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1.
Biochim Biophys Acta Mol Basis Dis ; 1870(5): 167207, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38701954

RESUMO

PURPOSE: In this study, we identified and diagnosed a novel inherited condition called Dyschromatosis, Ichthyosis, Deafness, and Atopic Disease (DIDA) syndrome. We present a series of studies to clarify the pathogenic variants and specific mechanism. METHODS: Exome sequencing and Sanger sequencing was conducted in affected and unaffected family members. A variety of human and cell studies were performed to explore the pathogenic process of keratosis. RESULTS: Our finding indicated that DIDA syndrome was caused by compound heterozygous variants in the oxysterol-binding protein-related protein 2 (OSBPL2) gene. Furthermore, our findings revealed a direct interaction between OSBPL2 and Phosphoinositide phospholipase C-beta-3 (PLCB3), a key player in hyperkeratosis. OSBPL2 effectively inhibits the ubiquitylation of PLCB3, thereby stabilizing PLCB3. Conversely, OSBPL2 variants lead to enhanced ubiquitination and subsequent degradation of PLCB3, leading to epidermal hyperkeratosis, characterized by aberrant proliferation and delayed terminal differentiation of keratinocytes. CONCLUSIONS: Our study not only unveiled the association between OSBPL2 variants and the newly identified DIDA syndrome but also shed light on the underlying mechanism.


Assuntos
Surdez , Ictiose , Linhagem , Fosfolipase C beta , Humanos , Surdez/genética , Surdez/patologia , Fosfolipase C beta/genética , Fosfolipase C beta/metabolismo , Feminino , Masculino , Ictiose/genética , Ictiose/patologia , Ictiose/metabolismo , Heterozigoto , Ubiquitinação , Queratinócitos/metabolismo , Queratinócitos/patologia , Sequenciamento do Exoma , Adulto , Síndrome , Células HEK293 , Receptores de Esteroides
2.
EBioMedicine ; 89: 104453, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36736132

RESUMO

BACKGROUND: Keratitis ichthyosis deafness (KID) syndrome is a rare disorder caused by hemichannel (HC) activating gain-of-function mutations in the GJB2 gene encoding connexin (Cx) 26, for which there is no cure, or current treatments based upon the mechanism of disease causation. METHODS: We applied Adeno Associated Virus (AAV) mediated mAb gene transfer (AAVmAb) to treat the epidermal features of KID syndrome with a well-characterized HC blocking antibody using male mice of a murine model that replicates the skin pathology of the human disease. FINDINGS: We demonstrate that in vivo AAVmAb treatment significantly reduced the size and thickness of KID lesions, in addition to blocking activity of mutant HCs in the epidermis in vivo. We also show that AAVmAb treatment eliminated abnormal keratinocyte proliferation and enlarged cell size, decreased apoptosis, and restored the normal distribution of keratin expression. INTERPRETATION: Our findings reinforce the critical role played by increased HC activity in the skin pathology associated with KID syndrome. They also underscore the clinical potential of anti-HC mAbs coupled with genetic based delivery systems for treating the underlying mechanistic basis of this disorder. Inhibition of HC activity is an ideal therapeutic target in KID syndrome, and the genetic delivery of mAbs targeted against mutant HCs could form the basis of new therapeutic interventions to treat this incurable disease. FUNDING: Fondazione Telethon grant GGP19148 and University of Padova grant Prot. BIRD187130 to FM; Foundation for Ichthyosis and Related Skin Types (FIRST) and National Institutes of Health grant EY 026911 to TWW.


Assuntos
Conexinas , Surdez , Ictiose , Ceratite , Animais , Masculino , Camundongos , Anticorpos , Conexinas/genética , Surdez/genética , Epiderme/metabolismo , Técnicas de Transferência de Genes , Ictiose/genética , Ictiose/metabolismo , Ictiose/patologia , Ceratite/genética , Ceratite/metabolismo , Ceratite/patologia , Mutação
3.
Neuropathology ; 40(6): 559-569, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33073872

RESUMO

Tubular aggregate myopathy (TAM) is a progressive disorder characterized by muscle weakness, cramps, and myalgia. TAM clinically overlaps with Stormorken syndrome (STRMK), combining TAM with miosis, thrombocytopenia, hyposplenism, ichthyosis, short stature, and dyslexia. TAM and STRMK arise from gain-of-function mutations in STIM1 (stromal interaction molecule 1) or ORAI1, both encoding key regulators of Ca2+ homeostasis, and mutations in either gene result in excessive extracellular Ca2+ entry. The pathomechanistic similarities and differences between TAM and STRMK are only partially understood. Here we provide functional in vitro experiments demonstrating that STIM1 harboring the TAM D84G or the STRMK R304W mutation similarly cluster and exert a dominant effect on the wild-type protein. Both mutants recruit ORAI1 to the clusters, increase cytosolic Ca2+ levels, promote major nuclear import of the Ca2+ -dependent transcription factor NFAT (nuclear factor of activated T cells), and trigger the formation of circular membrane stacks. In conclusion, the analyzed TAM and STRMK mutations have a comparable impact on STIM1 protein function and downstream effects of excessive Ca2+ entry, highlighting that TAM and STRMK involve a common pathomechanism.


