RESUMO
Darier disease is caused by heterozygous loss of function variants in the ATP2A2 gene encoding the endoplasmic/sarcoplasmic reticulum Ca2+ pump ATP2A2. Defective intracellular calcium signaling in the epidermis results in a loss of desmosomal adhesion and the development of characteristic skin lesions. In this study, we investigated a Shih Tzu that developed erythematous papules on the ventrum and, over time, the dorsal neck and a nodule in the right ear canal with secondary ear infection. Histopathologic examination demonstrated discrete foci of acantholysis affecting suprabasal layers of the epidermis. Whole genome sequencing of the affected dog identified a heterozygous missense variant, p.N809H, affecting an evolutionarily conserved amino acid residue of the ATP2A2 protein. The highly characteristic clinical and histopathologic findings together with a plausible variant in the only known functional candidate gene establish the diagnosis of canine Darier disease in the studied dog and highlight the potential of genetic analyses as complementary diagnostic approach in veterinary medicine.
Assuntos
Doença de Darier , Doenças do Cão , Animais , Cães , Doença de Darier/genética , Doença de Darier/veterinária , Doença de Darier/diagnóstico , Mutação de Sentido Incorreto , Heterozigoto , Cálcio/metabolismo , Linhagem , Doenças do Cão/genéticaAssuntos
ATPases Transportadoras de Cálcio/genética , Doença de Darier/genética , Mutação , Sequência de Bases , DNA Complementar/genética , Feminino , Humanos , Hungria , Íntrons , Masculino , Mutação de Sentido Incorreto , Linhagem , Sítios de Splice de RNA , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático , Deleção de SequênciaRESUMO
Steady-state and rapid kinetic studies were conducted to functionally characterize the overall and partial reactions of the Ca2+ transport cycle mediated by the human sarco(endo)plasmic reticulum Ca2+-ATPase 2 (SERCA2) isoforms, SERCA2a and SERCA2b, and 10 Darier disease (DD) mutants upon heterologous expression in HEK-293 cells. SERCA2b displayed a 10-fold decrease in the rate of Ca2+ dissociation from E1Ca2 relative to SERCA2a (i.e. SERCA2b enzyme manifests true high affinity at cytosolic Ca2+ sites) and a lower rate of dephosphorylation. These fundamental kinetic differences explain the increased apparent affinity for activation by cytosolic Ca2+ and the reduced catalytic turnover rate in SERCA2b. Relative to SERCA1a, both SERCA2 isoforms displayed a 2-fold decrease of the rate of E2 to E1Ca2 transition. Furthermore, seven DD mutants were expressed at similar levels as wild type. The expression level was 2-fold reduced for Gly23 --> Glu and Ser920 --> Tyr and 10-fold reduced for Gly749 --> Arg. Uncoupling between Ca2+ translocation and ATP hydrolysis and/or changes in the rates of partial reactions account for lack of function for 7 of 10 mutants: Gly23 --> Glu (uncoupling), Ser186 --> Phe, Pro602 --> Leu, and Asp702 --> Asn (block of E1 approximately P(Ca2) to E2-P transition), Cys318 --> Arg (uncoupling and 3-fold reduction of E2-P to E2 transition rate), and Thr357 --> Lys and Gly769 --> Arg (lack of phosphorylation). A 2-fold decrease in the E1 approximately P(Ca2) to E2-P transition rate is responsible for the 2-fold decrease in activity for Pro895 --> Leu. Ser920 --> Tyr is a unique DD mutant showing an enhanced molecular Ca2+ transport activity relative to wild-type SERCA2b. In this case, the disease may be a consequence of the low expression level and/or reduction of Ca2+ affinity and sensitivity to inhibition by lumenal Ca2+.
Assuntos
ATPases Transportadoras de Cálcio/química , Mutação , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/química , Sequência de Aminoácidos , Animais , Western Blotting , Cálcio/metabolismo , ATPases Transportadoras de Cálcio/genética , Catálise , Linhagem Celular , DNA Complementar/metabolismo , Doença de Darier/genética , Doença de Darier/metabolismo , Humanos , Hidrólise , Cinética , Ligantes , Modelos Químicos , Dados de Sequência Molecular , Fosforilação , Conformação Proteica , Isoformas de Proteínas , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Transporte Proteico , Coelhos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático , Fatores de TempoRESUMO
CONTEXT: One strategy for identifying susceptibility genes for common disorders is to investigate Mendelian diseases, cosegregating with these common disease phenotypes. CASE REPORT: A family with seven members is described, in which three members present Darier's disease and depression. This apparent cosegregation, if true, would support the hypothesis that in some pedigrees, a gene for mood disorder may be located on chromosome 12.
Assuntos
Doença de Darier/genética , Depressão/genética , Predisposição Genética para Doença , Adulto , Segregação de Cromossomos/genética , Cromossomos Humanos Par 12/genética , Doença de Darier/complicações , Doença de Darier/psicologia , Humanos , Masculino , Transtornos do Humor/genética , LinhagemRESUMO
CONTEXT: One strategy for identifying susceptibility genes for common disorders is to investigate Mendelian diseases, cosegregating with these common disease phenotypes. CASE REPORT: A family with seven members is described, in which three members present Darier's disease and depression. This apparent cosegregation, if true, would support the hypothesis that in some pedigrees, a gene for mood disorder may be located on chromosome 12