[Show abstract][Hide abstract] ABSTRACT: Parabiosis has been found to modify the expected blood pressure response of rats from two strains with opposite genetic propensities for experimental hypertension. When a member from one strain was united in parabiosis with a member from the other and both were maintained on high NaCl diet, the rat from the strain ordinarily resistant to it rapidly developed hypertension, in contrast to appropriate controls from this strain. The development of hypertension in this resistant animal preceded that in its mate from the strain highly sensitive to hypertension. In the latter, both the level of hypertension and mortality were significantly less than in its control. It seems likely that the hypertension observed is the resistant parabiont was initiated in its partner from the sensitive strain. This modification in blood pressures was not observed in the absence of a high NaCl diet. Parabiosis between animals from the same strain did not alter their response. Thus, as in earlier experiences (1–4) the interaction of a nongenetic factor (NaCl) with the appropriate genetic substrate appeared to be necessary for the development of hypertension. The findings are interpreted as evidence that a transmittable humoral influence plays an important role in the pathogenesis of rat hypertension. The presence of this agent is genetically determined but, under the conditions of these experiments, it took the added stimulus of dietary NaCl to demonstrate its existence.
Journal of Experimental Medicine 05/1962; 115(6):1173-1190. DOI:10.1084/jem.115.6.1173 · 12.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Holt-Oram syndrome (HOS) is a rare autosomal dominant heart-hand syndrome due to mutations in the TBX5 transcription factor. Affected individuals can have structural cardiac defects and/or conduction abnormalities, and exclusively upper limb defects (typically bilateral, asymmetrical radial ray defects). TBX5 mutations reported include nonsense, missense, splicing mutations and exon deletions. Most result in a null allele and haploinsufficiency, but some impair nuclear localisation of TBX5 protein or disrupt its interaction with co-factors and downstream targets. We present a five generation family of nine affected individuals with an atypical HOS phenotype, consisting of ulnar ray defects (ulnar hypoplasia, short fifth fingers with clinodactyly) and very mild radial ray defects (short thumbs, bowing of the radius and dislocation of the radial head). The cardiac defects seen are those more rarely reported in HOS (atrioventricular septal defect, hypoplastic left heart syndrome, mitral valve disease and pulmonary stenosis). Conduction abnormalities include atrial fibrillation, atrial flutter and sick sinus syndrome. TBX5 mutation screening (exons 3-10) identified no mutations. Array comparative genomic hybridisation (CGH) revealed a 48 kb duplication at 12q24.21, encompassing exons 2-9 of the TBX5 gene, with breakpoints within introns 1-2 and 9-10. The duplication segregates with the phenotype in the family, and is likely to be pathogenic. This is the first known report of an intragenic duplication of TBX5 and its clinical effects; an atypical HOS phenotype. Further functional studies are needed to establish the effects of the duplication and pathogenic mechanism. All typical/atypical HOS cases should be screened for TBX5 exon duplications.
European journal of human genetics: EJHG 02/2012; 20(8):863-9. DOI:10.1038/ejhg.2012.16 · 4.35 Impact Factor
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