Assuntos
Transtornos Plaquetários/genética , Dislexia/genética , Ictiose/genética , Transtornos de Enxaqueca/genética , Miose/genética , Miopatias Congênitas Estruturais/genética , Proteínas de Neoplasias/genética , Baço/anormalidades , Molécula 1 de Interação Estromal/genética , Animais , Transtornos Plaquetários/metabolismo , Transtornos Plaquetários/patologia , Células Cultivadas , Dislexia/metabolismo , Dislexia/patologia , Eritrócitos Anormais/metabolismo , Eritrócitos Anormais/patologia , Humanos , Ictiose/metabolismo , Ictiose/patologia , Camundongos , Transtornos de Enxaqueca/metabolismo , Transtornos de Enxaqueca/patologia , Miose/metabolismo , Miose/patologia , Fadiga Muscular/genética , Mutação , Miopatias Congênitas Estruturais/metabolismo , Miopatias Congênitas Estruturais/patologia , Fatores de Transcrição NFATC/metabolismo , Proteína ORAI1/metabolismo , Baço/metabolismo , Baço/patologia , Transfecção
4.
Mol Genet Metab ; 131(1-2): 253-258, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32800643

RESUMO

Sjögren-Larsson syndrome (SLS) is an inherited metabolic disease characterized by ichthyosis, spasticity, intellectual disability and deficient oxidation and accumulation of of fatty aldehydes and alcohols. We investigated whether excess fatty alcohols in SLS are diverted into biosynthesis of ether glycerolipids (eGLs) by measuring the 1-O-alkylglycerol (AG) backbone of eGLs in stratum corneum, plasma and red blood cells (RBCs). In all tissues, saturated and monounsaturated AGs were detected. In stratum corneum from SLS patients, saturated AGs (C15-C20) were increased 97-fold (range: 86- to 169-fold) compared to controls. AGs were largely (67 ± 9%) derived from neutral esterified eGLs (i.e. alkyl-diacylglyerol) and free non-esterified AGs (28 ± 10%), but very little from plasmalogens (3 ± 5%). Plasma from SLS patients had 2-fold more C18:0-AG (p < 0.005) and 40% less C16:1-AG (p < 0.01) than controls but the total concentration of AGs was not increased, and the AG profile in RBCs from SLS subjects was normal. All AGs were profoundly reduced in plasma and RBCs from patients with Zellweger spectrum disorder, who have impaired eGL (i.e. plasmalogen) synthesis. The striking accumulation of AGs in stratum corneum of SLS patients constitutes a novel lipid biomarker for this disease, and may contribute to the pathogenesis of the ichthyosis. Measurement of AGs is a simple and convenient method to assess global synthesis of eGLs and potentially identify patients with defects in their metabolism.


Assuntos
Aldeídos/metabolismo , Ácidos Graxos/metabolismo , Álcoois Graxos/metabolismo , Metabolismo dos Lipídeos/genética , Síndrome de Sjogren-Larsson/metabolismo , Células Cultivadas , Epiderme/metabolismo , Epiderme/patologia , Éteres/metabolismo , Feminino , Fibroblastos/metabolismo , Humanos , Ictiose/complicações , Ictiose/genética , Ictiose/metabolismo , Ictiose/patologia , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Espasticidade Muscular/complicações , Espasticidade Muscular/genética , Espasticidade Muscular/metabolismo , Espasticidade Muscular/patologia , Oxirredução , Síndrome de Sjogren-Larsson/complicações , Síndrome de Sjogren-Larsson/genética , Síndrome de Sjogren-Larsson/patologia
5.
Hum Genet ; 139(10): 1247-1259, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32306098

RESUMO

Congenital diarrheal disorders (CDD) comprise > 50 monogenic entities featuring chronic diarrhea of early-onset, including defects in nutrient and electrolyte absorption, enterocyte polarization, enteroendocrine cell differentiation, and epithelial integrity. Diarrhea is also a predominant symptom in many immunodeficiencies, congenital disorders of glycosylation, and in some defects of the vesicular sorting and transporting machinery. We set out to identify the etiology of an intractable diarrhea in 2 consanguineous families by whole-exome sequencing, and identified two novel AP1S1 mutations, c.269T>C (p.Leu90Pro) and c.346G>A (p.Glu116Lys). AP1S1 encodes the small subunit of the adaptor protein 1 complex (AP-1), which plays roles in clathrin coat-assembly and trafficking between trans-Golgi network, endosomes and the plasma membrane. An AP1S1 knock-out (KO) of a CaCo2 intestinal cell line was generated to characterize intestinal AP1S1 deficiency as well as identified mutations by stable expression in KO background. Morphology and prototype transporter protein distribution were comparable between parental and KO cells. We observed altered localization of tight-junction proteins ZO-1 and claudin 3, decreased transepithelial electrical resistance and an increased dextran permeability of the CaCo2-AP1S1-KO monolayer. In addition, lumen formation in 3D cultures of these cells was abnormal. Re-expression of wild-type AP1S1 in CaCo2-AP1S1-KO cells reverted these abnormalities, while expression of AP1S1 containing either missense mutation did not. Our data indicate that loss of AP1S1 function causes an intestinal epithelial barrier defect, and that AP1S1 mutations can cause a non-syndromic form of congenital diarrhea, whereas 2 reported truncating AP1S1 mutations caused MEDNIK syndrome, characterized by mental retardation, enteropathy, deafness, neuropathy, ichthyosis, and keratodermia.


