RESUMO
Signaling through the store-operated Ca(2+) release-activated Ca(2+) (CRAC) channel regulates critical cellular functions, including gene expression, cell growth and differentiation, and Ca(2+) homeostasis. Loss-of-function mutations in the CRAC channel pore-forming protein ORAI1 or the Ca(2+) sensing protein stromal interaction molecule 1 (STIM1) result in severe immune dysfunction and nonprogressive myopathy. Here, we identify gain-of-function mutations in the cytoplasmic domain of STIM1 (p.R304W) associated with thrombocytopenia, bleeding diathesis, miosis, and tubular myopathy in patients with Stormorken syndrome, and in ORAI1 (p.P245L), associated with a Stormorken-like syndrome of congenital miosis and tubular aggregate myopathy but without hematological abnormalities. Heterologous expression of STIM1 p.R304W results in constitutive activation of the CRAC channel in vitro, and spontaneous bleeding accompanied by reduced numbers of thrombocytes in zebrafish embryos, recapitulating key aspects of Stormorken syndrome. p.P245L in ORAI1 does not make a constitutively active CRAC channel, but suppresses the slow Ca(2+)-dependent inactivation of the CRAC channel, thus also functioning as a gain-of-function mutation. These data expand our understanding of the phenotypic spectrum of dysregulated CRAC channel signaling, advance our knowledge of the molecular function of the CRAC channel, and suggest new therapies aiming at attenuating store-operated Ca(2+) entry in the treatment of patients with Stormorken syndrome and related pathologic conditions.
Assuntos
Transtornos Plaquetários/genética , Canais de Cálcio/genética , Sinalização do Cálcio/genética , Dislexia/genética , Ictiose/genética , Proteínas de Membrana/genética , Transtornos de Enxaqueca/genética , Miose/genética , Miopatias Congênitas Estruturais/genética , Proteínas de Neoplasias/genética , Baço/anormalidades , Animais , Sequência de Bases , Criança , Primers do DNA/genética , Eritrócitos Anormais , Feminino , Humanos , Dados de Sequência Molecular , Fadiga Muscular/genética , Mutagênese Sítio-Dirigida , Mutação/genética , Proteína ORAI1 , Técnicas de Patch-Clamp , Linhagem , Análise de Sequência de DNA , Molécula 1 de Interação Estromal , Peixe-ZebraRESUMO
Approximately 3.6% of patients with Parkinson's disease develop symptoms before age 45. Early-onset Parkinson's disease (EOPD) patients have a higher familial recurrence risk than late-onset patients, and 3 main recessive EOPD genes have been described. We aimed to establish the prevalence of mutations in these genes in a UK cohort and in previous studies. We screened 136 EOPD probands from a high-ascertainment regional and community-based prevalence study for pathogenic mutations in PARK2 (parkin), PINK1, PARK7 (DJ-1), and exon 41 of LRRK2. We also carried out a systematic review, calculating the proportion of cases with pathogenic mutations in previously reported studies. We identified 5 patients with pathogenic PARK2, 1 patient with PINK1, and 1 with LRRK2 mutations. The rate of mutations overall was 5.1%. Mutations were more common in patients with age at onset (AAO) < 40 (9.5%), an affected first-degree relative (6.9%), an affected sibling (28.6%), or parental consanguinity (50%). In our study EOPD mutation carriers were more likely to present with rigidity and dystonia, and 6 of 7 mutation carriers had lower limb symptoms at onset. Our systematic review included information from >5800 unique cases. Overall, the weighted mean proportion of cases with PARK2 (parkin), PINK1, and PARK7 (DJ-1) mutations was 8.6%, 3.7%, and 0.4%, respectively. PINK1 mutations were more common in Asian subjects. The overall frequency of mutations in known EOPD genes was lower than previously estimated. Our study shows an increased likelihood of mutations in patients with lower AAO, family history, or parental consanguinity.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação/genética , Proteínas Oncogênicas/genética , Doença de Parkinson/genética , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Ubiquitina-Proteína Ligases/genética , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Doença de Parkinson/epidemiologia , Proteína Desglicase DJ-1 , Reino Unido/epidemiologiaRESUMO
The past 10 years has seen a shift in our etiological concepts of Parkinson's disease, moving from a nearly exclusively environmentally mediated disease towards a complex disorder with important genetic contributors. The identification of responsible mutations in certain genes, particularly alpha-synuclein, Parkin, PINK1, DJ-1 and LRRK2, has increased our understanding of the clinical and pathological changes underlying Parkinson's disease, with implications for patient diagnosis, management and future research. This review will outline the specific genetic advances, discuss their implications for clinical practice and hint at future directions for research into this common and disabling disease.