RESUMO
Darier disease (DD) is an autosomal dominant genodermatosis characterized by multiple warty papules coalescing in seborrheic areas and specific histological skin changes. Heterozygous mutations in ATP2A2, encoding the sarco-endoplasmic reticulum calcium pumping ATPase type 2, are identified as the molecular basis of DD. In this study, molecular features in a large cohort of Italian patients are reported. Molecular data were collected along with the main clinical features. Genomic DNA was used for direct sequencing of ATP2A2. The effect of selected mutations was predicted by in silico analysis or investigated by gene expression studies. 10 different ATP2A2 mutations were identified. Three mutations (c.2300A>G, c.2794G>A, c.569delAins34) have been previously described, while 7, including 2 missense (c.545G>A and c.2116G>A), 2 nonsense (c.1372G>T and c.1675C>T), 1 small deletion (c.142delA), 1 duplication (c.2935_2949dup15) and 1 splice-site mutation (c.2742-1G>A), were novel. Collected data added new variants to the ATP2A2 repertoire and confirmed that ATP2A2 mutations are scattered over the entire gene and, in most cases, private.
Assuntos
DNA/genética , Doença de Darier/genética , Predisposição Genética para Doença , Mutação , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Adolescente , Adulto , Criança , Análise Mutacional de DNA , Doença de Darier/epidemiologia , Doença de Darier/metabolismo , Feminino , Heterozigoto , Humanos , Itália/epidemiologia , Masculino , Linhagem , Prevalência , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Adulto JovemRESUMO
The distal arthrogryposes are a heterogeneous group of conditions characterized by congenital contractures of hands and feet, and autosomal dominant inheritance. The concurrence of ophthalmoplegia and additional ocular findings distinguish distal arthrogryposis type 5 (DA5). This rare subtype has been described in 33 patients to date and its clinical spectrum of physical findings is still poorly understood. We report on a family with three individuals with DA5. The index case came to our attention because of restricted forearm pronation-supination and juvenile macular dystrophy. Further examination revealed short stature, firm muscles, stiff spine with lumbar hyperlordosis, generalized mild limitation of the large joints, external rotation of the hips, unilateral ptosis, exophoria, and abnormal photopic and scotopic responses on electroretinogram testing. However, there was no overt evidence of contractures of the distal joints. Examination of other affected family members revealed restricted range of movement of the small joints together with ulnar deviation of the fingers, and clarified the diagnosis. Our observations suggest that DA5 may have a very mild musculoskeletal phenotype and it should be considered in the differential of congenital contracture syndromes even in the absence of obvious distal joint involvement. Our observations also suggest that fundoscopy and ocular electrophysiological studies might be helpful in the evaluation of patients with otherwise unclassified distal arthrogryposes.
Assuntos
Artrogripose/classificação , Artrogripose/genética , Pronação , Doenças Retinianas/genética , Supinação , Artrogripose/diagnóstico , Antebraço , Humanos , Masculino , Linhagem , Adulto JovemRESUMO
Darier disease (DD) is an autosomal dominant genodermatosis caused by mutations in ATP2A2 and characterized by multiple warty papules coalescing in seborrheic areas and specific histological skin changes. Rare patients are described with variable bone involvement, but this association has never been sufficiently emphasized. Aniridia is a developmental disorder of the eye due to heterozygous mutations in PAX6. DD and aniridia are Mendelian traits mapping on independent loci and have never been reported in association. Here, we describe a 14-year-old girl showing the unique combination of DD, multiple bone cysts, and bilateral aniridia. Molecular investigations demonstrated that such a complex phenotype is due to double de novo heterozygous mutations in ATP2A2 and PAX6. Review of the literature indicates that, in DD, bone cysts are true developmental abnormalities of the skeleton. This finding suggests a role for ATP2A2 in bone biology. More systematic studies are expected in order to estimate the true prevalence of bone cysts in DD and the relationship between skeletal changes and ATP2A2 perturbation.
Assuntos
Aniridia/genética , Cistos Ósseos/genética , Doença de Darier/genética , Proteínas do Olho/genética , Heterozigoto , Proteínas de Homeodomínio/genética , Mutação/genética , Fatores de Transcrição Box Pareados/genética , Proteínas Repressoras/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Adolescente , Adulto , Aniridia/complicações , Cistos Ósseos/complicações , Cistos Ósseos/diagnóstico por imagem , Criança , Doença de Darier/complicações , Feminino , Humanos , Lactente , Masculino , Fator de Transcrição PAX6 , Radiografia , Adulto JovemRESUMO
Hailey-Hailey disease (HHD) is a rare autosomal dominant disorder characterized by recurrent skin lesions predominantly involving the body folds. It is caused by heterozygous mutations in the ATP2C1 gene, encoding the human secretory pathway Ca2+/Mn2+-ATPase protein 1 (hSPCA1). In this report we describe the molecular studies performed in eight HHD cases from Italy that led us to identify six different mutations scattered through the ATP2C1 gene in seven of eight cases. Four of the detected mutations were novel. Our results confirm the high allelic heterogeneity of the ATP2C1 gene and support the notion that HHD is a genetically homogeneous disorder. Furthermore, we created a table summarizing all previously reported ATP2C1 mutations, adapting the nomenclature, if needed, according to the guidelines of the Human Genome Variation Society.