Assuntos
Complexo 1 de Proteínas Adaptadoras/genética , Subunidades sigma do Complexo de Proteínas Adaptadoras/genética , Surdez/genética , Diarreia/genética , Ictiose/genética , Deficiência Intelectual/genética , Ceratodermia Palmar e Plantar/genética , Mutação de Sentido Incorreto , Complexo 1 de Proteínas Adaptadoras/deficiência , Subunidades sigma do Complexo de Proteínas Adaptadoras/deficiência , Sequência de Bases , Células CACO-2 , Claudina-3/genética , Claudina-3/metabolismo , Consanguinidade , Surdez/diagnóstico , Surdez/metabolismo , Surdez/patologia , Diarreia/diagnóstico , Diarreia/metabolismo , Diarreia/patologia , Feminino , Expressão Gênica , Técnicas de Inativação de Genes , Teste de Complementação Genética , Humanos , Ictiose/diagnóstico , Ictiose/metabolismo , Ictiose/patologia , Lactente , Recém-Nascido , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Ceratodermia Palmar e Plantar/diagnóstico , Ceratodermia Palmar e Plantar/metabolismo , Ceratodermia Palmar e Plantar/patologia , Linhagem , Permeabilidade , Sequenciamento do Exoma , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismo
6.
Cell Calcium ; 80: 112-116, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31009822

RESUMO

Ca2+ release-activated Ca2+ (CRAC) channels are intimately linked with health and disease. The gene encoding the CRAC channel, ORAI1, was discovered in part by genetic analysis of patients with abolished CRAC channel function. And patients with autosomal recessive loss-of-function (LOF) mutations in ORAI1 and its activator stromal interaction molecule 1 (STIM1) that abolish CRAC channel function and store-operated Ca2+ entry (SOCE) define essential functions of CRAC channels in health and disease. Conversely, gain-of-function (GOF) mutations in ORAI1 and STIM1 are associated with tubular aggregate myopathy (TAM) and Stormorken syndrome due to constitutive CRAC channel activation. In addition, genetically engineered animal models of ORAI and STIM function have provided important insights into the physiological and pathophysiological roles of CRAC channels in cell types and organs beyond those affected in human patients. The picture emerging from this body of work shows CRAC channels as important regulators of cell function in many tissues, and as potential drug targets for the treatment of autoimmune and inflammatory disorders.


Assuntos
Transtornos Plaquetários/metabolismo , Canais de Cálcio Ativados pela Liberação de Cálcio/metabolismo , Canalopatias/metabolismo , Dislexia/metabolismo , Ictiose/metabolismo , Transtornos de Enxaqueca/metabolismo , Miose/metabolismo , Mutação/genética , Miopatias Congênitas Estruturais/metabolismo , Proteínas de Neoplasias/genética , Proteína ORAI1/genética , Baço/anormalidades , Molécula 1 de Interação Estromal/genética , Animais , Transtornos Plaquetários/tratamento farmacológico , Transtornos Plaquetários/genética , Cálcio/metabolismo , Sinalização do Cálcio , Canalopatias/tratamento farmacológico , Canalopatias/genética , Modelos Animais de Doenças , Descoberta de Drogas , Dislexia/tratamento farmacológico , Dislexia/genética , Eritrócitos Anormais/metabolismo , Humanos , Ictiose/tratamento farmacológico , Ictiose/genética , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/genética , Miose/tratamento farmacológico , Miose/genética , Fadiga Muscular/genética , Miopatias Congênitas Estruturais/tratamento farmacológico , Miopatias Congênitas Estruturais/genética , Proteínas de Neoplasias/metabolismo , Proteína ORAI1/metabolismo , Baço/metabolismo , Molécula 1 de Interação Estromal/metabolismo
7.
Nat Commun ; 9(1): 825, 2018 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-29483506

RESUMO

STIM1 and Orai1 are key components of the Ca2+-release activated Ca2+ (CRAC) current. Orai1, which represents the subunit forming the CRAC channel complex, is activated by the ER resident Ca2+ sensor STIM1. The genetically inherited Stormorken syndrome disease has been associated with the STIM1 single point R304W mutant. The resulting constitutive activation of Orai1 mainly involves the CRAC-activating domain CAD/SOAR of STIM1, the exposure of which is regulated by the molecular interplay between three cytosolic STIM1 coiled-coil (CC) domains. Here we present a dual mechanism by which STIM1 R304W attains the pathophysiological, constitutive activity eliciting the Stormorken syndrome. The R304W mutation induces a helical elongation within the CC1 domain, which together with an increased CC1 homomerization, destabilize the resting state of STIM1. This culminates, even in the absence of store depletion, in structural extension and CAD/SOAR exposure of STIM1 R304W leading to constitutive CRAC channel activation and Stormorken disease.


