RESUMO
Polycystic ovary syndrome (PCOS) is a heterogeneous disorder with evidence of polygenetic components, and obesity may be a risk factor for hyperandrogenism. Previous studies have shown that LHCGR is enriched in the ovary and LHCGR deficiency causes infertility without typical PCOS phenotypes. ALMS1 is implicated in obesity and hyperandrogenism, the common phenotypes among PCOS patients. Through whole-exome sequencing of 22 PCOS families and targeted candidate gene sequencing of additional 65 sporadic PCOS patients, we identified potential causative mutations in LHCGR and ALMS1 in a sibling-pair PCOS family and three sporadic PCOS patients. The expression of LHCGRL638P in granulosa-like tumor cell line (KGN) cells promoted cyclic adenosine monophosphate production and granulosa cell proliferation, indicating that LHCGRL638P is an activating mutation. LhcgrL642P/L642P mice showed an irregular estrous cycle, reduced follicles with dynamic folliculogenesis, and increased testosterone (T), estradiol (E2), and dehydroepiandrosterone. Lhcgr+/L642PAlms1+/PB mice displayed increased T and E2 but decreased late secondary and preovulatory follicles. We showed that activating mutation of LHCGR likely plays important roles in the pathophysiology of PCOS involving abnormal reproductive physiology, whereas ALMS1 deficiency may promote anovulatory infertility via elevated androgens, suggesting that the disturbed LHCGR and ALMS1 cooperatively induce PCOS phenotypes, characterized as anovulation and hyperandrogenemia frequently observed in PCOS patients with obesity.
Assuntos
Predisposição Genética para Doença , Mutação , Síndrome do Ovário Policístico/genética , Receptores do LH/genética , Alelos , Animais , Vias Biossintéticas , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Análise Mutacional de DNA , Modelos Animais de Doenças , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Linhagem , Fenótipo , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/metabolismo , Receptores do LH/metabolismo , Esteroides/biossíntese , Sequenciamento do ExomaRESUMO
Hereditary spherocytosis (HS), the most common cause of congenital hemolytic anemia, is caused by deficiency of the erythrocyte membrane proteins. Five causative genes (ANK1, SPTB, SPTA1, SLC4A1, and EPB42) have been identified. To date, molecular genetic studies have been performed in different populations, including the American, European, Brazilian, Japanese and Korean populations, whereas only a few studies have been described in the Chinese population. Here, by reanalysis of the exome data, we revealed causative mutations and established a definitive diagnosis of HS in all 38 Chinese families. We found 34 novel mutations and four reported mutations in three known HS-causing genes-17 in ANK1, 17 in SPTB and four in SLC4A1, suggesting that ANK1 and SPTB are the major genes in Chinese patients with HS. All of the ANK1 or SPTB mutations, scattered throughout the entire genes, are non-recurrent; and most of them are null mutations, which might cause HS via a haploinsufficiency mechanism. De novo mutations in ANK1 or SPTB often occur with an unexpected high frequency (87.5% and 64.2%, respectively). Our study updates our knowledge about the genetic profile of HS in Chinese and shows that family-based, especially parent-offspring trio, sequencing analysis can help to increase the diagnostic power and improve diagnostic efficiency.
Assuntos
Sequenciamento do Exoma/métodos , Predisposição Genética para Doença/genética , Mutação , Esferocitose Hereditária/genética , Adolescente , Adulto , Proteína 1 de Troca de Ânion do Eritrócito/genética , Anquirinas/genética , Povo Asiático/genética , Criança , Pré-Escolar , China , Saúde da Família , Feminino , Predisposição Genética para Doença/etnologia , Humanos , Lactente , Masculino , Linhagem , Espectrina/genética , Esferocitose Hereditária/diagnóstico , Esferocitose Hereditária/etnologia , Adulto JovemRESUMO
This paper demonstrates a novel retro-reflective dome that enhances the directionality of a light emitting diode (LED) by recycling photons reflected by a textured LED die surface. A simulation model is developed to describe both the photon recycling process within the dome and the role of specific pyramid patterns on the top surface of the LED die. Advanced simulations showed that a perfectly polished surface with 100% reflectivity potentially enhances the directionality of the dome by 340%, 250%, and 240% using reflective domes with 10°, 20°, and 30° light cones, respectively. In the experiment, the directionality of the domes exhibiting surface imperfections is enhanced by approximately 160%, 150%, and 130% using 10°, 20°, and 30° light cones, respectively. By incorporating a textured top surface on the LED die, the proposed dome effectively increases the directionality of the LED light source.
