RESUMEN
Grange syndrome is an autosomal recessive condition characterized by arterial occlusions and hypertension. Syndactyly, brachydactyly, bone fragility, heart defects, and learning disabilities have also been reported. Loss-of-function variants in YY1AP1 have only recently been associated with Grange syndrome. YY1AP1 encodes for the transcription coactivator yin yang 1-associated protein 1 which regulates smooth muscle cell proliferation and differentiation. We here report on three siblings with steno-occlusive arterial disorder and syndactyly in two of them. Whole exome sequencing including near-splice regions led to the identification of two intronic YY1AP1 variants which were predicted to interfere with normal splicing. Sanger sequencing demonstrated compound-heterozygosity in all affected siblings. RT-PCR analyses confirmed skipping of exon 6 on one allele and exonization of 22 bp in intron 6 on the other. This is the first report of biallelic YY1AP1 variants in noncoding regions and just the second family with multiple affected siblings. Therefore, our report further delineates the phenotypic spectrum of Grange syndrome.
Asunto(s)
Arteriopatías Oclusivas/genética , Huesos/anomalías , Braquidactilia/genética , Proteínas de Ciclo Celular/genética , Predisposición Genética a la Enfermedad , Cardiopatías Congénitas/genética , Hipertensión/genética , Sindactilia/genética , Factores de Transcripción/genética , Adolescente , Adulto , Arteriopatías Oclusivas/fisiopatología , Huesos/fisiopatología , Braquidactilia/fisiopatología , Niño , Femenino , Cardiopatías Congénitas/fisiopatología , Humanos , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Linaje , Isoformas de Proteínas/genética , Sindactilia/fisiopatología , Secuenciación del ExomaRESUMEN
We undertook genetic and biochemical assays in patients with arterial (n = 146) and venous (n = 199) thromboembolism and survivors of pulmonary embolism (n = 58) to study causation and gene-life style interactions. In the clinical material from North Western Russia, factor V Leiden was found to be a risk factor in venous thrombosis (OR = 3.6), while the methylenetetrahydrofolate reductase (MTHFR) C677T mutation was a significant variable in both venous (p = 0.03) and arterial thrombosis (p = 0.004). Homocysteine levels were determined (n = 84) and hyperhomocysteinemia correlated with the T allele of the MTHFR gene, and with smoking and coffee consumption. Vitamin supplementation reduced homocysteine levels dependent on MTHFR genotype (36% TT, 25% CT, 22% CC). In pulmonary embolism patients, frequency of the -455G/A beta-fibrinogen dimorphism was studied. Carriers of this allele were significantly underrepresented (p < 0.02) among pulmonary embolism survivors (34.5%) compared to controls (56.7%). Additionally, -455AA homozygotes were found in 11.7% controls but only 1.7% of pulmonary embolism patients (p = 0.006). In venous and arterial thrombosis cases, MTHFR and homocysteine data led to effective dietary supplementation with a reduced risk of disease progression. Results from the pulmonary embolism study may indicate that screening tests for the -455G/A beta-fibrinogen genetic variation could be of prognostic value, and may point the way for novel anticoagulation strategies.
Asunto(s)
Arteriopatías Oclusivas/genética , Factor V/genética , Variación Genética/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/genética , Protrombina/genética , Tromboembolia/genética , Trombosis de la Vena/genética , Adulto , Arteriopatías Oclusivas/enzimología , Análisis Mutacional de ADN , Cartilla de ADN/química , Femenino , Fibrinógeno/genética , Genotipo , Humanos , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2) , Persona de Mediana Edad , Mutación , Reacción en Cadena de la Polimerasa , Tromboembolia/enzimología , Trombosis de la Vena/enzimologíaRESUMEN
It has been empirically known that Ginkgo extract is useful for reducing many symptoms associated with cerebral blood flow (CBF) insufficiency, but its mechanisms have been uncertain. In the present study, therefore, we gave Ginkgo extract to rats with per os digestion, and investigated its effect on CBF and ischemic brain damage with middle cerebral artery occlusion (MCAO). The treatment with Ginkgo extract (10 mg 100 g-1 rat) increased CBF in the normal condition, but the degree of increase in CBF was lesser during and after MCAO. TTC staining showed that infarct volume was reduced with Ginkgo treatment. TUNEL and HSP72 immunostaining confirmed the protective effect of Ginkgo treatment reducing numbers of TUNEL and HSP72 positive cells. Immunohistochemical analysis showed that caspase-3 expression was less abundant in Ginkgo treated rats. The present results suggest that Ginkgo extract contains a substance which increases normal CBF and reduces ischemic brain damage.