation encoding a Gly47Arg substitution, the German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations, and one Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations. In the endogamous Georgian Jewish population, the Gly47Arg carrier frequency was 0.102, which is consistent with the high prevalence of disease. The other mutations either were found in only one family member or patient or were extremely rare. ADA2 activity was significantly reduced in serum specimens from patients. Expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein. CONCLUSIONS Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression. (Funded by the Shaare Zedek Medical Center and others.).

Genomewide Scan for Linkage Reveals Evidence of Several Susceptibility Loci for Alopecia Areata

Alopecia areata (AA) is a genetically determined, immune-mediated disorder of the hair follicle that affects 1%-2% of the U.S. population. It is defined by a spectrum of severity that ranges from patchy localized hair loss on the scalp to the complete absence of hair everywhere on the body. In an effort to define the genetic basis of AA, we performed a genomewide search for linkage in 20 families with AA consisting of 102 affected and 118 unaffected individuals from the United States and Israel. Our analysis revealed evidence of at least four susceptibility loci on chromosomes 6, 10, 16 and 18, by use of several different statistical approaches. Fine-mapping analysis with additional families yielded a maximum multipoint LOD score of 3.93 on chromosome 18, a two-point affected sib pair (ASP) LOD score of 3.11 on chromosome 16, several ASP LOD scores >2.00 on chromosome 6q, and a haplotype-based relative risk LOD of 2.00 on chromosome 6p (in the major histocompatibility complex locus). Our findings confirm previous studies of association of the human leukocyte antigen locus with human AA, as well as the C3H-HeJ mouse model for AA. Interestingly, the major loci on chromosomes 16 and 18 coincide with loci for psoriasis reported elsewhere. These results suggest that these regions may harbor gene(s) involved in a number of different skin and hair disorders.

The H Syndrome Is Caused by Mutations in the Nucleoside Transporter hENT3

The H syndrome is a recently reported autosomal-recessive disorder characterized by cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, short stature, hallux valgus, and fixed flexion contractures of the toe joints and the proximal interphalangeal joints. Homozygosity mapping in five consanguineous families resulted in the identification of mutations in the SLC29A3 gene, which encodes the equilibrative nucleoside transporter hENT3. Three mutations were found in 11 families of Arab and Bulgarian origin. The finding of several different mutations in a small geographic region implies that the H syndrome might be rather common. The identification of mutations in the SLC29A3 gene in patients with a mild clinical phenotype suggests that this is a largely underdiagnosed condition and strongly suggests that even oligosymptomatic individuals might have the disorder.

Reversal of Alopecia Areata Following Treatment With the JAK1/2 Inhibitor Baricitinib.

Background Alopecia areata (AA) is an autoimmune disease resulting in hair loss with devastating psychosocial consequences. Despite its high prevalence, there are no FDA-approved treatments for AA. Prior studies have identified a prominent interferon signature in AA, which signals through JAK molecules. Methods A patient with AA was enrolled in a clinical trial to examine the efficacy of baricitinib, a JAK1/2 inhibitor, to treat concomitant CANDLE syndrome. In vivo, preclinical studies were conducted using the C3H/HeJ AA mouse model to assess the mechanism of clinical improvement by baricitinib. Findings The patient exhibited a striking improvement of his AA on baricitinib over several months. In vivo studies using the C3H/HeJ mouse model demonstrated a strong correlation between resolution of the interferon signature and clinical improvement during baricitinib treatment. Interpretation Baricitinib may be an effective treatment for AA and warrants further investigation in clinical trials.

Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production

Autosomal recessive mutations in proteasome subunit β 8 (PSMB8), which encodes the inducible proteasome subunit β5i, cause the immune-dysregulatory disease chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), which is classified as a proteasome-associated autoinflammatory syndrome (PRAAS). Here, we identified 8 mutations in 4 proteasome genes, PSMA3 (encodes α7), PSMB4 (encodes β7), PSMB9 (encodes β1i), and proteasome maturation protein (POMP), that have not been previously associated with disease and 1 mutation in PSMB8 that has not been previously reported. One patient was compound heterozygous for PSMB4 mutations, 6 patients from 4 families were heterozygous for a missense mutation in 1 inducible proteasome subunit and a mutation in a constitutive proteasome subunit, and 1 patient was heterozygous for a POMP mutation, thus establishing a digenic and autosomal dominant inheritance pattern of PRAAS. Function evaluation revealed that these mutations variably affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity. Moreover, defects in proteasome formation and function were recapitulated by siRNA-mediated knockdown of the respective subunits in primary fibroblasts from healthy individuals. Patient-isolated hematopoietic and nonhematopoietic cells exhibited a strong IFN gene-expression signature, irrespective of genotype. Additionally, chemical proteasome inhibition or progressive depletion of proteasome subunit gene transcription with siRNA induced transcription of type I IFN genes in healthy control cells. Our results provide further insight into CANDLE genetics and link global proteasome dysfunction to increased type I IFN production.

