RESUMEN
Pathological expansion of a G4C2 repeat, located in the 5' regulatory region of C9orf72, is the most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 patients have highly variable onset ages suggesting the presence of modifying factors and/or anticipation. We studied 72 Belgian index patients with FTLD, FTLD-ALS or ALS and 61 relatives with a C9orf72 repeat expansion. We assessed the effect of G4C2 expansion size on onset age, the role of anticipation and the effect of repeat size on methylation and C9orf72 promoter activity. G4C2 expansion sizes varied in blood between 45 and over 2100 repeat units with short expansions (45-78 units) present in 5.6% of 72 index patients with an expansion. Short expansions co-segregated with disease in two families. The subject with a short expansion in blood but an indication of mosaicism in brain showed the same pathology as those with a long expansion. Further, we provided evidence for an association of G4C2 expansion size with onset age (P<0.05) most likely explained by an association of methylation state of the 5' flanking CpG island and expansion size in blood (P<0.0001) and brain (P<0.05). In several informative C9orf72 parent-child transmissions, we identified earlier onset ages, increasing expansion sizes and/or increasing methylation states (P=0.0034) of the 5' CpG island, reminiscent of disease anticipation. Also, intermediate repeats (7-24 units) showed a slightly higher methylation degree (P<0.0001) and a decrease of C9orf72 promoter activity (P<0.0001) compared with normal short repeats (2-6 units). Decrease of transcriptional activity was even more prominent in the presence of small deletions flanking G4C2 (P<0.0001). Here we showed that increased methylation of CpGs in the C9orf72 promoter may explain how an increasing G4C2 size lead to loss-of-function without excluding repeat length-dependent toxic gain-of-function. These data provide insights into disease mechanisms and have important implications for diagnostic counseling and potential therapeutic approaches.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Proteínas/genética , Adulto , Edad de Inicio , Esclerosis Amiotrófica Lateral/metabolismo , Bélgica , Proteína C9orf72 , Islas de CpG/genética , Metilación de ADN/genética , Regulación hacia Abajo , Epigénesis Genética/genética , Epigenómica/métodos , Femenino , Degeneración Lobar Frontotemporal/genética , Degeneración Lobar Frontotemporal/metabolismo , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas/genética , Proteínas/metabolismoRESUMEN
In the title compound, C(14)H(14)BrNO(2)S, there are two similar non-equivalent mol-ecules in the asymmetric unit, displaying three chiral centres each. In the crystal structure, they are linked by inter-molecular N-Hâ¯O hydrogen bonds to form infinite chains, which are in turn connected by weak Brâ¯H and Sâ¯H inter-actions.
RESUMEN
In each of 2 yr, 20 Holstein steers (185+/-7 kg initial BW) were allocated to each of three treatments: pastured for 4.5 mo on grass/legume pastures and then fed 80% corn diets (DM basis) until slaughter; pastured for 4.5 mo on grass/legume pastures with ad libitum access to molasses-based protein supplements and fed 80% corn diets until slaughter; and placed in a feedlot and fed only 80% corn diets until slaughter (FEEDLOT). Half of the steers in each treatment were initially implanted with Revalor-S and not reimplanted. Supplemented steers on pasture had greater (P < 0.05) ADG than unsupplemented steers, and FEEDLOT steers gained faster and were fatter (P < 0.05) after 4.5 mo. Implanted steers had greater (P < 0.05) ADG with no significant treatment x implant status effect. Supplement intake was variable and related to ambient temperature. During the feedlot phase, steers previously on pasture had greater DMI and ADG (P < 0.05) but were not more efficient than FEEDLOT steers. Percentage of USDA Choice carcasses, fat thickness, dressing percentage, yield grade, and final weight were greater (P < 0.05) for FEEDLOT steers than for steers on other treatments. Implanting increased ADG of all steers but did not affect carcass traits, carcass composition, or feedlot performance during the finishing phase. Holstein steers consuming supplemented and unsupplemented pasture before slaughter will be leaner, have lower carcass weights, and have generally lower quality grades than those fed exclusively in a feedlot when slaughtered at similar ages.