Assuntos
Transtornos Plaquetários/genética , Cálcio/química , Dislexia/genética , Ictiose/genética , Transtornos de Enxaqueca/genética , Miose/genética , Proteínas de Neoplasias/química , Proteína ORAI1/química , Mutação Puntual , Baço/anormalidades , Molécula 1 de Interação Estromal/química , Sequência de Aminoácidos , Substituição de Aminoácidos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Transtornos Plaquetários/metabolismo , Transtornos Plaquetários/patologia , Cálcio/metabolismo , Dislexia/metabolismo , Dislexia/patologia , Eritrócitos Anormais/metabolismo , Eritrócitos Anormais/patologia , Expressão Gênica , Regulação da Expressão Gênica , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Ictiose/metabolismo , Ictiose/patologia , Transporte de Íons , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Transtornos de Enxaqueca/metabolismo , Transtornos de Enxaqueca/patologia , Miose/metabolismo , Miose/patologia , Modelos Moleculares , Fadiga Muscular/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteína ORAI1/genética , Proteína ORAI1/metabolismo , Técnicas de Patch-Clamp , Ligação Proteica , Conformação Proteica em alfa-Hélice , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Baço/metabolismo , Baço/patologia , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/metabolismo
8.
Cell Death Dis ; 8(6): e2845, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28569788

RESUMO

Several mutant mice have been generated to model connexin (Cx)-linked skin diseases; however, the role of connexins in skin maintenance and during wound healing remains to be fully elucidated. Here we generated a novel, viable, and fertile mouse (Cx26CK14-S17F/+) with the keratitis-ichthyosis-deafness mutant (Cx26S17F) driven by the cytokeratin 14 promoter. This mutant mouse mirrors several Cx26-linked human skin pathologies suggesting that the etiology of Cx26-linked skin disease indeed stems from epidermal expression of the Cx26 mutant. Cx26CK14-S17F/+ foot pad epidermis formed severe palmoplantar keratoderma, which expressed elevated levels of Cx26 and filaggrin. Primary keratinocytes isolated from Cx26CK14-S17F/+ neonates exhibited reduced gap junctional intercellular communication and migration. Furthermore, Cx26CK14-S17F/+ mouse skin wound closure was normal but repaired epidermis appeared hyperplastic with elevated expression of cytokeratin 6. Taken together, we suggest that the Cx26S17F mutant disturbs keratinocyte differentiation and epidermal remodeling following wound closure. We further posit that Cx26 contributes to epidermal homeostasis by regulating keratinocyte differentiation, and that mice harboring a disease-linked Cx26 mutant display epidermal abnormalities yet retain most wound healing properties.


Assuntos
Conexinas/genética , Surdez/genética , Epiderme/metabolismo , Ictiose/genética , Ceratodermia Palmar e Plantar/genética , Cicatrização/genética , Animais , Diferenciação Celular , Conexina 26 , Conexinas/metabolismo , Surdez/metabolismo , Surdez/patologia , Modelos Animais de Doenças , Epiderme/patologia , Feminino , Proteínas Filagrinas , Efeito Fundador , Junções Comunicantes/metabolismo , Junções Comunicantes/patologia , Expressão Gênica , Humanos , Ictiose/metabolismo , Ictiose/patologia , Proteínas de Filamentos Intermediários/genética , Proteínas de Filamentos Intermediários/metabolismo , Queratina-14/genética , Queratina-14/metabolismo , Queratinócitos/metabolismo , Queratinócitos/patologia , Ceratodermia Palmar e Plantar/metabolismo , Ceratodermia Palmar e Plantar/patologia , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Cultura Primária de Células , Regiões Promotoras Genéticas
9.
Cell Death Dis ; 8(6): e2840, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28569792

RESUMO

AP1 transcription factors are important controllers of epidermal differentiation. Multiple family members are expressed in the epidermis in a differentiation-dependent manner, where they function to regulate gene expression. To study the role of AP1 factor signaling, TAM67 (dominant-negative c-jun) was inducibly expressed in the suprabasal epidermis. The TAM67-positive epidermis displays keratinocyte hyperproliferation, hyperkeratosis and parakeratosis, delayed differentiation, extensive subdermal vasodilation, nuclear loricrin localization, tail and digit pseudoainhum and reduced filaggrin level. These changes are associated with increased levels of IFNγ, CCL3, CCL5, CXCL9, CXCL10, and CXCL11 (Th1-associated chemokines), and CCL1, CCL2, CCL5 and CCL11 (Th2-associated chemokines) in the epidermis and serum. S100A8 and S100A9 protein levels are also markedly elevated. These changes in epidermal chemokine level are associated with increased levels of the corresponding chemokine mRNA. The largest increases were observed for CXCL9, CXCL10, CXCL11, and S100A8 and S100A9. To assess the role of CXCL9, CXCL10, CXCL11, which bind to CXCR3, on phenotype development, we expressed TAM67 in CXCR3 knockout mice. Using a similar strategy, we examine the role of S100A8 and S100A9. Surprisingly, loss of CXCR3 or S100A8/A9 did not attenuate phenotype development. These studies suggest that interfering with epidermal AP1 factor signaling initiates a loss of barrier function leading to enhanced epidermal chemokine production, but that CXCR3 and S100A8/A9 do not mediate the phenotypic response.