Congenital atrichia in five Arab Palestinian families resulting from a deletion mutation in the human hairless gene

Abstract Congenital atrichia is a rare autosomal recessive disorder of hair development, characterized by complete loss of hair shortly after birth. Evidence of linkage to chromosome 8p12 has been established, implicating the human homolog of the mouse hairless (hr) gene as a candidate gene. We have previously identified missense mutations in families with congenital atrichia. Here, we report the first deletion mutation (2147del C) in exon 9 of the human hairless gene leading to a frameshift and downstream premature termination codon in five Palestinian families of Arab origin.

What causes alopecia areata

The pathobiology of alopecia areata (AA), one of the most frequent autoimmune diseases and a major unsolved clinical problem, has intrigued dermatologists, hair biologists and immunologists for decades. Simultaneously, both affected patients and the physicians who take care of them are increasingly frustrated that there is still no fully satisfactory treatment. Much of this frustration results from the fact that the pathobiology of AA remains unclear, and no single AA pathogenesis concept can claim to be universally accepted. In fact, some investigators still harbour doubts whether this even is an autoimmune disease, and the relative importance of CD8+ T cells, CD4+ T cells and NKGD2+ NK or NKT cells and the exact role of genetic factors in AA pathogenesis remain bones of contention. Also, is AA one disease, a spectrum of distinct disease entities or only a response pattern of normal hair follicles to immunologically mediated damage? During the past decade, substantial progress has been made in basic AA‐related research, in the development of new models for translationally relevant AA research and in the identification of new therapeutic agents and targets for future AA management. This calls for a re‐evaluation and public debate of currently prevalent AA pathobiology concepts. The present Controversies feature takes on this challenge, hoping to attract more skin biologists, immunologists and professional autoimmunity experts to this biologically fascinating and clinically important model disease.

Endocrine controls of keratin expression

Keratins are a family of intermediate filaments that serve various crucial roles in skin physiology. For mammalian skin to function properly, and to produce epidermal and hair keratins that are optimally adapted for their environment, it is critical that keratin gene and protein expression are stringently controlled. Given that the skin is not only targeted by multiple hormones, but also constitutes a veritable peripheral endocrine organ, it is not surprizing that intracutaneous keratin expression is underlined by tight endocrine controls. These controls encompass thyroid hormones, steroid hormones such as glucocorticoids (GCs), retinoic acid (RA) and vitamin D, and several neuroendocrine mediators. Here, we review why a better understanding of the endocrine controls of keratin expression is not only required for an improved insight into normal human skin and hair function, but may also open new therapeutic avenues in a wide range of skin and hair diseases.

A nonsense mutation in the desmoglein 1 gene underlies striate keratoderma

Abstract:  Striate keratodermas (PPKS) (OMIM 148700) are a rare group of autosomal dominant genodermatoses characterized by palmoplantar keratoderma typified by streaking hyperkeratosis along each finger and extending onto the palm of the hand. We report a four‐generation kindred originating from Iran‐Syria in which three members were affected with PPKS. Clinically, these patients present with hyperkeratotic palms and plantar plaques. Direct DNA sequencing analysis revealed a heterozygous C‐to‐A transversion at nt 395 of the DSG1 gene. This mutation converted a serine residue (TCA) in exon 5 to a nonsense mutation (TAA) designated S132X. The mutation identified in this study is a novel mutation in the DSG1 gene and extends the body of evidence implicating the desmoglein gene family in the pathogenesis of human skin disorders.

Identification of a locus for type I punctate palmoplantar keratoderma on chromosome 15q22–q24

Background: The identification of the molecular basis of disorders of keratinisation has significantly advanced our understanding of skin biology, revealing new information on key structures in the skin, such as the intermediate filaments, desmosomes, and gap junctions. Among these disorders, there is an extraordinarily heterogeneous group known as palmoplantar keratodermas (PPK), for which only a few molecular defects have been described. A particular form of PPK, known as punctate PPK, has been described in a few large autosomal dominant pedigrees, but its genetic basis has yet to be identified. Aim: Identification of the gene for punctate PPK. Methods: Clinical examination and linkage analysis in three families with punctate PPK. Results: A genomewide scan was performed on an extended autosomal dominant pedigree, and linkage to chromosome 15q22–q24 was identified. With the addition of two new families with the same phenotype, we confirmed the mapping of the locus for punctate PPK to a 9.98 cM interval, flanked by markers D15S534 and D15S818 (maximum two point lod score of 4.93 at θ = 0 for marker D15S988). Conclusions: We report the clinical and genetic findings in three pedigrees with the punctate form of PPK. We have mapped a genetic locus for this phenotype to chromosome 15q22–q24, which indicates the identification of a new gene involved in skin integrity.