Assuntos
Ictiose/genética , Proteínas de Filamentos Intermediários/genética , Fragmentos de Peptídeos/genética , Proteínas Proto-Oncogênicas c-jun/genética , Equilíbrio Th1-Th2/genética , Fator de Transcrição AP-1/genética , Animais , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Diferenciação Celular , Quimiocinas CC/genética , Quimiocinas CC/metabolismo , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Modelos Animais de Doenças , Epiderme/metabolismo , Epiderme/patologia , Feminino , Proteínas Filagrinas , Regulação da Expressão Gênica , Humanos , Ictiose/metabolismo , Ictiose/patologia , Interferon gama/genética , Interferon gama/metabolismo , Proteínas de Filamentos Intermediários/metabolismo , Queratinócitos/metabolismo , Queratinócitos/patologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Fragmentos de Peptídeos/metabolismo , Fenótipo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Transdução de Sinais , Fator de Transcrição AP-1/deficiência
10.
Hum Mutat ; 38(4): 426-438, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28058752

RESUMO

Calcium (Ca2+ ) is a physiological key factor, and the precise modulation of free cytosolic Ca2+ levels regulates multiple cellular functions. Store-operated Ca2+ entry (SOCE) is a major mechanism controlling Ca2+ homeostasis, and is mediated by the concerted activity of the Ca2+ sensor STIM1 and the Ca2+ channel ORAI1. Dominant gain-of-function mutations in STIM1 or ORAI1 cause tubular aggregate myopathy (TAM) or Stormorken syndrome, whereas recessive loss-of-function mutations are associated with immunodeficiency. Here, we report the identification and functional characterization of novel ORAI1 mutations in TAM patients. We assess basal activity and SOCE of the mutant ORAI1 channels, and we demonstrate that the G98S and V107M mutations generate constitutively permeable ORAI1 channels, whereas T184M alters the channel permeability only in the presence of STIM1. These data indicate a mutation-dependent pathomechanism and a genotype/phenotype correlation, as the ORAI1 mutations associated with the most severe symptoms induce the strongest functional cellular effect. Examination of the non-muscle features of our patients strongly suggests that TAM and Stormorken syndrome are spectra of the same disease. Overall, our results emphasize the importance of SOCE in skeletal muscle physiology, and provide new insights in the pathomechanisms involving aberrant Ca2+ homeostasis and leading to muscle dysfunction.


Assuntos
Ativação do Canal Iônico/genética , Mutação de Sentido Incorreto , Miopatias Congênitas Estruturais/genética , Proteína ORAI1/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Transtornos Plaquetários/genética , Transtornos Plaquetários/metabolismo , Cálcio/metabolismo , Células Cultivadas , Dislexia/genética , Dislexia/metabolismo , Eritrócitos Anormais/metabolismo , Feminino , Células HEK293 , Humanos , Ictiose/genética , Ictiose/metabolismo , Masculino , Camundongos Knockout , Microscopia de Fluorescência/métodos , Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/metabolismo , Miose/genética , Miose/metabolismo , Fadiga Muscular/genética , Miopatias Congênitas Estruturais/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteína ORAI1/metabolismo , Linhagem , Homologia de Sequência de Aminoácidos , Baço/anormalidades , Baço/metabolismo , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/metabolismo
11.
Am J Dermatopathol ; 39(1): 28-32, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27759688

RESUMO

Adult T-cell leukemia/lymphoma (ATLL) is a rare and often aggressive lymphoid malignancy known to be associated with human T-cell lymphotropic virus type 1. There are 2 broad categories: acute and chronic. In the acute category, there is a leukemic and a lymphomatous variant, whereas in the designated "chronic" form, there is mild peripheral blood lymphocytosis. The intermediate "smoldering" category is without peripheral blood lymphocytosis with only discernible skin involvement. We present a 68-year-old human T-cell lymphotropic virus type 1 seropositive female with a mild peripheral blood atypical lymphocytosis who had indurated nodules on her hands of 2 years duration and a new scaly ichthyosiform eruption on her lower extremities. Histopathologic examination of the hand biopsy revealed coalescing nodules of large atypical noncerebriform lymphocytes with focal areas of epidermotropism. Phenotypically, the infiltrate was positive for ß-F1, CD2, CD4, CD5, CD7, Foxp3, and CD25. In both biopsies, there was striking upregulation of TOX (thymocyte selection-associated high mobility group box factor) in the nuclei of neoplastic cells. The second biopsy taken from the ichthyotic patch on the patient's left leg showed a subtle pattern of epidermal infiltration by atypical noncerebriform lymphocytes and a distinct compact scale consistent with the clinical picture of ichthyosis. The histopathologic appearance was that of a yet undescribed ichthyosiform mycosis fungoides-like presentation of chronic ATLL. In addition, the observed upregulation of nuclear TOX may play an oncogenic role in ATLL. The course to date in this patient has been relatively indolent, although the patients believe that large cell transformation could portend more aggressive disease.


Assuntos
Biomarcadores Tumorais/análise , Proteínas de Grupo de Alta Mobilidade/análise , Ictiose/metabolismo , Leucemia-Linfoma de Células T do Adulto/metabolismo , Micose Fungoide/química , Neoplasias Cutâneas/química , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Feminino , Humanos , Ictiose/tratamento farmacológico , Ictiose/patologia , Imuno-Histoquímica , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Leucemia-Linfoma de Células T do Adulto/patologia , Micose Fungoide/tratamento farmacológico , Micose Fungoide/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Regulação para Cima
12.
Am J Med Genet A ; 170(7): 1799-805, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27127007

RESUMO

Shwachman-Diamond syndrome (SDS) is a recessive ribosomopathy, characterized by bone marrow failure and exocrine pancreatic insufficiency (ePI) often associated with neurodevelopmental and skeletal abnormalities. The aim of this report is to describe a SDS patient with early ichthyosis associated with dermal and epidermal intracellular lipid droplets (iLDs), hypoglycemia and later a distinctive clinical SDS phenotype. At 3 months of age, she had ichthyosis, growth retardation, and failure to thrive. She had not cytopenia. Ultrasonography (US) showed pancreatic diffuse high echogenicity. Subsequently fasting hypoketotic hypoglycemia occurred without permanent hepatomegaly or hyperlipidemia. Continuous gavage feeding was followed by clinical improvement including ichthyosis and hypoglycemia. After 14 months of age, she developed persistent neutropenia and ePI consistent with SDS. The ichthyotic skin biopsy, performed at 5 months of age, disclosed iLDs in all epidermal layers, in melanocytes, eccrine sweat glands, Schwann cells and dermal fibroblasts. These iLDs were reminiscent of those described in Dorfman-Chanarin syndrome (DCS) or Wolman's disease. Both LIPA and CGI-58 analysis did not revealed pathogenic mutation. By sequencing SBDS, a compound heterozygous for a previously reported gene mutation (c.258 + 2T>C) and a novel mutation (c.284T>G) were found. Defective SBDS may hypothetically interfere as in DCS, with neutral lipid metabolism and play a role in the SDS phenotype such as ichthyosis with dermal and epidermal iLDs and hypoglycemia. This interference with neutral lipid metabolism must most likely occur in the cytoplasm compartment as in DCS and not in the lysosomal compartment as in Wolman's disease. © 2016 Wiley Periodicals, Inc.


Assuntos
Doenças da Medula Óssea/fisiopatologia , Insuficiência Pancreática Exócrina/fisiopatologia , Hipoglicemia/fisiopatologia , Ictiose/fisiopatologia , Lipomatose/fisiopatologia , Doenças da Medula Óssea/diagnóstico , Doenças da Medula Óssea/metabolismo , Epiderme/metabolismo , Epiderme/patologia , Insuficiência Pancreática Exócrina/diagnóstico , Insuficiência Pancreática Exócrina/metabolismo , Feminino , Humanos , Hipoglicemia/diagnóstico , Ictiose/diagnóstico , Ictiose/metabolismo , Lactente , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/patologia , Lipomatose/diagnóstico , Lipomatose/metabolismo , Fenótipo , Síndrome de Shwachman-Diamond
14.
Mol Genet Metab ; 114(3): 474-82, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25577287

RESUMO

Store-operated Ca(2+) entry is the major route of replenishment of intracellular Ca(2+) in animal cells in response to the depletion of Ca(2+) stores in the endoplasmic reticulum. It is primarily mediated by the Ca(2+)-selective release-activated Ca(2+) (CRAC) channel, which consists of the pore-forming subunits ORAI1-3 and the Ca(2+) sensors, STIM1 and STIM2. Recessive loss-of-function mutations in STIM1 or ORAI1 result in immune deficiency and nonprogressive myopathy. Heterozygous gain-of-function mutations in STIM1 cause non-syndromic myopathies as well as syndromic forms of miosis and myopathy with tubular aggregates and Stormorken syndrome; some of these syndromic forms are associated with thrombocytopenia. Increased concentration of Ca(2+) as a result of store-operated Ca(2+) entry is essential for platelet activation. The York Platelet syndrome (YPS) is characterized by thrombocytopenia, striking ultrastructural platelet abnormalities including giant electron-opaque organelles and massive, multilayered target bodies and deficiency of platelet Ca(2+) storage in delta granules. We present clinical and molecular findings in 7 YPS patients from 4 families, demonstrating that YPS patients have a chronic myopathy associated with rimmed vacuoles and heterozygous gain-of-function STIM1 mutations. These findings expand the phenotypic spectrum of STIM1-related human disorders and define the molecular basis of YPS.


Assuntos
Plaquetas/patologia , Canalopatias/genética , Proteínas de Membrana/genética , Doenças Musculares/genética , Proteínas de Neoplasias/genética , Adulto , Transtornos Plaquetários/genética , Transtornos Plaquetários/metabolismo , Plaquetas/fisiologia , Plaquetas/ultraestrutura , Cálcio/metabolismo , Criança , Pré-Escolar , Dislexia/genética , Dislexia/metabolismo , Eritrócitos Anormais/metabolismo , Exoma/genética , Feminino , Heterozigoto , Humanos , Ictiose/genética , Ictiose/metabolismo , Lactente , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/metabolismo , Miose/genética , Miose/metabolismo , Fadiga Muscular/genética , Doenças Musculares/metabolismo , Mutação , Linhagem , Análise de Sequência de DNA , Baço/anormalidades , Baço/metabolismo , Molécula 1 de Interação Estromal , Trombocitopenia
15.
Hum Mutat ; 35(10): 1221-32, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25044882

RESUMO

Stormorken syndrome is a rare autosomal dominant disorder characterized by a phenotype that includes miosis, thrombocytopenia/thrombocytopathy with bleeding time diathesis, intellectual disability, mild hypocalcemia, muscle fatigue, asplenia, and ichthyosis. Using targeted sequencing and whole-exome sequencing, we identified the c.910C > T transition in a STIM1 allele (p.R304W) only in patients and not in their unaffected family members. STIM1 encodes stromal interaction molecule 1 protein (STIM1), which is a finely tuned endoplasmic reticulum Ca(2+) sensor. The effect of the mutation on the structure of STIM1 was investigated by molecular modeling, and its effect on function was explored by calcium imaging experiments. Results obtained from calcium imaging experiments using transfected cells together with fibroblasts from one patient are in agreement with impairment of calcium homeostasis. We show that the STIM1 p.R304W variant may affect the conformation of the inhibitory helix and unlock the inhibitory state of STIM1. The p.R304W mutation causes a gain of function effect associated with an increase in both resting Ca(2+) levels and store-operated calcium entry. Our study provides evidence that Stormorken syndrome may result from a single-gene defect, which is consistent with Mendelian-dominant inheritance.


Assuntos
Transtornos Plaquetários/genética , Dislexia/genética , Ictiose/genética , Proteínas de Membrana/genética , Transtornos de Enxaqueca/genética , Miose/genética , Proteínas de Neoplasias/genética , Mutação Puntual , Baço/anormalidades , Adolescente , Adulto , Idoso , Transtornos Plaquetários/metabolismo , Transtornos Plaquetários/patologia , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Criança , Pré-Escolar , Dislexia/metabolismo , Dislexia/patologia , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/ultraestrutura , Eritrócitos Anormais/metabolismo , Eritrócitos Anormais/patologia , Feminino , Humanos , Ictiose/metabolismo , Ictiose/patologia , Lactente , Recém-Nascido , Masculino , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Transtornos de Enxaqueca/metabolismo , Transtornos de Enxaqueca/patologia , Miose/metabolismo , Miose/patologia , Fadiga Muscular/genética , Fibras Musculares Esqueléticas/patologia , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Linhagem , Estrutura Secundária de Proteína , Baço/metabolismo , Baço/patologia , Molécula 1 de Interação Estromal
16.
J Invest Dermatol ; 132(10): 2368-2375, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22622417

RESUMO

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of skin barrier diseases due inter alia to mutations in transglutaminase-1 (TGM1), in lipoxygenases (LOXs) of the hepoxilin pathway, and in ichthyin, a putative Mg(2+) transporter encoded by the NIPAL4 gene. In search of a common pathogenic pathway for ARCI, we investigated the epidermal expression of TGM1, 12R-LOX, eLOX-3, and ichthyin in skin biopsies from four healthy controls and nine patients with ARCI. In healthy skin, TGM1, ichthyin, and the LOX enzymes were predominantly expressed in the upper epidermis where colocalization signals could also be demonstrated by in situ proximity ligation assay. In patients with ALOX12B mutations and abnormal 12R-LOX expression, the colocalization signal for eLOX-3 and TGM1 was increased 4-fold. In contrast, patients with NIPAL4 mutations and abnormal ichthyin expression showed increased 12R-LOX and eLOX-3 staining and a colocalization signal of these LOXs that was three times the normal intensity. Treatment of these patients with a retinoid-mimetic drug, liarozole, normalized the expression of 12R-LOX and attenuated the colocalization signal. Altogether, our data indicate that ichthyin and TGM1 are functionally closely related in the lipid processing and that this metabolic pathway can be modified by retinoids.


Assuntos
Permeabilidade da Membrana Celular/fisiologia , Epiderme/metabolismo , Ictiose/metabolismo , Lipoxigenases/metabolismo , Redes e Vias Metabólicas/fisiologia , Mutação/genética , Receptores de Superfície Celular/genética , Transglutaminases/metabolismo , Adulto , Biópsia , Epiderme/patologia , Feminino , Homeostase/fisiologia , Humanos , Ictiose/tratamento farmacológico , Ictiose/genética , Masculino , Pessoa de Meia-Idade , Receptores de Superfície Celular/metabolismo , Retinoides/uso terapêutico , Fenômenos Fisiológicos da Pele
17.
Mol Biol Cell ; 22(24): 4776-86, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22031297

RESUMO

Mutations in the GJB2 gene (Cx26) cause deafness in humans. Most are loss-of-function mutations and cause nonsyndromic deafness. Some mutations produce a gain of function and cause syndromic deafness associated with skin disorders, such as keratitis-ichthyosis-deafness syndrome (KIDS). Cx26-G45E is a lethal mutation linked to KIDS that forms constitutively active connexin hemichannels. The pathomechanism(s) by which mutant Cx26 hemichannels perturb normal epidermal cornification are poorly understood. We created an animal model for KIDS by generating an inducible transgenic mouse expressing Cx26-G45E in keratinocytes. Cx26-G45E mice displayed reduced viability, hyperkeratosis, scaling, skin folds, and hair loss. Histopathology included hyperplasia, acanthosis, papillomatosis, increased cell size, and osteal plugging. These abnormalities correlated with human KIDS pathology and were associated with increased hemichannel currents in transgenic keratinocytes. These results confirm the pathogenic nature of the G45E mutation and provide a new model for studying the role of aberrant connexin hemichannels in epidermal differentiation and inherited connexin disorders.


Assuntos
Conexinas/biossíntese , Surdez/metabolismo , Surdez/patologia , Modelos Animais de Doenças , Ictiose/metabolismo , Ictiose/patologia , Ceratite/metabolismo , Ceratite/patologia , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Animais , Conexina 26 , Conexinas/genética , Surdez/genética , Epiderme/metabolismo , Epiderme/patologia , Células HeLa , Humanos , Ictiose/genética , Queratinócitos/metabolismo , Queratinócitos/patologia , Ceratite/genética , Camundongos , Camundongos Transgênicos
19.
Biochem Biophys Res Commun ; 395(1): 25-30, 2010 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-20307501

RESUMO

KID syndrome (MIM 148210) is an ectodermal dysplasia characterized by the occurrence of localized erythematous scaly skin lesions, keratitis and severe bilateral sensorineural deafness. KID syndrome is inherited as an autosomic dominant disease, due to mutations in the gene encoding gap junction protein GJB2 (connexin 26, Cx26). Cx26 is a component of gap junction channels in the epidermis and in the stria vascularis of the cochlea. These channels play a role in the coordinated exchange of molecules and ions occurring in a wide spectrum of cellular activities. In this paper we describe two patients with Cx26 mutations cause cell death by the alteration of protein trafficking, membrane localization and probably interfering with intracellular ion concentrations. We discuss the pathogenesis of both the hearing and skin phenotypes.


Assuntos
Conexinas/genética , Displasia Ectodérmica/genética , Perda Auditiva/genética , Ictiose/genética , Apoptose/genética , Criança , Conexina 26 , Conexinas/metabolismo , Análise Mutacional de DNA , Displasia Ectodérmica/metabolismo , Displasia Ectodérmica/patologia , Feminino , Perda Auditiva/metabolismo , Humanos , Ictiose/metabolismo , Ictiose/patologia , Masculino , Transporte Proteico , Síndrome , Adulto Jovem
20.
Am J Hum Genet ; 86(4): 596-603, 2010 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-20226437

RESUMO

KLICK syndrome is a rare autosomal-recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic papules, and ichthyosiform scaling. In order to establish the genetic cause of this disorder, we collected DNA samples from eight European probands. Using high-density genome-wide SNP analysis, we identified a 1.5 Mb homozygous candidate region on chromosome 13q. Sequence analysis of the ten annotated genes in the candidate region revealed homozygosity for a single-nucleotide deletion at position c.-95 in the proteasome maturation protein (POMP) gene, in all probands. The deletion is included in POMP transcript variants with long 5' untranslated regions (UTRs) and was associated with a marked increase of these transcript variants in keratinocytes from KLICK patients. POMP is a ubiquitously expressed protein and functions as a chaperone for proteasome maturation. Immunohistochemical analysis of skin biopsies from KLICK patients revealed an altered epidermal distribution of POMP, the proteasome subunit proteins alpha 7 and beta 5, and the ER stress marker CHOP. Our results suggest that KLICK syndrome is caused by a single-nucleotide deletion in the 5' UTR of POMP resulting in altered distribution of POMP in epidermis and a perturbed formation of the outermost layers of the skin. These findings imply that the proteasome has a prominent role in the terminal differentiation of human epidermis.


Assuntos
Regiões 5' não Traduzidas/genética , Epiderme/patologia , Ictiose/genética , Ceratose/genética , Chaperonas Moleculares/genética , Polimorfismo de Nucleotídeo Único , Complexo de Endopeptidases do Proteassoma/metabolismo , Esclerodermia Localizada/genética , Transcrição Gênica , Adulto , Sequência de Bases , Estudos de Casos e Controles , Células Cultivadas , Epiderme/metabolismo , Família , Deleção de Genes , Homozigoto , Humanos , Ictiose/metabolismo , Queratinócitos/citologia , Queratinócitos/metabolismo , Ceratose/metabolismo , Masculino , Dados de Sequência Molecular , Esclerodermia Localizada/metabolismo , Homologia de Sequência do Ácido Nucleico , Síndrome
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